i

Neuroethics
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Neuroethics
Anticipating the Future
Editor
Judy Illes

Associate Editor

Sharmin Hossain

1
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 v

Foreword: Forays into neuroethics

It is early 2001, I had just been appointed as the inaugural Scientific Director of the Institute
of Neuroscience, Mental Health and Addiction (INMHA) of the Canadian Institutes of
Health Research (CIHR). The CIHR was created to usher in a new generation of thinking,
action, and innovation about basic and translational research, for junior and more senior
scientists and scholars alike.
One of the most exciting changes brought about by the creation of CIHR and its 13 insti-
tutes was the Institute Advisory Board structure and mandate enabling and encouraging
the exploration of novel research avenues and frontiers without the traditional bound-
aries. For those of us in brain research, mental health, and addiction, the work of my
inaugural Board and its vision were transformational. We nearly immediately departed
from conventional ideas about funding in neuroscience to support a New Emerging Team
(NET) program in 2002–​2003, with topics such as the impacts of early life events on the
developmental course of brain disorders, regenerative medicine, and understanding the
placebo effect. This was merely our first call. The second followed directly from my own
experiences and leadership of over 20  years in my laboratories at the Douglas Mental
Health Institute affiliated with McGill University in Montreal. I was highly aware of ethi-
cal issues and challenges to optimal care for the mentally ill, their involvement in various
types of clinical trials, and the high incidence of co-​morbidity between mental health
and addiction. Accordingly, I was keen to promote innovative research on ethical issues
related to the broad mandate of INMHA. But neuroethics?
I first heard about neuroethics in the early years of the CIHR. I asked some of my col-
leagues and few ethicists locally and internationally about it. Most basically said that “It
is a fad.” They saw no reason to create this specialty or subfield. In their minds, research
on ethics was complicated enough; neuroethics would only complicate the complicated
further. In retrospect, by most measures, they were wrong. Neuroethics may have added a
layer of complex inquiry to both neuroscience and biomedical ethics, but the sole fact that
Neuroethics: Anticipating the Future (2017) today follows Neuroethics: Defining the Issue
in Theory, Practice and Policy (2006), speaks for the need, force, and what was to come.
INMHA launched two calls to create NET teams on Neuroethics (awarded to research-
ers at Dalhousie University in Halifax, Nova Scotia) in addition to a partnered Chair in
Neuroethics to recruit an expert from outside Canada. The University of British Columbia
won the call, and book Editor Dr. Judy Illes was recruited back to Canada from the United
States as the chair holder. This was great coup for all in Canada and for the field as it would
ground neuroethics with the highest nationally named position and center yet.
Research in neuroethics by many scholars authoring chapters in this book and oth-
ers has moved the field forward significantly over the past decade on topics as varied as
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vi Foreword: Forays into neuroethics

incidental findings in brain imaging, forensic psychiatry, improved design of clinical trials
in the fields of mental illnesses, addiction and incurable neurodegenerative diseases, neu-
rotechnology, cognitive enhancements, consciousness, and brain death, to name a few.
Of course, cutting-​edge research in neuroethics is still urgently needed on these topics.
Novel areas have also emerged over the last few years to which neuroethics must lead
with evidence-​based, best-​way-​forward guidelines for experts and the civil society. Take
for example, artificial intelligence and the interface between robots and the mind: How
can the discourse of neuroethics help society to take up related challenges in a sensi-
ble, balanced manner? Where will the novel concept of a cognitive footprint take us?
Will gene editing (CRISPR-​Casp9-​type) edit out incurable brain conditions or undesir-
able behavioral traits and states—​and who will decide? How will the role and impact of
various cultures and the environment on values relevant to mental health and addiction
evolve? Will wearable technology, social media, digital e-​health, and open access to large
public and private sets of data bring solutions to global attitudes and demands of societ-
ies toward brain diseases and various forms of addiction? And, link to these consider-
ations: cybersecurity and open access to large data sets.
Neuroethics has matured. It feels unstoppable not only because of the energy brought
to it by its current and future leaders, but by the pressing issues awaiting discovery, defi-
nition, awareness, and answers. Neuroethics: Anticipating the Future is a signature of this
momentum.
Rémi Quirion
Professor of Psychiatry, McGill University
Distinguished Researcher, Douglas Mental Health Institute
Quebec Chief Scientist
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Preface

Part 1: Looking to the future
—Judy Illes and Sharmin Hossain
This publication of Neuroethics: Anticipating the Future marks both an anniversary of one
of the first edited neuroethics volumes for the field (Illes 2006), as well as of the found-
ing of the International Neuroethics Society, the major professional organization for the
field. Like the publication of the first book volume that took the groundwork laid out at
the Mapping the Field neuroethics meeting in San Francisco, California—​now 15 years
ago, and another anniversary—​and gave it content anchor points in theory, practice, and
policy, this one also signals milestones. The authors contributing to the original volume
wrote to answer the question: Where should the field go? In this new volume, contributing
authors answer the question: Where must the field go next? With significant progress over
more than a decade, this is a critical undertaking with both legitimacy and gravitas.
In preparing this volume, the three sections on neurotechnology, healthcare, and policy
emerged naturally from the contributions we received. The prescient Joseph J. Fins pre-
dicted the neurotechnology focus in his epilogue to the Oxford Handbook of Neuroethics
(Illes & Sahakian 2011). Healthcare and public good are unwavering themes for the field,
involving ethical challenges around brain future of youth, aging and dementia, brain
injury and consciousness, stem cells and neurologic conditions, and global health and
cross-​cultural justice, among others. With one foot within and one foot outside the walls
of the hospital and academy, neuroethics in the wild brings considerations of social and
regulatory challenges to a leading role in new discourse about the environment, brain,
and mental health, in part in a global rapprochement between neurology and psychiatry,
internationalization and intersections of brain and security, and criminal justice.
Among the mix of authors are neuroethicists in the pipeline for leadership who are
playing a pivotal role in charting the course of the field for decades to come. Like those
who are more senior, they hail from diverse disciplines, spanning the humanities, public
health and public policy, and science and medicine. Their diversity is reflected not only in
their disciplines, but also in their cultural backgrounds—​different lenses that bring focus
and richness to any area of ethical inquiry.
Ten years ago, the International Neuroethics Society provided a platform for a small
neuroethics community to engage; today it offers hundreds of faculty, trainees, and col-
laborators from around the globe expanded opportunities for networking, showcasing
research, and career development, as well as a place to call a professional home. Over the
past year, Sharmin Hossain also participated in a further initiative focused on the next gen-
eration of ethics and policy leaders: the Trainee Policy and Advocacy Committee (T-​PAC)
formed under the wing of Kids Brain Health Network (formerly NeuroDevNet, Inc.),
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viii Preface

a trans-​Canada Network of Centres of Excellence. T-​PAC aims to engage research trainees

to advocate for evidence-informed policy making to benefit children living with neuro-
developmental disorders, and serves as a practical example of initiatives that neuroethics
scholars in training can and, we would argue, should undertake to collaborate toward a
unified mission to bring about positive changes to people and society.
Throughout the volume, contributing authors bring both deep experience and fresh
insights to critical issues in neuroethics, and they bring advanced scholarship, accounta-
bility, and transparency to the profoundly interlocking themes of human rights and pro-
tections, freedoms, and autonomy. Echoing Hillary Clinton’s nod to the African proverb
“It takes a village to raise a child” (Clinton 2006), we say that it takes a community to
make a field. Much good work has been done in the 10 years past; and, as the chapters in
this volume describe, there is much to do in those to come.
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Preface

Part 2: A brief look back
—Judy Illes
Learning from lessons of the past
In the firm belief that to move forward it is essential to learn lessons from the past, the
second part of this Preface is a brief look at the history of modern neuroethics. As I reflect
on this task, one of the most frequently asked questions comes to mind: Why do we,
citizens and beneficiaries of advances in the neuroscience, need neuroethics? And, formu-
lated slightly differently: How is neuroethics different than bioethics? My regular answer is:
neuroexceptionalism. Unlike the knee or the elbow, the liver or pancreas (but, with new
knowledge about the microbiome, perhaps like the gut (Mayer et al. 2014)), the brain
connects each of us to who we are. In health and in disease, it links us to our identity,
relations, autonomy, personality, capacity to make decisions, and much more. Each is
intricately intertwined with the other like the threads of a rope embedded in the context
in which we thrive, derive, and survive. It has allowed scholars in the field to frame and
reframe ethical concerns explicitly associated with the brain sciences, and to similarly
consider governance and advisory frameworks carefully attuned to relevant issues, help-
ing to define both good and ethically defensible neuroscience.

Reflections
I reflect on probably the most quoted phrase for the field, and I give it another nod here:
Adina Roskies’ “Ethics of neuroscience; neuroscience of ethics” (Roskies 2002). I have
never quite agreed with this dichotomy as the latter cannot exist except within the context
of the former, but no matter: even if the phrase is not perfectly dichotomous, its simplicity
gave us a welcome and forceful catch phrase to propel neuroethics forward.
I continue with other reflections. The topic that never dies: enhancement, whether for
the competitive boost or improved mental health (Illes 2016), and more recently for moral
fortitude (Persson & Savulescu 2008). If the use of drugs for the moral application could
give even a modicum of relief from its terror-​riddled world, I would be all for it. Topics
that should never die: addiction and mental health, aging and dementia, consciousness,
justice and human rights, consent, dignity, pain, regenerative medicine, agency.
A topic that took on a life of its own: the management of unexpected (incidental, study
off-​target) findings in brain imaging research. As much as the question about how to
handle incidental findings of possible health significance was not new to genetics, and
was introduced originally by the US National Bioethics Commission in 1999 (National
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Bioethics Advisory Commission 1999), the potency of the question took the neuroimag-
ing community by surprise. Lively debates since 2005 and ongoing today (Illes et al. 2006,
2008; Wolf et al. 2008) have yielded well-​balanced policies and guidance for brain anato-
mies. And, while ample questions still remain (Gibson et al. Chapter 3, this volume), new
ones about the interpretation of the functional data in the context of functional outliers
that may be medically or societally significant (Scott et al. 2012) are arising. They require
urgent attention before solutions to inevitable challenges have to become reactive rather
than anticipatory and thoughtfully proactive (Foster et al. 2003).
Allow me to move to other enduring imperatives: I would place education and mentor-
ship of interested researchers and clinicians of all ranks and disciplines, and engagement
of the community outside the Academy at the top of the list of priorities. Neuroethics
teachers and mentors must support the move from didactic, unidirectional schooling
of foundational theories and axioms to modern case-​and problem-​based teaching. The
Internet has fueled a craving for autonomy in learning; classroom teaching should now
elevate do-​it-​yourself learning in this digital age, rather than the historical reverse where
book learning elevated lessons imparted from the more learned.
Similarly, there has not been a time in the history of biomedicine when the importance
of including the voice of research participants and patients in the design, execution, and
dissemination of research through methods such as participatory action and collaborative
research (Stevenson et al. 2016) has been as recognized if not mandated. These interactions
have brought a new level of meaningfulness to the specific translational goals of the biosci-
ences (Illes et al. 2011), human subjects protection (Eijkholt et al. 2012), rights (Human
Rights for Neuroethics:  Reflection or Refraction, International Neuroethics Society
Meeting, Washington, DC, November 2014), and public engagement (Robillard et al. 2015).
This discussion brings me now to one of the most cited text in neuroethics, Mapping
the Field (Marcus 2002), the edited volume created from the transcripts of the landmark
neuroethics meeting in San Francisco in that same year. The field has many thanks to offer
to the Dana Foundation whose support is unfailing even 15 years later, and the vision for
neuroethics of the late William Safire (said to have been first articulated in a conversation
with Zack Hall in a taxi in New York City). Deep gratitude is also due to investment of
the late William Stubing of the Greenwall Foundation whose support was foundational
(e.g., Illes & Raffin 2002; Farah & Wolpe 2004), and also continues to date. Beyond these
neuroethics funding visionaries, I count more than two dozen other private and govern-
ment sponsors of research to whom the field owes thanks. Their financial contributions
to the advancement of critical thinking about ethics, society, policy, and law alongside
advances in the neurosciences, have enabled the field to gain traction, credibility, and
sustainability. As Professor of Medicine and Director of the Usher Institute of Population
Health Sciences and Informatics, Dr. Andrew Morris said at the International Association
of Bioethics meeting in Edinburgh, Scotland in June 2016 (a meeting at which neuroeth-
ics was only minimally represented), ethics must be (and I paraphrase) “a first thought;
not an after thought … in confluence to improve human and public health.”
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Preface xi

Perhaps it is both the alignment of neuroethics with neuro, and its practical pro-​
positioning in science that best define the field as it is today more than any particular the-
oretical construct. Indeed, neuroethics seems well defined by what we, as scholars in the
field do with it and the interdisciplinary, often pragmatic approach we take (Racine 2010).
That is not to say that the theoreticians among us have not played a key role in integrat-
ing philosophy fundamentally into the field, but still, as University of British Columbia
Sociologist Professor D. Ralph Matthews and I concur about neuroethics at present: “We
are what we study” (loosely translated from “You are what you eat”). To this end, per-
haps we are raising more questions than answers, but that is not a failure, just a signal of
dimensionality.

Measurables
There is little doubt that this is the century of the brain. As University of Chicago bio-
ethicist Mark Siegler and I have discussed, technical advances in the last 75 years exceed
those of 2000–​3000 years that precede it. With each advance in the brain sciences, ques-
tions about ethics arise. Think about end-​of-​life decision-​making and today’s new laws;
predicting Alzheimer’s disease in the absence of cure, or predicting adult-​onset diseases
in newborns and children; stem cells for autism or cerebral palsy; gene therapy; psychi-
atric neurosurgery for mental health disorders; technologically assisted communication
for the minimally conscious and other diagnostic and therapeutic advances for the spec-
trum of mild to severe central nervous system injuries; magnetic resonance imaging in
the courtroom; commercialization of health technology (some that preys on the most
vulnerable in our society); big data; environment and culture; and manipulating genes
to edit out disease and edit in desirable behavioral traits. The hype is phenomenal; pub-
lic interest growing and unprecedented (Beaulieu 2000; Whiteley 2012). Are we doing
enough? Are we progressing fast enough, meaningfully, transparently, interactively, and
effectively enough?
The answer is, on the most part, yes, judging from the numbers of books and edited vol-
umes, and international efforts in public engagement (Illes et al. 2005) ever since the early
days of neuroethics. For example, shortly after the 2002 meeting, the Dana Foundation’s
journal Cerebrum published a special issue on neuroethics in Fall 2004. A special issue
of the journal Brain and Cognition was published in 2005 devoted to ethical issues in
advanced neuroimaging. The American Journal of Bioethics published its own special
issue on neuroethics in 2005 and today, with a booming impact factor of more than 6, is
accepting target articles in the area. I created the AJoB–​Neuroscience series and served as
its inaugural editor. It is now in Paul Wolpe’s capable hands as the official journal of the
International Neuroethics Society (INS). There are numerous relevant publications by the
US Presidential Commission on the Study of Bioethical Issues (PCSBI; from 2008 to 2016,
more than 50 neuroscientists and neuroethics scholars testified to the Commission).
Journal papers, trainees in a diverse range of disciplines and presenters at the annual
meeting of the INS and elsewhere, faculty in tenured, tenure-​line, research stream, and
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xii Preface

private and government sector positions, programs of one type or another (41 worldwide
at last count), media coverage abound.
The first-​ever formal strategic plan of the INS, the major professional society for neu-
roethics, speaks clearly to accomplishments of the past and aspirations for the future with
four priorities. With some editorial paraphrasing, the priorities are to:
1. position the INS, with its multidisciplinary membership and leadership, as an author-
itative body on matters pertaining to neuroethics
2. promote and support research, scholarship, and education in all aspects of
neuroethics
3. develop sustainable funding for the profession
4. grow in number and size.
The strategic achievement of the goals assigned to each of these priorities (http://​www.
neuroethicssociety.org/​strategic) will bring the membership closer to citable policy or
legal changes where it has yet to show its colors and truly define a legacy. The Neuroethics
Response Task Force (now Emerging Issues Task Force) of the INS that I struck in 2016,
initially chaired by Board of Directors member Mark Frankel, and engagement of the
broadest range of the profession’s diverse membership in rank, discipline, gender, and
geographic background, will further enable this goal and the positioning of the INS as the
authoritative go-​to body in neuroethics.

Anniversaries
With this historical perspective, I also celebrate one of the concurrent past anniversaries
of neuroethics—​the 10th—​the meeting of a small group neuroscientists and bioethicists
in Asilomar, California in Spring 2006, to discuss a plan for the now established profes-
sional society. Early names were Neuroethics Interdisciplinary Association, competing
with Society for Interdisciplinary Neuroethics. It would draw upon knowledge gained in
prior meetings: besides the 2002 meeting (the 15th anniversary), in September 2003, the
American Association for the Advancement of Science (AAAS) sponsored a meeting on
neuroscience and law and, in 2005, another on neuroethics and religion. In May 2005, the
Library of Congress sponsored a neuroethics meeting called Hard Science—​Hard Choices.
These are just to name a few.
We were a small group (Figure 0.1) in a small conference room—​the rest of the rustic
retreat center on the magnificent Pacific Ocean was occupied by a gathering of nearly
1000 church members seeking answers to questions of their own. In many ways, both
the content and interpersonal dynamics of that 2-​day meeting foreshadowed the many
faces of neuroethics today: collaborations and entanglements; warmth and tensions;
rigor and fluidity; curiosity and resistance; friends, no fig leafs. In that setting, we cre-
ated a space for the liberal multiculturalism for the neuroethics that we live today.
Culture is a hybrid of internal and external principles. Principles, like ideas, travel.
I believe that we got it right then and that we continue to evolve productively. One
aspect of the evolution, in fact, was a name-​change from the originally settled-​upon
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Preface xiii

Figure 0.1  Participants at the Asilomar Neuroethics Society planning meeting 2006. Kneeling
from left to right: Martha Farah, Patricia Churchland. Standing from left to right: Anjan
Chaterjee, Turhan Canli, Allison Mackey, Elizabeth Phelps, Hank Greely, Judy Illes, Laurie Zoloth,
Mike Gazzaniga, Barbara Sahakian, Paul Wolpe. Not shown: Steve Hyman and Stephen Morse.
Reproduced courtesy of Judy Illes

Neuroethics Society to the International Neuroethics Society signaling a genuine com-

mitment to a global involvement for the field.
With what historical events do we share 10th and 15th anniversaries? Here are a few
examples for 2002 and 2006 that coincide with our own:
2002:
◆ George W. Bush signs into law the No Child Left Behind Act.
◆ The Netherlands legalizes euthanasia, becoming the first nation in the world to do so.
◆ The United States is re-​elected to the United Nations Commission on Human Rights,
1 year after losing the seat it had held for 50 years.
◆ Michael Jackson dangles son Prince Michael II off a balcony from a Berlin hotel room
(a zany and tragic example of a mental health challenge).
2006:
◆ The United Nations General Assembly votes to establish the UN Human Rights
Council.
◆ Element 111, roentgenium (Rg) is officially named.
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xiv Preface

◆ Canadian researchers make two biomedical breakthroughs by stopping the build-​up

of toxic plaque in mice with Alzheimer’s disease using a sugar-​like substance known
as scyllo-​cyclohexanehexol; and, stopping a mutant gene from being split apart
effectively preventing the onset of degenerative symptoms associated Huntington’s
disease.

Values and understanding

What constitutes knowledge, values, and understanding in neuroethics? I would argue it is
both ways of knowing and ways of doing. Both contribute to good judgment, as do oper-
ational tools such as decision trees, logic models, checklists, and case studies. Questions
are hard when values differ, and understandings perhaps even harder as they are further
shaped by situational context. Neuroethics must continue to contribute to the marketplace
of ideas or our work will become nothing more than a collection of rhetorical exercises.
Similarly, time will tell whether investments in ethics and big neuroscience will inspire
wave changes or only ripples of incremental impact in a sea of activity.
To conclude, I return to the first question I raised in its most simplistic form: Why
neuroethics? Many scholars have spent time over the years in verbal and written dis-
course upholding this challenge (de Vries 2005, 2006; Wilfond & Ravitsky 2005; Parens &
Johnston 2007). Much like competition in business, the existential question yields benefit
by powering a critical reflexivity needed for the undeterred to stay sharp. We can be grati-
fied that this healthy debate across our areas of specialty did not lead to a modern day Tale
of Two Cities (Dickens 2012), with an irreparable collision of neuroethics revolutionaries
toward older discipline aristocracy. Indeed, we are a collectively kind community focused
on human health and well-​being.
To conclude, as Chief of the Neuroethics Studies Program at Georgetown University,
James Giordano has said, “No new neuroscience without neuroethics.” And, as I said to
the esteemed French neuroscientist Jean Pierre Changeux from the Collège de France,
Institut Pasteur in a heated neuroethics meeting in Heidelburg, Germany in 2006, “It
doesn’t matter what we call it, it only matters that we do it” (Illes 2006).

References
Beaulieu, A.E. (2000). The brain at the end of the rainbow: the promises of brain scans in the research
field and in the media. In: Marchessault, J. and Sawchuk K. (Eds.) Wild Science: Reading Feminism,
Medicine and the Media, pp.39–​54. London: Routledge.
Clinton, H.R. (2006). It Takes a Village. New York: Simon and Schuster.
De Vries, R.D. (2005). Framing neuroethics: a sociological assessment of the neuroethical imagination.
American Journal of Bioethics, 5, 25–​27.
De Vries, R.D. (2006, November). Firing the neuroethical imagination. In: 7th EMBL/​EMBO Joint
Conference Programme, Genes/​Brain, Mind and Behavior, Heidelberg, Germany.
Dickens, C. (2012). A Tale of Two Cities. New York: Vintage.
 xv

Preface xv

Eijkholt, M., Anderson, J.A., and Illes, J. (2012). Picturing neuroscience research through a human
rights lens: imaging first-​episode schizophrenic treatment-​naïve individuals. International Journal of
Law and Psychiatry, 35, 146–​152.
Farah, M.J. and Wolpe, P.R. (2004). Monitoring and manipulating the human brain: new neuroscience
technologies and their ethical implications. Hastings Center Report, 34, 35–​45.
Fins, J.J. (2011). Epilogue. In: Illes, J. and Sahakian, B. (Eds.). The Oxford Handbook of Neuroethics,
pp.895–​907. Oxford: Oxford University Press.
Foster, K.R., Wolpe, P.R., and Caplan, A.L. (2003). Bioethics and the brain. IEEE Spectrum,
40, 34–​39.
Illes, J. (Ed.) (2006). Neuroethics: Defining the Issues in Theory, Practice, and Policy. Oxford: Oxford
University Press.
Illes, J. (2006, November). From genetics to neuroethics: is imaging “visualizing” human thought?
In: 7th EMBL/​EMBO Joint Conference Programme, Genes/​Brain, Mind and Behavior, Heidelberg,
Germany.
Illes, J. (2016). A feast of thinking on the naturalization of enhancement neurotechnology. In: Jotterand,
F. and Dubljević, V. (Eds.) Cognitive Enhancement: Ethical and Policy Implications in International
Perspectives, pp.346–​350. Oxford: Oxford University Press.
Illes, J. and Raffin, T.A. (2002). Neuroethics: a new discipline is emerging in the study of brain and
cognition. Brain and Cognition, 50, 341–​344.
Illes, J., Blakemore, C., Hansson, M.G., et al. (2005). International perspectives on engaging the public
in neuroethics. Nature Reviews Neuroscience, 6, 977–​982.
Illes, J., Kirschen, M.P., Edwards, E., et al. (2006). Ethics: incidental findings in brain imaging research.
Science, 311, 783–​784.
Illes, J., Kirschen, M.P., Edwards, E., et al. (2008). Practical approaches to incidental findings in brain
imaging research. Neurology, 70, 384–​390.
Illes, J., Reimer, J.C., and Kwon, B.K. (2011). Stem cell clinical trials for spinal cord injury: readiness,
reluctance, redefinition. Stem Cell Reviews and Reports, 7, 997–​1005.
Mayer, E.A., Knight, R., Mazmanian, S.K., Cryan, J.F., and Tillisch, K. (2014). Gut microbes and the
brain: paradigm shift in neuroscience. Journal of Neuroscience, 34, 15490–​15496.
Marcus, S.J. (2002). Neuroethics: Mapping the Field, Conference Proceedings. New York: Dana Press.
National Bioethics Advisory Commission (1999). Research Involving Human Biological
Materials: Ethical Issues and Policy Guidance. Available from: https://​bioethicsarchive.georgetown.
edu/​nbac/​hbm.pdf [accessed August 4, 2016.
Parens, E. and Johnston, J. (2007). Does it make sense to speak of neuroethics? EMBO Reports, 8,
S61–​64.
Persson, I. and Savulescu, J. (2008). The perils of cognitive enhancement and the urgent imperative to
enhance the moral character of humanity. Journal of Applied Philosophy, 25, 162–​177.
Racine, E. (2010). Pragmatic Neuroethics: Improving Treatment and Understanding of the Mind-​Brain.
Cambridge, MA: MIT Press.
Robillard, J.M., Cabral, E., Hennessey, C., Kwon, B.K., and Illes, J. (2015). Fueling hope: stem cells in
social media. Stem Cell Reviews and Reports, 11, 540–​546.
Roskies, A. (2002). Neuroethics for the new millennium. Neuron, 35, 21–​23.
Scott, N.A., Murphy, T.H., and Illes, J. (2012). Incidental findings in neuroimaging research: a
framework for anticipating the next frontier. Journal of Empirical Research on Human Research
Ethics, 7, 53–​57.
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Stevenson, S., Beattie, B.L., Bruce, L., and Illes, J. (2016). When culture informs neuroscience:
considerations for community-​based neurogenetics research and clinical care in a First Nation
Community with early onset familial Alzheimer disease. In: Chiao, J.Y. (Ed.) Cultural Neuroscience,
pp.171–​181. Oxford: Oxford University Press.
Whiteley, L. (2012). Resisting the revelatory scanner? Critical engagements with fMRI in popular
media. BioSocieties, 7, 245–​272.
Wilfond, B.S. and Ravitsky, V. (2005). On the proliferation of bioethics sub-​disciplines: do we really
need “genethics” and “neuroethics”? American Journal of Bioethics, 5, 20–​21.
Wolf, S.M., Lawrenz, F.P., Nelson, C.A., et al. (2008). Managing incidental findings in human subjects
research: analysis and recommendations. Journal of Law, Medicine & Ethics, 36, 219–​48.
 xvi

Acknowledgments

We are deeply grateful for research funding and support over the past 15  years from
numerous organizations: the Canadian Institutes of Health Research, US National
Institutes of Health, Canada Research Chairs Program, Canada Foundation for
Innovation, British Columbia Knowledge Development Fund, Vancouver Coastal
Health Research Institute, Genome BC, Genome Canada, Stem Cell Network, Kids
Brain Health Network (formerly NeuroDevNet, Inc.), Canadian Dementia Knowledge
Translation Network, Vancouver Foundation, Djavad Mowafaghian Centre for Brain
Health at the University of British Columbia (UBC), W.  Maurice Young Centre for
Applied Ethics at UBC, Peter Wall Institute of Advanced Studies, the Foundation for
Ethics and Technology, Institute of Mental Health, American Academy of Neurology,
Dana Foundation, Greenwall Foundation, North Growth Foundation, the Office for
Science and Technology of the Embassy of France to Canada, and the British Consulate
based in Vancouver, BC, and others. We extend our many thanks also to the team at the
National Core for Neuroethics at UBC, colleagues, collaborators, trainees within and
outside our university, province, and country, and family and friends who share and live
the vision for neuroethics with us.

The opinions expressed in the chapters are solely those of the contributing authors, and do
not necessarily reflect the views of the editors or research sponsors.
xvi
 xi

Contents

List of contributors  xxiii

Part I  Neurotechnology: Today and tomorrow

1 When emerging biomedical technologies converge or collide  3
Debra J.H. Mathews
2 Emerging neuroimaging technologies: Toward future personalized
diagnostics, prognosis, targeted intervention, and ethical challenges  15
Urs Ribary, Alex L. MacKay, Alexander Rauscher, Christine M. Tipper,
Deborah E. Giaschi, Todd S. Woodward, Vesna Sossi, Sam M. Doesburg,
Lawrence M. Ward, Anthony Herdman, Ghassan Hamarneh, Brian G. Booth,
and Alexander Moiseev
3 Incidental findings: Current ethical debates and future challenges in
advanced neuroimaging  54
Lorna M. Gibson, Cathie L.M. Sudlow, and Joanna M. Wardlaw
4 Vulnerability, youth, and homelessness: Ethical considerations on the
roles of technology in the lives of adolescents and young adults  70
Niranjan S. Karnik
5 The neuroethical future of wearable and mobile health technology  80
Karola V. Kreitmair and Mildred K. Cho
6 Technologies of the extended mind: Defining the issues  108
Peter B. Reiner and Saskia K. Nagel
7 Neuromodulation ethics: Preparing for brain–​computer interface
medicine  123
Eran Klein
8 Integrating ethics into neurotechnology research and development: The
US National Institutes of Health BRAIN Initiative®  144
Khara M. Ramos and Walter J. Koroshetz

Part II  Neuroethics at the frontline of healthcare

9 What do new neuroscience discoveries in children mean for their open
future?  159
Cheryl D. Lew
10 Neuroprognostication after severe brain injury in children: Science
fiction or plausible reality?  180
Sarah S. Welsh, Geneviève Du Pont-​Thibodeau, and Matthew P. Kirschen
x

xx Contents

11 No pain no gain: A neuroethical place for hypnosis in invasive

intervention  197
Elvira V. Lang
12 Placebo beyond controls: The neuroscience and ethics of navigating a
new understanding of placebo therapy  214
Karen S. Rommelfanger
13 Ethical challenges of modern psychiatric neurosurgery  235
Sabine Müller
14 At the crossroads of civic engagement and evidence-​based
medicine: Lessons learned from the chronic cerebrospinal venous
insufficiency experience  264
Shelly Benjaminy and Anthony Traboulsee
15 Ethical dilemmas in neurodegenerative disease: Respecting patients at
the twilight of agency  274
Agnieszka Jaworska
16 Anticipating a therapeutically elusive neurodegenerative
condition: Ethical considerations for the preclinical detection of
Alzheimer’s disease  294
Hervé Chneiweiss
17 When bright lines blur: Deconstructing distinctions between disorders of
consciousness  305
David B. Fischer and Robert D. Truog
18 Brain death and the definition of death  336
James L. Bernat

Part III  Social, legal, and regulatory frameworks: Lessons

of the past guide policy for the future
19 Minors and incompetent adults: A tale of two populations  369
Vasiliki Rahimzadeh, Karine Sénécal, Erika Kleiderman, and Bartha M. Knoppers
20 Behavioral and brain-​based research on free moral agency: Threatening
or empowering?  388
Eric Racine and Veljko Dubljević
21 Cognitive enhancement of today may be the normal of tomorrow  411
Fabrice Jotterand
22 Environmental neuroethics: Setting the foundations  426
Laura Y. Cabrera
23 First Nations and environmental neuroethics: Perspectives on brain
health from a world of change  455
Jordan Tesluk, Judy Illes, and Ralph Matthews
 xxi

Contents xxi

24 The neurobiology of addiction as a window on voluntary control of

behavior and moral responsibility  477
Steven E. Hyman
25 Looking to the future: Clinical and policy implications of the brain
disease model of addiction  497
Adrian Carter and Wayne Hall
26 Concussion, neuroethics, and sport: Policies of the past do not suffice for
the future  515
Brad Partridge and Wayne Hall
27 Security threat versus aggregated truths: Ethical issues in the use of
neuroscience and neurotechnology for national security  531
Michal N. Tennison, James Giordano, and Jonathan D. Moreno
28 Communicating about the brain in the digital era  554
Julie M. Robillard and Emily Wight
29 The impact of neuroscience in the law: How perceptions of control and
responsibility affect the definition of disability  570
Jennifer A. Chandler
30 Neuroethics and global mental health: Establishing a dialogue  591
Dan J. Stein and James Giordano

Part IV Epilogue
31. Neuroethics and neurotechnology: Instrumentality
and human rights  603
Joseph J. Fins

Author Index  615

Subject Index  633
xxi
 xxi

List of contributors

Shelly Benjaminy is a doctoral candidate at the National Core for Neuroethics, University
of British Columbia, and a Clinical Ethics Fellow at Providence Health Care in Vancouver,
BC. Her research interests lie at the intersection of ethics and novel biotechnologies that
present the potential for new knowledge, therapeutics, and improved clinical care.
James L. Bernat is the Louis and Ruth Frank Professor of Neuroscience and Professor
of Neurology and Medicine at the Geisel School of Medicine at Dartmouth. His research
interests are in brain death, the definition and criterion of death, and chronic disorders
of consciousness. He is the author of Ethical Issues in Neurology, 3rd edition (Lippincott
Williams & Wilkins, 2008).
Brian G. Booth is a postdoctoral researcher at the University of Antwerp. His research
interests are in medical image analysis with a focus on using machine learning techniques
to identify patterns of abnormality in medical images. He received his PhD in computing
science from Simon Fraser University where his thesis focused on diffusion magnetic
resonance imaging analysis techniques specialized for the preterm infant brain.
Laura Y. Cabrera is Associate Professor of Neuroethics at Michigan State University. Her
research focuses on the exploration of attitudes, perceptions, and values of the general
public toward neurotechnologies, the normative implications of using neurotechnologies
for medical and nonmedical purposes, and on the ethical and social implications of
environmental changes for brain and mental health. She received a BSc in Electrical and
Communication Engineering from the Instituto Tecnológico de Estudios Superiores de
Monterrey (ITESM) in Mexico City, a MA in Applied Ethics from Linköping University
in Sweden, and a PhD in Applied Ethics from Charles Sturt University in Australia.
Adrian Carter is Senior Research Fellow and Head of the Neuroethics and Policy Group,
Monash Institute of Cognitive and Clinical Neurosciences, Monash University. His
research interests are the impact of neuroscience on our understanding and treatment of
addictive behaviors, including agency, identity, and moral responsibility; coercion; and
the use of emerging technologies, such as deep brain stimulation and brain imaging, to
treat addiction. Dr.  Carter has been an advisor to the World Health Organization, the
European Monitoring Centre for Drugs and Drug Addiction, the Australian Ministerial
Council on Drugs Strategy, and United Nations Office on Drugs and Crime.
Jennifer A. Chandler is a Professor of Law and holds the Bertram Loeb Research Chair
at the University of Ottawa. She researches and writes about the legal and ethical aspects
of advances in biomedical science and technology, with particular interest in neuroethics,
organ donation, and regenerative medicine. Recently she has written on the legal
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xxiv List of Contributors

implications of advances in neurological therapies and neuroimaging technologies, the use

of neuroscientific evidence in criminal law, regulatory policy related to medical practices
such as organ donation and transplantation, and the ethics and law of scientific inquiry.
Hervé Chneiweiss is a Research Director at CNRS, neuroscientist, and neurologist.
His research interests are the mechanisms linking the plasticity of the phenotype of the
main population of cells of the nervous system, glial cells, and the development of brain
tumors. He is Director of the research center Neuroscience Paris Seine-​IBPS at Pierre and
Marie Curie University in Paris, France, Chairman of the Ethics Committee of INSERM,
and a member of the National Consultative Ethics Committee and of the International
Bioethics Committee of UNESCO.
Mildred K. Cho is a Professor in the Departments of Medicine and Pediatrics at the
Stanford University School of Medicine and Associate Director of the Stanford Center for
Biomedical Ethics. Her research interests are in the ethics of research and translation of
emerging biotechnologies.
Sam M. Doesburg is the Callum Frost Professor of Autism and Associate Professor
of Biomedical Physiology and Kinesiology at Simon Fraser University. He completed
his PhD in Neuroscience at the University of British Columbia (UBC) in 2008, and a
postdoctoral fellowship at the UBC Department of Pediatrics. His research focuses on
how brain network communication develops throughout childhood and adolescence and
contributes to cognitive development and difficulties in clinical child populations.
Geneviève Du Pont-​Thibodeau is an Assistant Professor of Pediatric Critical Care
Medicine at Sainte-​Justine University Hospital, University of Montreal. Her research
interests include transfusion medicine as well as the neuromonitoring, neuroprotection
and neuroprognostication of critically ill children with acute brain injury.
Veljko Dubljević is an Assistant Professor of Philosophy and affiliate of the Science,
Technology and Society program at North Carolina State University. Before arriving at
NC State, he spent 3  years as a Postdoctoral Fellow at the Neuroethics Research Unit
at IRCM and McGill University in Montreal, Canada. His research focuses on ethics of
neuroscience and technology, and the cognitive neuroscience of ethics. He coedited the
volume Cognitive Enhancement (Oxford University Press, 2016) with Fabrice Jotterand,
and is the inaugural managing editor and coeditor for the book series Advances in
Neuroethics (Springer)
Joseph J. Fins is the E. William Davis, Jr. MD Professor of Medical Ethics, Professor of
Medicine, Professor of Medical Ethics in Neurology, Professor of Medicine in Psychiatry
and Chief of the Division of Medical Ethics at Weill Cornell Medical College, Co-​
Director of the Consortium for the Advanced Study of Brain Injury (CASBI) at Weill
Cornell and Rockefeller University, and the Solomon Center Distinguished Scholar in
Medicine, Bioethics and the Law at Yale Law School. His most recent book is Rights Come
to Mind: Brain Injury, Ethics, and The Struggle for Consciousness published by Cambridge
University Press.
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List of Contributors xxv

David B. Fischer is a Resident Physician at the Harvard Neurology Residency Program

at Brigham and Women’s Hospital and Massachusetts General Hospital. His research
interests are the neurobiology of consciousness, disorders of consciousness, and brain
stimulation.

Deborah E. Giaschi is a Professor of Ophthalmology and Visual Sciences at the University

of British Columbia. Her research interests are the typical and atypical development of
visual perception and reading ability. She uses behavioral and MRI techniques to assess
children with amblyopia or dyslexia.
Lorna M. Gibson is a Wellcome Trust Clinical Research Training Fellow at the University
of Edinburgh and Honorary Specialty Trainee in Clinical Radiology in the National
Health Service. Her research interests are in brain imaging, epidemiology, and research
ethics. Her fellowship is focused on the epidemiology and impact on participants and
health services of potentially serious incidental findings on brain and body magnetic
resonance imaging in the UK Biobank cohort study.

James Giordano is a Professor in the Departments of Neurology and Biochemistry, and

Chief of the Neuroethics Studies Program of the Pellegrino Center for Clinical Bioethics
at Georgetown University Medical Center, Washington DC, USA. He serves as Senior
Science Advisory Fellow of the Strategic Multilevel Assessment Group of the Joint Staff
at The Pentagon, and is an appointed member of the Neuroethics, Legal and Social Issues
Advisory Panel of the Defense Advanced Research Projects Agency (DARPA).

Wayne Hall is Professor and Director of the Centre for Youth Substance Abuse Research,
University of Queensland, and Professor of the National Addiction Centre, Kings College
London. His research interests are in drug use and addiction, epidemiology, mental health,
ethics, and public health policy. He was formerly an NHMRC Australia Fellow at the
University of Queensland Centre for Clinical Research and the University of Queensland
Brain Institute (2009–​2014), Professor of Public Health Policy, School of Population Health,
University of Queensland (2005–​2009), and Director of the Office of Public Policy and
Ethics at the Institute for Molecular Bioscience (2001–​2005), University of Queensland.

Ghassan Hamarneh is a Professor of Computing Science at Simon Fraser University

(SFU). His research interests are in medical image analysis, and computer vision,
optimization, and machine learning for biomedical imaging applications. Dr. Hamarneh
is a Senior Member of the Institute of Electrical and Electronics Engineers (IEEE) and a
Senior Member of the Association for Computing Machinery. He is the co-​founder and
director of the Medical Image Analysis Lab at SFU and a founding member of the IEEE
Engineering in Medicine and Biology Chapter—​Vancouver Section.
Anthony Herdman is an Associate Professor of Audiology at the University of British
Columbia. His research interests are in the understanding of the brain dynamics
involved in auditory and visual perceptions, attention, and language, and in advancing
neuroimaging methodology to measure brain dynamics.
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xxvi List of Contributors

Sharmin Hossain is a Postdoctoral Research Fellow at the National Core for Neuroethics
at the University of British Columbia (UBC) and at Kids Brain Health Network (formerly
NeuroDevNet, Inc.), a Canadian Network of Centres of Excellence. She received a PhD in
Neuroscience from UBC with a thesis focused on revealing the dynamic growth patterns
of immature neurons in the brain. Her current research focuses on neurodevelopmental
disorders, ethics, and policy.
Steven E. Hyman is Harvard University Distinguished Service Professor of Stem Cell and
Regenerative Biology, a core faculty member of the Broad Institute of Harvard and MIT,
and Director of the Stanley Center for Psychiatric Research at the Broad Institute. From
2001 to 2011, he served as Provost of Harvard University and from 1996 to 2001, director
of the US National Institute of Mental Health. He is former Editor of the Annual Review
of Neuroscience and served formerly as President of the Society for Neuroscience and the
International Neuroethics Society.
Judy Illes is Professor of Neurology and Canada Research Chair in Neuroethics at the
University of British Columbia, in Vancouver, Canada. She is a pioneer of the field of
neuroethics, and has made ground-​making contributions to a broad range of ethical,
social, and policy challenges at the intersection of biomedical ethics and neuroscience.
She is a Fellow of the Royal Society of Canada, Canadian Academy of Health Sciences,
and the American Association for the Advancement of Science. She is the editor of the
original neuroethics volume Neuroethics: Defining the Issues in Theory, Practice, and Policy
(Oxford University Press, 2006).
Agnieszka Jaworska is Associate Professor of Philosophy at the University of California,
Riverside. Her research interests are at the intersection of ethical theory, medical ethics,
and moral psychology. Her current book in preparation concerns the ethics of treatment
of individuals whose status as moral agents and persons seems compromised or uncertain,
such as Alzheimer’s patients, addicts, psychopaths, and young children. It is part of a
larger project on the nature of the specifically human agency and the role of the capacity
to care in moral psychology. She has published in Ethics, Philosophy and Public Affairs,
and Philosophy and Phenomenological Research.
Fabrice Jotterand is Associate Professor of Bioethics and Medical Humanities and Director
of the Graduate Program in Bioethics at the Center for Bioethics and Medical Humanities,
Medical College of Wisconsin, Milwaukee, and Senior Researcher in Bioethics/​Neuroethics
at the University of Basel. His scholarship and research interests focus on issues including
moral enhancement, neurotechnologies and human identity, the use of neurotechnologies
in psychiatry, medical professionalism, and moral and political philosophy. He is the
co-editor of Cognitive Enhancement (Oxford University Press, 2016, with Veljko Dubljeviić)
and the co-editor of the book series Advances in Neuroethics (Springer).
Niranjan S. Karnik is the Cynthia Oudejans Harris, MD Professor of Psychiatry at the
Rush University Medical Center in Chicago. In the Department of Psychiatry, he serves
 xxvi

List of Contributors xxvii

as the Director of the Section of Population Behavioral Health and Medical Director of
the Road Home Program: Center for Veterans and their Families. He is also an Associate
Faculty Member of the Maclean Center for Clinical Medical Ethics at the University of
Chicago. His research interests are focused on homeless and underserved youth, mobile
technologies, and the mental health needs of veterans and their families.
Matthew P. Kirschen is an Assistant Professor of Anesthesiology and Critical Care
Medicine, Pediatrics and Neurology at the University of Pennsylvania Perelman School
of Medicine and The Children’s Hospital of Philadelphia. His research interests are
neuromonitoring of critically ill children with acute brain injury, early detection of brain
injury in critically ill children, neuroprognostication after acute brain injury in children,
and death by neurologic criteria determination in children.
Erika Kleiderman is an Academic Associate at the Centre of Genomics and Policy at
McGill University. Her research interests are the ethical, legal, and social implications
surrounding minors, access to data and genetic information, and the regulation of stem
cells, gene editing technologies, and regenerative medicine. She has also been involved in
the development of controlled data and biosamples access documentation for longitudinal
biobanks.

Eran Klein is a neurologist and philosopher at the Oregon Health and Science University,
Portland VA Medical Center, and Department of Philosophy and the Center for
Sensorimotor Neural Engineering at the University of Washington. His interests reside at
the intersection of neurology, neurotechnology, and philosophy.

Bartha M. Knoppers is a Professor in the Department of Human Genetics in the Faculty

of Medicine at McGill University, and Director of the Centre of Genomics and Policy. She
is a Canadian lawyer and is an expert on the ethical aspects of genetics, genomics, and
biotechnology. She holds a Canada Research Chair in Law and Medicine and is an Officer
of the Order of Canada and Quebec.
Walter J. Koroshetz is the Director of the National Institute of Neurological Disorders
and Stroke (NINDS). He works to advance the mission of the Institute, to improve
fundamental knowledge about the brain and the nervous system, and to use that
knowledge to reduce the burden of neurological disorders. He joined NINDS as the
Deputy Director in 2007. Before coming to NIH, Dr. Koroshetz was a Harvard Professor
of Neurology, Vice Chair of Neurology at the Massachusetts General Hospital, Director
of Stroke and Neurointensive Care, and a member of the Huntington’s disease unit. His
research activities spanned basic neurobiology to clinical trials.
Karola V. Kreitmair is a Clinical Ethics Fellow at the Stanford Center for Biomedical Ethics.
Her research interests include ethical aspects of mobile health and wearable technology,
developments in citizen science, biohacking, and gaming, as well as questions surrounding
justice and stewardship with respect to the minimally conscious state diagnosis.
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xxviii List of Contributors

Elvira V. Lang is a former Associate Professor of Radiology at Harvard Medical School

and current CEO of Hypnalgesics, LLC d/​b/​a Comfort Talk®. Her research interests are
use of nonpharmacologic analgesia interventions and hypnoidal language during invasive
medical procedures which she tested in large-​scale clinical trials. She further developed and
also rigorously tested training in these methods, expanding their use to anxiety provoking
medical examinations such as magnetic resonance imaging. Her recent interests examine
patient/​provider interactions and their impact on health outcomes, patient throughout
and satisfaction, as well as overall impact on operational efficiency of healthcare systems.
Cheryl D. Lew is a Clinical Professor of Pediatrics (Clinician-​Educator) at the University
of Southern California Keck School of Medicine and Children’s Hospital Los Angeles. Her
research interests within biomedical ethics center on the unique moral status of children
and the role of emotional investment in determining ethical values frameworks which
drive clinical decision-​making. In the biomedical clinical milieu, Dr. Lew is a specialist
in pediatric rare lung diseases and is interested in the promises as well as pitfalls of
regenerative medicine in ameliorating these diseases.
Alex L. MacKay is a Professor at the University of British Columbia with a joint
appointment in the Department of Radiology and the Department of Physics and
Astronomy. He is the Director of the UBC Magnetic Resonance Imaging Research Centre
which hosts magnetic resonance projects in humans and in animal models for human
disease. Dr. MacKay’s research area is the application of magnetic resonance techniques
to study brain pathology in neurodegenerative disorders. His research group developed a
myelin water imaging technique that measures myelin content in vivo in brain and spine.
Debra J. H. Mathews is the Assistant Director of Science Programs in the Johns Hopkins
Berman Institute of Bioethics and an Associate Professor in the Department of Pediatrics,
Johns Hopkins University School of Medicine. Her research interests are around ethics and
policy issues raised by emerging biotechnologies, with particular focus on neuroscience,
genetics, stem cell science, and synthetic biology.
Ralph Matthews is Professor of Sociology at the University of British Columbia (UBC).
His research focuses on resource management, climate change, and socioeconomic
development. He has done research with First Nation indigenous groups in Canada on
well-​being, health, education, resource management, and environmental policy. With
Judy Illes, he initiated the Environmental Neuroethics area of research inquiry. He
is Past-​President of the Canadian Sociological Association and Past-​President of the
International Sociological Association’s Research Committee on Science and Technology.
In 2014 he was named a UBC Senior Killam Research Fellow.
Alexander Moiseev is a Senior Scientist at the Behavioural and Cognitive Neuroscience
Institute, Simon Fraser University, Vancouver, Canada. His research interests are
in neuroimaging, data analysis, statistics and signal processing in MEG and EEG,
bioelectromagnetic inverse solutions including traditional and multisource beamformers
and other spatial filters, machine learning, and brain–​computer interfaces.
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List of Contributors xxix

Jonathan D. Moreno is the David and Lyn Silfen University Professor at the University of
Pennsylvania where he is a Penn Integrates Knowledge (PIK) professor. At Penn he is also
Professor of Medical Ethics and Health Policy, of History and Sociology of Science, and of
Philosophy. His books include The Body Politic, which was named a Best Book of 2011 by
Kirkus Reviews, Mind Wars (Bellevue Literary Press, 2012), and Undue Risk (Routledge,
2000). Moreno also frequently contributes to such publications as The New York Times,
The Wall Street Journal, The Huffington Post, Psychology Today, and Nature and appears
on broadcast and online media. In 2008–​2009 he served as a member of President Barack
Obama’s transition team. The American Journal of Bioethics has called him “the most
interesting bioethicist of our time.”
Sabine Müller is an Assistant Professor of Neurophilosophy and Medical Ethics at the
Charité–​Universitätsklinik Berlin. Her research interests are ethical issues of psychiatric
neurosurgery, particularly of deep brain stimulation, as well as ethical issues of psychiatry,
neurology, and neurology.
Saskia K. Nagel is an Assistant Professor of Philosophy and Ethics of Technology at
the University of Twente, Netherlands. Her research interests are at the intersection of
ethics, philosophy, life sciences, and technologies. Her background is in cognitive science
and philosophy. She works on approaches to individual and societal challenges in a
technological culture, with a focus on the ethical, anthropological, and social consequences
of neuroscientific progress. She is particularly interested in how technologies influence
our self-​understanding, and how they impact our understanding of autonomy and
responsibility.
Brad Partridge is a Senior Research Fellow in the Research Development Unit at
Caboolture Hospital, Queensland. His research interests are ethical issues in sport, and
the use of human enhancement technologies.
Rémi Quirion is a Professor and Québec’s first chief scientist since 2011. Until his
appointment, Rémi Quirion was the vice-​dean for science and strategic initiatives at
McGill University. He was the scientific director of the Douglas Mental Health Institute
and the executive director of the International Collaborative Research Strategy for
Alzheimer’s Disease of the CIHR. Professor Quirion was the first scientific director of
the Institute of Neurosciences, Mental Health and Addiction (INMHA). He has received
several awards and honours, including the Order of Canada (OC) and is a member of the
Royal Society of Canada.
Eric Racine is Director of the Neuroethics Research Unit and Full Research Professor
at the Institut de recherches cliniques de Montréal, Canada. Inspired by philosophical
pragmatism, his research aims to understand and bring to the forefront the experience
of ethically problematic situations by patients and stakeholders and then to resolve them
collaboratively through deliberative and evidenced-​informed processes.
Vasiliki Rahimzadeh is a PhD Candidate with the Centre of Genomics and Policy at
McGill University and a 2016 Vanier Canada Graduate Scholar. Her doctoral thesis
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xxx List of Contributors

explores ethics governance of research with children in the data-​intensive, biomedical

sciences and its impact on national and international data sharing.
Khara M. Ramos is a Senior Science Policy Analyst in the Office of Scientific Liaison
within the Office of the Director of the National Institute of Neurological Disorders and
Stroke, a part of the National Institutes of Health (NIH). A  neuroscientist and former
AAAS Science and Technology Policy Fellow, she has a broad interest in neuroscience
research, with a specific focus on how advances in neuroscience intersect with society. She
serves as Executive Secretary of the Neuroethics Division of the NIH BRAIN Initiative®
Multi-​Council Working Group.
Alexander Rauscher is a Physicist and Assistant Professor in the Department of Pediatrics
at the University of British Columbia. His research interests are the development and
utilization of quantitative magnetic resonance imaging techniques for the characterization
of tissue damage and repair in the central nervous system.
Peter B. Reiner is a Professor at the National Core for Neuroethics at the University
of British Columbia. His research interests include cognitive and moral enhancement,
autonomy, and technologies of the extended mind.
Urs Ribary is the BC LEEF Leadership Chair in Cognitive Neuroscience, Director of the
Behavioral and Cognitive Neuroscience Institute (BCNI), and Professor of Psychology,
Pediatrics and Psychiatry at SFU and UBC in Vancouver, Canada. After graduating from
neuroscience and neuropharmacology at the Swiss Federal Institute of Technology in
Zurich, Switzerland, he was Professor in Neuroscience and Director of the functional
Brain Imaging Center at the NYU Medical Center in New York. He is known as a pioneer
in human brain imaging with expertise in functional brain network connectivity and
dynamics within the typical and pathological human brain.
Julie M. Robillard is Assistant Professor of Neurology at the University of British
Columbia and Faculty of the Djavad Mowafaghian Centre for Brain Health and of
the National Core for Neuroethics at the University of British Columbia. She brings
her multidisciplinary background in neuroscience and biomedical ethics to the study
of issues at the intersection of dementia, technology, and ethics. Dr.  Robillard has
developed innovative techniques for the analysis of brain health and new media and
has unveiled areas of critical need in the field of neuroscience communication.
Karen S. Rommelfanger is an Assistant Professor in the Departments of Neurology and
Psychiatry and Behavioral Sciences and the Neuroethics Program Director at Emory
University’s Center for Ethics, and Neuroscience Editor-​in-​Residence at the American
Journal of Bioethics Neuroscience. She also serves on the National Institutes of Health
BRAIN Initiative® Multi-​Council Working Group Neuroethics Division. Her research
explores how evolving neuroscience and neurotechnologies challenge societal definitions
of disease and medicine. A  key part of her work is fostering communication across
multiple stakeholders and, as such, she edits the largest international online neuroethics
discussion forum, The Neuroethics Blog.
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List of Contributors xxxi

Karine Sénécal is an Academic Associate at the Centre of Genomics and Policy at

McGill University. Specializing in ethical, legal, and social issues arising in the domains
of pediatric research and genetic research, Karine’s work focuses on genetic testing and
screening of minors, as well as pediatric biobanking.
Vesna Sossi is a Professor in the University of British Columbia Physics and Astronomy
Department. Her main areas of expertise are development of positron emission
tomography (PET) instrumentation, data quantification, and image analysis methods as
well as application of PET to the study of neurodegeneration in rodent models of disease
and human disease. She is interested in exploiting the synergy provided by multiparameter,
multimodality imaging.
Dan J. Stein is a Professor of Psychiatry at the University of Cape Town. His research
interests lie in anxiety and related disorders, and more recently in the intersection of
global mental health, neuroscience, and neuroethics.
Cathie L.M. Sudlow is Professor of Neurology and Clinical Epidemiology at the University
of Edinburgh, Chief Scientist of UK Biobank, and Honorary Consultant Neurologist in
the National Health Service. Her research interests include prospective epidemiological
studies, genetic and environmental determinants of stroke and neurodegenerative diseases,
and deriving clinical phenotypes from routine healthcare datasets. As UK Biobank’s
Chief Scientist, she has been responsible for developing and evaluating procedures for
feedback of incidental findings as part of UK Biobank’s large multimodal imaging study.
Professor Sudlow also leads the UK Biobank follow-​up program, coordinating linkages
to national death, cancer, hospital, primary care and other datasets, and expert outcomes
adjudication subgroups.
Michael N. Tennison completed his MA in bioethics at Wake Forest University, NC, and
his JD at the University of Maryland Carey School of Law. He has held positions at the
Presidential Commission for the Study of Bioethical Issues, University of Pennsylvania
Department of Medical Ethics & Health Policy, Wake Forest University’s Center for
Bioethics, Health, & Society, and University of Maryland’s Thurgood Marshall Law Library.
Mr. Tennison researches issues at the intersections of law, ethics, and neuroscience,
including biomedical human enhancement and the role of neuroscience as an empirical
basis for law and legal policy.
Jordan Tesluk is a Postdoctoral Fellow at the University of British Columbia, in the
National Core for Neuroethics and the Department of Sociology. His research interests
include cross-​
cultural translation of information related to the brain, relationships
between environmental change and the human brain, and the protection of brain and
mental health in occupational settings.
Christine M. Tipper is an Assistant Professor of Psychiatry at the University of British
Columbia and Neuroimaging Scientist at the BC Children’s Hospital Research Institute.
Her research utilizes cognitive neuroscience, multimodal brain imaging, high-​density
EEG, and emerging network analysis techniques to map and quantify dynamic brain
xxxi

xxxii List of Contributors

systems that support complex social and cognitive functions. She investigates how
brain systems supporting how we respond to subtle social cues, understand actions, and
manage attention to pursue goals are compromised across a range of neurodevelopmental,
neuropsychiatric, and neurological conditions that are characterized by social and
cognitive symptoms.
Anthony Traboulsee is an Associate Professor and Research Chair of the MS Society of
Canada at the University of British Columbia in Vancouver. He is the Director of the MS/​
NMO Clinic and Clinical Trials Research Group at UBC Hospital. His research focus is
on clinical trial design, the development of practice guidelines for the use of magnetic
resonance imaging (MRI) in the management of multiple sclerosis, establishing advanced
MRI imaging outcomes in multiple sclerosis, and the treatment of neuromyelitis optica.
Robert D. Truog is the Frances Glessner Lee Professor of Medical Ethics, Anesthesia
and Pediatrics at Harvard Medical School, where he serves as Director of the Center for
Bioethics. He is also a Senior Associate in Critical Care Medicine at Boston Children’s
Hospital, where he has practiced pediatric intensive care medicine for more than 30 years.
Lawrence M. Ward is a Full Professor of Psychology at the University of British
Columbia. He investigates brain regional interactions underlying a variety of visual,
auditory, and higher cognitive processes using EEG and MEG and advanced techniques
such as independent component analysis, phase synchronization, and transfer entropy.
He is currently focusing on the cognitive neuroscience of attention, memory, reading,
and consciousness, the effects of challenges such as drugs and dying on brain network
interactions, the effects of neural noise on cognition and perception, and mathematical
and computer modeling of neuronal oscillations and synchronization.
Joanna M. Wardlaw is a Professor and Chair of Applied Neuroimaging and Director of
Edinburgh Imaging, Neuroimaging Sciences and the Brain Research Imaging Centre at
the University of Edinburgh, and Honorary Consultant Neuroradiologist in the National
Health Service. Her research focuses on the pathophysiology, diagnosis, treatment, and
prevention of stroke, most recently focusing specifically on cerebral small vessel disease.
She led a UK-​wide initiative to establish standards for management of incidental findings
during research imaging.
Sarah S. Welsh is a Fellow in Pediatric Critical Care Medicine at The Children’s Hospital
of Philadelphia. Her research interests include drug monitoring and pharmacokinetics in
pediatric status epilepticus, as well as the neuromonitoring and neuroprognostication of
children with acute brain injury.
Emily Wight is Communications Manager at the Djavad Mowafaghian Centre for Brain
Health at the University of British Columbia. Her focus is on plain-​language science and
academic communication, and her background is in nonfiction writing and publishing.
 xxixi

List of Contributors xxxiii

Todd S. Woodward is a Professor of Psychiatry at the University of British Columbia.

His research interests are in cognitive neuropsychiatry and functional neuroimaging. The
objectives of the cognitive neuropsychiatry research are to identify the cognitive operations
underlying the primary symptoms of psychosis and schizophrenia. The objectives of the
functional neuroimaging research are to gain an understanding of the cognitive systems
involved in psychosis and schizophrenia, and to develop new multivariate methods for
analyzing fMRI data, with applications to integrating information from fMRI, EEG,
and MEG.
xvxi
  1
0–100 100–200 200–300 300–400 400–500 500–600 600–700 700–800 800–900
theta

(a) Theta PLVs

(All ROIs)

(b) Theta PLVs

(vOT)

(c) Theta
Transfer
Entropy (vOT)

(d) Gamma
PLVs
(All ROIs)

(e) Gamma
PLVs (vOT)

(e) Gamma
Transfer
Entropy
(vOT)
gamma

Figure 2.1  Example of dynamic EEG synchronization and transfer entropy results from a word reading task. Synchronization was measured with
phase locking value (PLV), and narrow band transfer entropy was measured using an adaptation of the Kullback entropy (for vOT to/​from other areas
only). Theta band is 3–​7 Hz and gamma band is 35–​45 Hz. Black lines (arrows) indicate significant interaction (directed information flow) between the
connected reading-​related brain areas during the time period (ms after stimulus presentation) indicated at the top of the figure. vOT indicates ventral
occipital-​temporal brain region, the putative word-​form area. 
Reproduced from Bedo N, Ribary U, and Ward LM. (2014) ‘Fast dynamics of cortical functional and effective connectivity during word reading’, PLoS ONE, Volume 9, Issue 2, e88940,
doi:10.1371/​journal.pone.0088940, Copyright © 2014 Bedo et al. Reproduced under the terms of the Creative Commons Attribution Version 4.0 International (CC BY 4.0), https://​
creativecommons.org/​licenses/​by/​4.0/​.
 2
Source waveforms Fast-Fourier Transform
Anterior
25
LCMV

Source Amplitude
50 20 MCMV

Amplitude |y(f)|
16-Hz Mixing

(nAmp)
15
0
10

–50 5

0
0 50 100 150 200 0 10 20 30 40 50 60
Time (ms) Frequency (Hz)
25
LCMV
50 20

Amplitude |y(f)|
MCMV
Amplitude 36-Hz Mixing
15
(nAmp)
0
10

–50 5
LH RH 0
Posterior
0 50 100 150 200 0 10 20 30 40 50 60
Time (ms) Frequency (Hz)
Figure 2.2  EEG localization and connectivity accuracy. Left panel shows a simulated source location (blue square) that had only a 16-​Hz oscillation and
a neighboring (within 15 mm) source location (red square) that had only a 36-​Hz oscillation. Source mixing of 16-​and 36-​Hz oscillations were clearly
visible in the traditional beamformer (LCMV) reconstructed source waveforms (blue and red lines; middle panel). Amplitude spectra (right panels)
showed that both red and blue LCMV sources contained energies at 16 and 36 Hz (i.e., source mixing). Because of this source mixing, phase-​coherence
between the sources existed and functional connectivity was falsely revealed (green line; left panel). Our MCMV beamformer (black lines), however,
prevented source mixing. MCMV sources only had 16-​Hz (lower panels’ black lines) or 36-​Hz oscillations (upper panels’ black lines). Obviously, false-​
connections were not found for the MCMV beamformer.
 3

Anterior

LH RH

Figure 2.3  Challenge in EEG connectivity maps. Traditional LCMV-​beamformer connectivity map

(left) for alpha-​band (9–​10 Hz) revealed highly synchronized (red lines) local couplings in visual
cortices at 380 ms after letter onset. However, MCMV-​beamformer connectivity map (right)
revealed strongly desynchronized (blue lines) couplings. The MCMV-​connectivity maps fit better
with known event-​related desynchronizations that occur after a visual stimulus onset for this
band and latency. Thus, the MCMV map is likely the real map.
4

Figure 2.4  Examples of visualizations associated with diffusion MRI (dMRI) data. Some
visualizations highlight the brain’s diffusion properties (a–​e), while others highlight its geometric
properties (f–​h), while still others highlight brain connectivity (i–​l). See the text for a description
of each visualization technique: (a) mean diffusivity (MD); (b) fractional anisotropy (FA); (c) color-​
coded FA; (d) ellipsoidal visualization of diffusion tensors; (e) perceptual color visualization of
diffusion tensors; (f) tubular structure detection in dMRI; (g) dMRI segmentation of corpus
callosum (above) and the cingulum (right), visualized in 2D and 3D respectively; (h) dMRI image
difference overlaid on MD image; (i) streamline tractography; (j) visualization of tract confidence
regions; (k) a connectome visualized as a circular graph; (l) a connectome overlaid on a brain
silhouette.
 1

Part I

Neurotechnology: Today
and tomorrow
2
 3

Chapter 1

When emerging biomedical

technologies converge or collide
Debra J.H. Mathews

Introduction
Neuroethics, like bioethics more broadly, has grown up alongside of and has, in many
ways, been propelled by emerging biomedical technologies. Over time, they have sorted
themselves into broad areas largely along the lines of clinical practice, public health, and
biomedical and research ethics. Each of these broad research areas can be further divided
into more specialized areas of research and scholarship. Within the ethics of biomedi-
cal research, subdisciplines have emerged around genetics and genomics, regenerative
medicine, synthetic biology, nanotechnology, and neuroscience. Neuroethics coalesced
in the early 2000s to focus on ethical issues raised by the neurosciences and their applica-
tion in medicine and society, as well as on issues related to the emerging neuroscience
of ethics (Marcus 2002; Illes & Bird 2006). Over the past 10 or 15  years, neuroethics
has founded an international professional society (http://​www.neuroethicssociety.org/​),
created specialist journals, and supported the development of an active community of
scholars. Neuroethics scholars have prompted and contributed to critical debates about
disorders of consciousness, research with brain-​interfacing devices, criminal justice, and
moral decision-​making, to name a few.
Neuroscience sometimes employs other emerging biomedical technologies, such as
genetics, regenerative medicine, and synthetic biology, which generate their own ethics
and policy conundrums. When emerging biomedical technologies converge or collide,
the challenges inherent to each can be compounded. These challenges are of at least two
types:  First, emerging technologies are new by definition, fast moving, and have only
nascent and rapidly evolving theoretical and empirical scholarship on the associated ethi-
cal issues. When two or more such technologies are combined, existing ethics, governance,
and public engagement challenges are magnified. Second, communities of ethicists1 tend
to coalesce around specific technologies, and study the ethical, legal, and social implica-
tions (ELSI), and the governance landscape related to that particular technology or class
of technologies; however, these communities often have little overlap. Neuroethics schol-
ars are frequently, though certainly not always, different from ELSI scholars, who study
the ethical, legal, and social implications of genetics and genomics, who are often different
from ethicists who study regenerative medicine, synthetic biology, or nanotechnology.
4  5

4 When emerging biomedical technologies converge or collide

The separation is particularly acute for the latter two, originating, as they have, largely
outside biomedicine. This siloing limits information exchange and the benefit that can
come from cross-​pollination and collaboration not only between biomedical scientists
and ethicists, but also across scholars working on different emerging technologies.
As technologies mature and become tools for other areas of science, emerging biomedi-
cal technologies will increasingly converge in ways that bring these challenges into sharp
relief. In addition, the difficulty of staying up to date on bleeding-​edge science, the silo-
ing of the science itself, and personal academic interest all suggest that the challenges of
siloing in the ethics community will persist. However, both sets of challenges might be
attenuated by a more systematic approach to ethical analysis across subdisciplines, and
at least some focus not on the details of the technologies but rather on the nature of the
technologies. The development of frameworks for ethical analysis based on shared char-
acteristics, including that the technologies are emerging, rapidly evolving, and ethically
contentious, provide a process for mutual learning and growth across a variety of emerg-
ing biomedical technologies, easing the challenges of bringing together not just two, but
many cultures (Snow 1998).

Multiple morally contested areas

The sorts of technologies with which neuroethicists and bioethicists engage are rarely
straightforward, conventional, modest innovations. The emerging biomedical technolo-
gies at issue here are those associated with fundamental moral disagreements about their
development and use, for example, deep brain stimulation, whole genome sequencing,
neural imaging, embryonic stem cells, and genome editing. When a new technology
emerges and gains traction, scientists flock to the new research area, the science is pro-
pelled forward, and the ethics community engages. The science evolves in parallel with the
theoretical and empirical ethics scholarship, both often running ahead of public aware-
ness, understanding, and engagement. Morally contested terrain takes time and effort to
map, understand, explore, and develop norms and governance for use. Technologies can
mature and diffuse rapidly, becoming tools in other areas of science before norms and
governance structures are in place, leading to the convergence of two, or more, emerging
and morally contested technologies in ways that can magnify existing ethics, governance,
and public engagement challenges. Potential effects of such convergence, and sometimes
collision, can be seen in the examples of whole genome sequencing and regenerative med-
icine that follow.

Whole genome sequencing

As the cost of whole genome sequencing has fallen from about $100  million USD per
human genome sequenced at the end of the Human Genome Project, to about $1000
USD today, the technology has increasingly been integrated into research and clinical
care. In the past, only targeted sequencing was feasible—​the sequencing of the gene or
genes of interest—​such that the test results were narrowly targeted to the question being
 5

Multiple morally contested areas 5

asked. Whole genome and whole exome (the part of the genome that codes for proteins)
sequencing, however, produces a huge amount of data, much of which has unclear or
unknown implications for the health of the individual. Some may have very serious, con-
crete, and medically actionable implications; the remainder of the data falls somewhere
in between these two ends of the spectrum. One particularly vexing type of data includes
genetic variants associated with serious adult-​onset neurological conditions identified in
young people and in particular, in children (e.g., Anderson et al. 2015). The genetics and
ELSI communities have been working mightily to try to understand how best to manage
these data—​whether, how, and in what format any or all of it should be returned (e.g.,
Haga & Zhao 2013; Kleiderman et al. 2014; Kullo et al. 2014; Lewis & Goldenberg 2015).
There remain many unsettled questions, and despite a strong and growing literature and
multiple frameworks and recommendations for managing these data (e.g., Fabsitz et al.
2010; Wolf et  al. 2012; Sénécal et  al. 2015), a review suggests that changes in practice
responding to these recommendations have been slow (Franca & Mathews, manuscript
in preparation).

Regenerative medicine
In the field of regenerative medicine, meanwhile, ethicists had been exploring the issues
raised by embryonic stem cell research, and developing relevant guidelines and gov-
ernance structures (Institute of Medicine and National Research Council 2005), when
Shinya Yamanaka announced at the annual meeting of the International Society for Stem
Cell Research that he had developed a way to turn adult cells into pluripotent stem cells
with properties similar to those of embryonic stem cells (Takahashi & Yamanaka 2006).
Unlike embryonic stem cells, to which so many scholars and members of the public voiced
moral objections due to their origins in the destruction of human embryos, these induced
pluripotent stem cells (iPSCs) required only somatic or body cells from a person, and
were therefore thought to be less problematic. In particular, somatic tissue such as that
from the skin is much easier to obtain and is readily available, unlike human embryos that
are usually obtained from couples who have completed in vitro fertilization treatment and
have leftover embryos stored in a clinic freezer. Due to this lower barrier to entry, many
investigators began studying and using iPSCs in their research, and the field accelerated
rapidly. Foreskin from infant circumcisions is a frequent source. Another source is left-
over pathology samples. Not only are there large institutional banks of such tissue, but if
the tissue was obtained in the course of clinical care and has had identifiers stripped from
the sample, its use in research does not require human subject research oversight in the
United States, under current regulations (US Department of Health & Human Services
2008). However, current regulations are under revision, recent events related to the family
of Henrietta Lacks (Skloot 2010; Callaway 2013), and existing data on patients’ views of
different uses of their archived tissue samples have led to new recommendations about the
use of archived tissue in iPSC research (Dasgupta et al. 2014; Lomax et al. 2015). As such,
institutions and stem cell research oversight committees are still trying to determine the
appropriate path forward.
6  7

6 When emerging biomedical technologies converge or collide

Convergence
Now, imagine the convergence of these two rapidly evolving areas of biomedicine. Each
raises vexing ethics and policy issues in the absence of sufficient theoretical and empirical
research for norms or policy-​making, or both, that come together under one umbrella
of research. Imagine, for example, a project that uses de-​identified pathology samples to
derive iPSC lines and then uses those to derive neurons. As part of this research, whole
genome sequencing is completed for each cell line. Further, the data are posted to a pub-
licly available database to maximize the utility of the (possibly publicly funded) resource
that is this collection of lines. Sequence data reveal that several of the lines contain serious
mutations that would result in an immediate medical response, if known by the person
from whom the tissue was taken. Several contain mutations that guarantee that the per-
son from whom the tissue was taken will develop a serious neurological condition later in
life. How does the researcher respond?
Because the barrier to entry for iPSC research is so low and genome and exome
sequencing are now so affordable, this situation is likely to become increasingly common.
The genetics community may be well aware of the debate around the return of results and
incidental findings (e.g., Wolf et al. 2012; Sénécal et al. 2015), in particular those associ-
ated with neurological disease (e.g., Illes et al. 2004), but the stem cell scientists, who are
not technically working with human subjects, and perhaps never have, may not have any
familiarity with these debates. Neither of these communities may be well acquainted with
the debates within neuroethics about neurodegenerative disease, advance care planning,
and loss of cognitive capacities and self (e.g., Mathews et al. 2009; Pierce 2009; Robillard
et al. 2011).
This is but one example of how the convergence of emerging technologies can mag-
nify existing ethics, governance, and public engagement challenges. While the above-​
mentioned example is hypothetical, real cases exist and are likely to become more
prevalent, both across biomedical technologies, such as deep brain stimulation, fetal
tissue research, novel treatments for psychiatric disease, genome editing, and including
other emerging technologies, as well (e.g., Chen et al. 2014; Hutmacher et al. 2015; Meshi
et al. 2015; Sproul 2015; Teoh et al. 2015).

Siloed research and analysis

A second challenge raised by converging technologies is the problem of siloing. Although
pervasive in academia, siloing has particular implications for ethics and policy work
related to emerging biomedical technologies. Neuroethics has grown and evolved in par-
allel with other subdisciplines of biomedical ethics, including those who work in ELSI,
regenerative medicine, synthetic biology, and nanotechnology. Each of these subdisci-
plines has grown up around the technology at its center. ELSI is arguably the largest and
most mature subdiscipline, having been established and supported by a large extramu-
ral funding program associated with the Human Genome Project (Meslin et  al. 1997).
Though the many subdisciplines have common features and often face analogous ethical
 7

Siloed research and analysis 7

issues, there is relatively little overlap in the researchers generating the related scholarship.
The separation is particularly acute for synthetic biology and nanotechnology for exam-
ple, originating as they have largely outside biomedicine and more closely associated with
engineering. This sorting of bioethics into increasingly specialized subdisciplines often
means that the scholars who read, write, and research ethics and policy issues related to
neuroscience do not necessarily—​and often do not—​overlap with the scholars who focus
on other emerging biomedical technologies.
It is not that there is no cross-​talk or overlap across the subdisciplines—​in the example
in the prior section, the work on return of results in the ELSI literature was helpfully
informed by parallel prior work in neuroimaging (e.g., Illes & Chin 2008; Illes et al. 2008).
Indeed, there are a number of prominent cross-​pollinators between neuroethics and
ELSI, including several authors involved in the current volume (e.g., Cho and Knoppers).
Likewise, there are cross-​pollinators between ELSI and regenerative medicine, but these
are emissaries, not robust conduits for data and knowledge exchange. For example, those
in regenerative medicine and the associated ethics community will not necessarily be
familiar with the theoretical and empirical research that has been done in neuroethics in
response to a search for ways to diagnose dementia and other cognitive disorders earlier
and earlier, in an effort to intervene before irreversible damage is done, and when a better
chance at delaying onset or otherwise mitigating the damage wrought by disease might
exist (e.g., Illes et  al. 2007; Arias et  al. 2015). Concerns have been raised and studied
regarding the psychological implications of presymptomatic diagnosis, discrimination,
stigma, and how preferences for individual care, life, and death might change as capacities
are lost and the self changed.
Another example of potentially problematic siloing may be found in synthetic biology,
for which many of the individuals working on the ethical implications of the science are
members of fields outside of ethics. This is not to disparage those scholars or their work
in synthetic biology in any way, only to note that synthetic biology, despite the explicit
intentions of the field to develop health-​related biomedical applications, has not thus far
been a major focus of the biomedical ethics community. This disconnect exists despite
continuity with prior work in genetics, recombinant DNA and the Asilomar conference of
1975, and existing governance structures in biomedicine, most notably the Recombinant
DNA Advisory Committee. Instead, the ethics touchstones in synthetic biology are more
likely to be genetically modified organisms, such as golden rice (Enserink 2008), or dual-​
use concerns, such as those raised by the introduction of new mutations that increased
the transmissibility of the H1N1 virus (Enserink 2012; Herfst et al. 2012). While these are
important and relevant cases, as synthetic biology moves more into biomedical science,
there is critical history and literature tied to their origins and future in genetics, about
which they must know. The story of Henrietta Lacks, her descendants, and the HeLa
cell line, and the human genetic modification debates that have been going on in genet-
ics for 30 years (President’s Commission for the Study of Ethical Problems in Medicine
Biomedical Behavioral Research 1982; Skloot 2010) are merely examples. Again, that is
not to say that there is not any cross-​pollination—​the Hastings Center had a large project
8  9

8 When emerging biomedical technologies converge or collide

on synthetic biology (http://​www.thehastingscenter.org/​publications-​resources/​special-​

reports-​2/​synthetic-​future-​can-​we-​create-​what-​we-​want-​out-​of-​synthetic-​biology/​)—​
but rather that cross-​pollination is the exception rather than the norm, and this comes
with serious opportunity costs.
Though frustrating, siloing is understandable. Members of the Academy—​whether in
the sciences or humanities—​cannot all be expert in everything. It takes a great deal of
time to keep up both on the ethics and scientific literature related to work in one rapidly
evolving area, let alone multiple sets of such literature pairs. Furthermore, there is clear
value in specializing, given the importance of the technical and scientific details to fore-
casting, identifying, and analyzing related ethical issues. But for funding and time, one
could spend many weeks attending even only to the major ethics and science conferences
relevant to multiple subdisciplines. Furthermore, there are long-​standing, entrenched
reasons for such siloing, including institutional structures and constraints, and incentives
and recognition in academia (Snow 1998; Kahn 2011). Understanding the origins of the
problem does not mitigate its effects, however. Disciplinary segregation continues to limit
information exchange and the benefits that can come from collaboration across the ethics
communities associated with different technologies.
By relying on emissaries rather than principal conduits or stronger connections, sci-
entists and ethicists risk losing relevant data, knowledge, and experience that can help
an emerging field, for example, through understanding how early decisions (e.g., about
shared, open resources) can shape downstream development and use. Further, direct
connections can lead a new field to avoid reinventing a preexisting wheel (e.g., a useful
and well-​justified governance model, or an approach to incidental findings). Finally, the
impact of ethics research and scholarship is very much linked to the scholars themselves
(Mathews, unpublished data):  if the scholars with valuable historical understanding,
research experience, and networks are not at the table in other subdisciplines—​at profes-
sional meetings, in governance committees, on advisory boards—​if the right people are
in parallel but non-​overlapping fields, the potential impact is lost.
There have been attempts to counteract this siloing, most notable perhaps, James
Crow’s efforts at Arizona State University (https://​newamericanuniversity.asu.edu/​),
where interdisciplinarity has been embraced and elevated, and academic divisions are
being nucleated around problems to be solved, rather than traditional academic disci-
plines. Institutional issues can be mitigated by such innovative restructuring and cul-
ture change, but the change must extend beyond the borders of a single institution if the
broader challenges faced by the many existing divisions of biomedical ethics writ large
will be addressed.

A shared analytic framework

It is unlikely that there will ever be a grand, unifying framework for the analysis and
structuring of all emerging biotechnologies: histories differ, the constellation of leading
voices and stakeholders differ, technical details differ. Context matters deeply. However,
 9

A shared analytic framework 9

new morally contentious biomedical fields, the ethicists who study them, and the public
who funds and ultimately lives in the world that is shaped by the science, would all benefit
from a more systematic approach to information exchange and ethical analysis. One pos-
sible solution is a shared method or analytic framework, akin to technology assessment
but on a broader scale, to help emerging fields and the associated ethics community to
ask the right questions, learn from analogous prior cases in other fields, identify shared
challenges, and benefit from knowledge gained elsewhere, and to help both scientists and
ethicists to gain a broader understanding of the relationship of their research to other
areas of biomedical science. This analytic framework would focus not on the details of
the technology but rather on its nature, based on shared characteristics, including that the
technologies are emerging, rapidly evolving, and ethically contentious.
Late in its life in the US Congress, the Office of Technology Assessment (OTA)
produced a report assessing the content and quality of its policy analysis (Office of
Technology Assessment 1993). The OTA was a small shop that served the Congress
internally, and was a model for many similar entities internationally. The non-​partisan
agency was charged with providing “thorough, objective information and analysis to
help Members of Congress understand and plan for the short-​and long-​term conse-
quences of the applications of technology, broadly defined.” One of the findings of the
1993 report was that there was little consistency in how different programs within the
OTA approached policy analysis. There were, however, commonalities. In developing
the context for their reports to Congress, the OTA often evaluated the historical con-
text and status quo, conducted a stakeholder analysis (including individuals, groups,
and institutions), identified key assumptions around the technology, determined the
international context and identified relevant international comparisons, and assessed
the legal and regulatory landscape. While some of these components would be more
easily addressed for a specific technology than for an entire field, these components are
a solid starting point. It should be noted, though, that there are other models of, and
exercises in, technology assessment and ethical analysis that can also serve as resources
for the development of a shared analytic framework (e.g., Tairyan & Illes 2009; Sclove
2010; Chameau et al. 2014).
Based on my own work across subdisciplines in bioethics, policy analysis, and tech-
nology assessment, I would add the following: First, stakeholder analysis, in particular
the role and views of the public, is critical. Scientists and ethicists need to know who
cares about this area of science, why, and what their views are. The public will be heard
at some point, so better earlier than later; besides, it is the right thing to do. Second, a
discussion about intellectual property and precompetitive public resources, their support,
and use should start early, though collective action may take time (Hinxton Group 2010).
This is particularly true in morally contentious areas of science that work with a scarce
or contested resource, or both, such as human embryos. Overall, from an ethics stand-
point, researchers engaged with contentious emerging technologies, in particular when
developing in pluralistic democracies, should be expected to identify key stakeholders, to
articulate what is morally at stake, and to ask and answer questions about the social goals
10  1

10 When emerging biomedical technologies converge or collide

of the research, the anticipated benefits and harms and their distribution, the develop-
ment of shared resources, and governance.
In addition to facilitating ethics and policy analysis of converging technologies and
mitigating the negative effects of siloing, the broadest goal of this sort of systematic
effort at assessment or mapping of subdisciplines should be the same as the over-
arching goal of ethics in biomedicine, including neuroethics: to identify, frame, and
solve problems in medicine, public health, and the biosciences (Mathews et al. 2016).
Ideally, the process of working through the model would also facilitate stakeholder
engagement.
Table 1.1 combines the OTA components and the ethics-​oriented components, and
provides an outline for a shared analytic framework. The approach is designed to produce
a series of reports on different emerging biotechnologies that would facilitate both infor-
mation flow across subdisciplines and comparison of different emerging biotechnologies
converging in a new project, application, or product, as well as the identification of novel
issues raised by that convergence.
The development of a shared analytic framework is, of course, only the first step. The
framework must also be put into practice, and there remain many practical questions;
in particular, how would these analyses be conducted and by whom? Two possibili-
ties are that this work could be centralized or distributed. The Human Fertilization and

Table 1.1  Potential components of a shared analytic framework for emerging biomedical

technologies

Framework component Key question(s)

Historical context What are the key scientific antecedents and ethics
touchstones?

Status quo What are the key questions, research areas, and prod-
ucts/​applications in the field today?
Stakeholder analysis Which individuals, groups, and institutions have an inter-
est or role in the emerging biomedical technology?
Key assumptions around the technology What are the key assumptions of both the scientists and
the other stakeholders that may impede communication
and understanding or illuminate attitudes?
International context and relevant How is the technology and associated ethics and gover-
international comparisons nance landscape evolving internationally? Are there use-
ful international models?
Legal and regulatory landscape What are the laws and policies that currently apply and
what are the holes or challenges in current oversight?
Ethical and societal implications What is morally at stake? What are the sources of ethi-
cal controversy in the field? What are the other societal
concerns?
Social goals of the research What are the goals of the field that are oriented toward
improving the human condition? Are there other goals?
 1

Conclusion 11

Embryology Authority in the United Kingdom currently does much of this analytic and
governance work across technologies related to reproductive medicine and research. In
addition, technology assessment of varying sorts occurs at national academies, national
bioethics commissions, and similar organizations internationally. But again, this work is
currently ad hoc, often in response to concerns about a particular application or product,
rather than a proactive, systematic effort to understand and help shape an emerging sub-
discipline. However, these centralized bodies do have significant authority and convening
power, which may allow them to both conduct the analysis and disseminate the products
effectively.
An alternative model would be to distribute the work to the subdisciplines themselves
through their relevant professional societies. These societies are likely to include many
of the relevant stakeholders, to encompass a broad understanding of the field, and to
hold the respect of their professional community. However, this model may perpetuate
the problem of siloing. To counteract this risk, a networked institution model might be
applied (Sclove 2010) wherein the professional societies ally with one another in a struc-
tured collaboration to exchange information and even partner in the work of analysis.
This virtual network of professional societies would also then be well positioned to dis-
seminate the products not only to the individual subdisciplines, but also across them, and
even to embody that work through, for example, the creation of cross-​pollination ses-
sions at academic meetings or similar sections of specialist journals that explicitly solicit
cross-​disciplinary views.
Regardless of the model for implementation of the shared analytic framework, given the
nature of emerging biomedical technologies, all analyses must be reviewed and refined
periodically with the natural ebb and flow of science and ethics.

Conclusion
When emerging biomedical technologies converge or collide, new challenges can arise.
These challenges are of at least two types: (1) Emerging technologies are new by definition,
fast moving, and have only nascent and rapidly evolving theoretical and empirical schol-
arship on the associated ethical issues. The combination of two or more technologies can
magnify existing ethics, governance, and public engagement challenges. (2) Communities
of ethicists tend to coalesce around specific technologies, to study the ethical, legal, and
social implications, and the governance landscape related to that particular technology or
class of technologies; however, these communities often have little overlap.
Just as the founders of a scientific field are responsible for laying the experimental
groundwork for that field, so too do they have a responsibility for laying the ethics and
governance groundwork. This responsibility applies to both scientists and ethicists. Each
new, morally contested field in biomedicine has the opportunity to try again to get it
right, in terms of evolution and shaping of the field, as well as in its governance. This
will only work, however, if we learn from the experience of other disciplines at different
developmental stages. Creation and implementation of a shared analytic framework will
12  1

12 When emerging biomedical technologies converge or collide

accelerate this learning and improve the chances of getting it right—​or some approxima-
tion thereof—​more quickly and with fewer mistakes. Such a framework will also ease
the assessment of projects, applications, or products in which multiple emerging bio-
medical technologies converge or collide, and mitigate the effects of academic siloing.
Customization will always be required, and systematizing will never completely eliminate
siloing in academia. Neuroethics is a prime testing ground for a shared analytic frame-
work, and for the learning and collaboration that can benefit both biomedical research
and ethics overall.

Note
1. For the purposes of this chapter, I will use the term ethicist to mean the diverse array of scholars from
areas such as philosophy, theology, medicine, biology, public health, history, ethnography, economics,
sociology, political science, law, literature, and more, who focus on ethics and policy issues related to
biomedicine. I appreciate that this is an imperfect shorthand, but it has been adopted here for simplic-
ity and brevity.

References
Anderson, J.A., Hayeems, R.Z., Shuman, C., et al. (2015). Predictive genetic testing for adult-​onset
disorders in minors: a critical analysis of the arguments for and against the 2013 ACMG guidelines.
Clinical Genetics, 87(4), 301–​310.
Arias, J.J., Cummings, J., Grant, A.R., and Ford, P.J. (2015). Stakeholders’ perspectives on preclinical
testing for Alzheimer’s disease. Journal of Clinical Ethics, 26(4), 297–​305.
Callaway, E. (2013). Deal done over HeLa cell line. Nature, 500(7461), 132–​133.
Chameau, J.L., Ballhaus, W.F., and Lin, H.S. (Eds.) (2014). Emerging and Readily Available Technologies
and National Security: A Framework for Addressing Ethical, Legal, and Societal Issues. Washington,
DC: National Academies Press.
Chen, L., Qiu, R., and Li, L. (2014). The role of nanotechnology in induced pluripotent and embryonic
stem cells research. Journal of Biomedical Nanotechnology, 10(12), 3431–​3461.
Dasgupta, I., Bollinger, J., Mathews, D.J.H., Neumann, N.M., Rattani, A., and Sugarman, J. (2014).
Patients’ attitudes toward the donation of biological materials for the derivation of induced
pluripotent stem cells. Cell Stem Cell, 14(1), 9–​12.
Enserink, M. (2008). Tough lessons from golden rice. Science, 320(5875), 468–​471.
Enserink, M. (2012, June 2). Free to speak, Kawaoka reveals flu details while Fouchier stays mum.
[News story.] Science. Available from: http://​news.sciencemag.org/​2012/​04/​free-​speak-​kawaoka-​
reveals-​flu-​details-​while-​fouchier-​stays-​mum [accessed July 12, 2015].
Fabsitz, R.R., McGuire, A., Sharp, R.R., et al. (2010). Ethical and practical guidelines for reporting
genetic research results to study participants: updated guidelines from a National Heart, Lung, and
Blood Institute working group. Circulation: Cardiovascular Genetics, 3(6), 574–​580.
Franca, A. and Mathews, D.J.H. Review of return of results policy, as reflected in clinical trial informed
consent documents. Manuscript in preparation.
Haga, S.B. and Zhao, J.Q. (2013). Stakeholder views on returning research results. Advances in Genetics,
84, 41–​81.
Herfst, S., Schrauwen, E.J., Linster, M., et al. (2012). Airborne transmission of influenza A/​H5N1 virus
between ferrets. Science, 336(6088), 1534–​1541.
 13

References 13

Hinxton Group (2010). Statement on Policies and Practices Governing Data and Materials Sharing and
Intellectual Property in Stem Cell Science. Available from: http://​hinxtongroup.org/​Consensus_​
HG10_​FINAL.pdf [accessed May 29, 2016].
Hutmacher, D.W., Holzapfel, B.M., De-​Juan-​Pardo, E.M., et al. (2015). Convergence of regenerative
medicine and synthetic biology to develop standardized and validated models of human diseases
with clinical relevance. Current Opinion in Biotechnology, 35, 127–​132.
Illes, J. and Bird, S.J. (2006). Neuroethics: a modern context for ethics in neuroscience. Trends in
Neurosciences, 29(9), 511–​517.
Illes, J. and Chin, V.N. (2008). Bridging philosophical and practical implications of incidental findings
in brain research. The Journal of Law, Medicine & Ethics, 36(2), 298–​304.
Illes, J., Rosen, A., Huang, L., et al. (2004). Ethical consideration of incidental findings on adult MRI in
research. Neurology, 62(6), 888–​890.
Illes, J., Rosen, A., Greicius, M., and Racine, E. (2007). Ethics analysis of neuroimaging in Alzheimer’s
disease. Annals of the New York Academy of Sciences, 1097, 278–​295.
Illes, J., Kirschen, M.P., Edwards, E., et al. (2008). Practical approaches to incidental findings on brain
imaging research. Neurology, 70(5), 384–​390.
Institute of Medicine and National Research Council (2005). Guidelines for Human Embryonic Stem
Cell Research. Washington, DC: National Academies Press.
Kahn, J. (2011). The two (institutional) cultures: a consideration of structural barriers to
interdisciplinarity. Perspectives in Biology and Medicine, 54(3), 399–​408.
Kleiderman, E., Knoppers, B.M., Fernandez, C.V., et al. (2014). Returning incidental findings from
genetic research to children: views of parents of children affected by rare diseases. Journal of Medical
Ethics, 40(10), 691–​696.
Kullo, I.J., Haddad, R., Prows, C.A., et al. (2014). Return of results in the genomic medicine projects of
the eMERGE network. Frontiers in Genetics, 26(5), 50.
Lewis, M.H. and Goldenberg, A.J. (2015). Return of results from research using newborn screening
dried blood samples. The Journal of Law, Medicine & Ethics, 43(3), 559–​568.
Lomax, G.P., Hull, S.C., and Isasi, R. (2015). The DISCUSS Project: revised points to consider for the
derivation of induced pluripotent stem cell lines from previously collected research specimens. Stem
Cells Translational Medicine, 4(2), 123–​129.
Marcus, S. (Ed.) (2002). Neuroethics: Mapping the Field, Conference Proceedings. New York: Dana Press.
Mathews, D.J.H., Bok, H., and Rabins, P.V. (Eds.) (2009). Personal Identity and Fractured Selves: Perspectives
from Philosophy, Ethics, and Neuroscience. Baltimore, MD: Johns Hopkins University Press.
Mathews, D.J.H., Hester, M., Kahn, J., et al. (2016). A conceptual model for the translation of bioethics
research and scholarship. Hastings Center Report 46(5), 34–​39.
Meshi, D., Tamir, D.I., and Heekeren, H.R. (2015). The emerging neuroscience of social media. Trends
in Cognitive Sciences, 19(12), 771–​782.
Meslin, E.M., Thomson, E.J., and Boyer, J.T. (1997). The Ethical, Legal, and Social Implications
Research Program at the National Human Genome Research Institute. Kennedy Institute of Ethics
Journal, 7(3), 291–​298.
Office of Technology Assessment (1993). Policy Analysis at OTA: A Staff Assessment. Available
from: http://​ota.fas.org/​reports/​PAatOTA.pdf [accessed August 14, 2015].
Pierce, R. (2009). A changing landscape for advance directives in dementia research. Social Science &
Medicine, 70(4), 623–​630.
President’s Commission for the Study of Ethical Problems in Medicine Biomedical Behavioral
Research (1982). Splicing Life: A Report on the Social and Ethical Issues of Genetic Engineering with
14

14 When emerging biomedical technologies converge or collide

Human Beings. Washington, DC: President’s Commission for the Study of Ethical Problems in
Medicine and Biomedical and Behavioral Research.
Robillard, J.M., Federico, C.A., Tairyan, K., Ivinson, A.J., and Illes, J. (2011). Untapped ethical
resources for neurodegeneration research. BMC Medical Ethics, 12. Available from: http://​www.
biomedcentral.com/​1472-​6939/​12/​9 [accessed May 27, 2016].
Sclove, R. (2010). Reinventing Technology Assessment: A 21st Century Model. Washington, DC: Science
and Technology Innovation Program, Woodrow Wilson International Center for Scholars.
Sénécal, K., Rahimzadeh, V., Knoppers, B.M., Fernandez, C.V., Avard, D., and Sinnett, D. (2015).
Statement of principles on the return of research results and incidental findings in paediatric
research: a multi-​site consultative process. Genome, 58(12), 541–​548.
Skloot, R. (2010). The Immortal Life of Henrietta Lack. New York: Crown Publishing Group.
Snow, C.P. (1998). The Two Cultures. New York: Cambridge University Press.
Sproul, A.A. (2015). Being human: the role of pluripotent stem cells in regenerative medicine and
humanizing Alzheimer’s disease models. Molecular Aspects of Medicine, 43–​44, 54–​65.
Tairyan, K. and Illes, J. (2009). Imaging genetics and the power of combined technologies: a perspective
from neuroethics. Neuroscience, 164(1), 7–​15.
Takahashi, K. and Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and
adult fibroblast cultures by defined factors. Cell, 126(4), 663–​676.
Teoh, G.Z., Klanrit, P., Kasimatis, M., and Seifalian, A.M. (2015). Role of nanotechnology in
development of artificial organs. Minerva Medica, 106(1), 17–​33.
US Department of Health & Human Services (2008). Code of Federal Regulations Title 45, Section 46.
In: Federal Policy for the Protection of Human Subjects. Washington, DC: US Government.
Wolf, S.M., Crock, B.N., Van Ness, B., et al. (2012). Managing incidental findings and research results
in genomic research involving biobanks and archived data sets. Genetics in Medicine, 14(4),
361–​384.
 15

Chapter 2

Emerging neuroimaging technologies:

Toward future personalized
diagnostics, prognosis, targeted
intervention, and ethical challenges
Urs Ribary, Alex L. MacKay, Alexander Rauscher,
Christine M. Tipper, Deborah E. Giaschi,
Todd S. Woodward, Vesna Sossi, Sam M. Doesburg,
Lawrence M. Ward, Anthony Herdman,
Ghassan Hamarneh, Brian G. Booth,
and Alexander Moiseev

Introduction
In this chapter, we highlight a selection of advances, future challenges, and limitations of
emerging multimodal neuroimaging technologies, data signal processing, and visualiza-
tion strategies. We bring these examples to the forefront as experts in the field who are
also attentive to the ethical challenges they pose for personalized diagnostics, prognosis,
and targeted intervention into clinical practice.

Advances in structural magnetic resonance imaging:

Toward the quantification of tissue properties
The basis of structural magnetic resonance imaging (MRI) is the three conventional mag-
netic resonance (MR) contrasts: proton density, T1 weighting, and T2 weighting. While
the detailed mechanisms of T1 and T2 in brain tissue are not well understood, these
processes provide qualitative contrast weightings that yield superb in vivo visualization
of central nervous system tissue and have proved invaluable as a diagnostic and patient
management tool. These days, MR is evolving into a quantitative tool due to incorpora-
tion of improvements in both hardware and software that allow for much faster scanning,
such as parallel imaging (Pruessmann et al. 1999) and simultaneous multislice imaging
techniques (Barth et al. 2016). These approaches facilitate the introduction of otherwise
time-​consuming MRI scans into clinical research and potentially into routine clinical
16  1

16 Emerging neuroimaging technologies

practice. New MRI sequences have vastly expanded the types of information available by
MRI and the latest developments blur the boundaries between structural and functional
information. The new frontier in MRI is the quantification of changes in tissue due to
development, aging, disease, and therapy. In this very brief overview we highlight a few of
the most exciting developments.
A variety of imaging techniques measure brain perfusion (MacDonald & Frayne 2015);
for example, arterial spin labeling can yield estimates of cerebral blood flow rates without
requiring injection of a contrast agent. While most MR images arise from water, by using
magnetization transfer techniques, one can access protons resident on other molecules;
chemical exchange saturation transfer (CEST) (Ward K.M. 2000) promises to be able to
produce images of the distribution of several biologically important molecules like glucose
(Nasrallah et al. 2013) and amino acids residues in proteins. Inhomogeneous magnetization
transfer produces images that are specific for membrane lipids in brain (Varma et al. 2015).
There is a large literature on measurement of water diffusion in brain (Jones 2016).
Diffusion tensor imaging (DTI) enables tractography, which is the visualization of nerve
tracts in brain. DTI provides mean diffusivity and fractional anisotropy, which are highly
sensitive to subtle changes in microscopic brain structure. Despite limitations in terms of
specificity (Beaulieu 2002; Jones et al. 2013), DTI has been used widely in neuroimaging.
Advanced diffusion techniques, for example, diffusion-​based size imaging (Wang Y. et al.
2011), enable more quantitative analyses including the proportion of axonal water and of
inflammatory cells.
A specific measurement of myelin can be accomplished by myelin water imaging
(MacKay et al. 1994; Prasloski et al. 2012). Assessment of myelin using this technique has
been performed in multiple sclerosis (Laule et al. 2008; Vavasour et al. 2009; Manogaran
et al. 2015), schizophrenia (Lang et al. 2014), stroke (Borich et al. 2013), and mild trau-
matic brain injury (Wright et al. 2016).
Probing the central nervous tissue using the phase information of MRI scans has
become an active field of research. Phase provides information on the magnetic properties
of tissue at high spatial resolution (Rauscher et al. 2005; Duyn et al. 2007). Considerable
research efforts have been going into turning the phase images into maps of underlying
magnetic tissue properties (quantitative susceptibility mapping (QSM) (Schweser et al.
2011, 2016; Bilgic et al. 2012; Liu C. et al. 2015)). Applications of phase-​based contrast
and QSM range from the investigation of the developing (Lodygensky et al. 2011) and
aging brain (Li W. et al. 2014) to the assessment of changes in tissue structure and com-
position in neurodegenerative diseases (Wiggermann et al. 2013; Li X. et al. 2015; Guan
et al. 2016).
Using MR spectroscopy (Oz et al. 2014), researchers can create images of the concen-
trations of important brain metabolites, for example, N-​acetylaspartate (measure of neu-
ronal integrity), the creatine/​phosphocreatine pool (brain energetics), and glutamate (an
important excitatory neurotransmitter).
Surgical procedures can become much less invasive and more effective when the sur-
geon has access to real-​time MR images of the subject. For example, abnormal brain tissue
 17

Advances in functional magnetic resonance imaging 17

may be ablated using high-​intensity focused ultrasound while monitoring the health of
adjacent organs of risk using MR images sensitive to temperature (Coluccia et al. 2014).
Imaging of nuclei other than hydrogen introduces novel new imaging contrasts: hyper-​
polarized MRI with carbon-​13 nuclei enables detailed measurement of metabolic path-
ways (Ross et al. 2010) and sodium imaging (Shah et al. 2016) provides an indication of
cellular and metabolic integrity.
Fueled by the imagination of MRI scientists, advancements in MRI hardware have been
driving progress in MRI software (i.e., scans) and vice versa, transforming MRI from a
tool for the visualization of structure into a science of quantitative mapping of central
nervous system tissue properties.

Advances in functional magnetic resonance imaging

By measuring brain activity-​related changes in blood oxygenation that are linked to spe-
cific sensory or cognitive events, functional MRI (fMRI) provides a remarkable window
into the mind, and has revealed a great deal about patterns of functional brain anatomy
underlying attention, memory, perception, social understanding, and affective responses.
The first fMRI studies used simple blocked designs and echo-​planar imaging to measure
changes in blood oxygenation level-​dependent (BOLD) contrast in response to robust
visual (Kwong et al. 1992; Ogawa et al. 1992) or motor (Bandettini et al. 1992) stimula-
tion. Advances in scanner technology, experimental design, and data analysis techniques
have led to improved spatial and temporal resolution, making it possible to image more
complex aspects of perception and cognition. These advances have also paved the way for
the use of fMRI as a tool to establish the neural basis and determine the effects of treat-
ment of neurodevelopmental disorders such as amblyopia, dyslexia, and autism spectrum
disorder.
Typical event-​related fMRI analyses rely on comparing brain activity engaged by exper-
imental and control tasks, with the assumption that the only difference is the particular
cognitive process of interest. While this approach has been fruitful in revealing brain
activity associated with broad cognitive domains, such as attention and memory, advanc-
ing fMRI depends on developing nuanced techniques for quantifying complex interac-
tions between concurrently engaged cognitive processes that support these broader
cognitive domains (Decety & Cacioppo 2010; Poldrack 2010).

Embracing cognitive complexity

Significant advances in the past decade in the investigation of the brain basis of complex
cognitive functions have opened up new domains of cognitive and clinical neuroscience
research. There is growing momentum toward investigating the brain basis of complex,
deeply human aspects of the mind that define experience in both health and illness, such
as attitudes (McCall et  al. 2012), morality (Kaplan et  al. 2016), creativity (Beaty et  al.
2015), and social understanding (Tipper et  al. 2008; Immordino-​Yang & Singh 2013;
Saggar et al. 2016). A notable example is that of observing and understanding the actions
18  1

18 Emerging neuroimaging technologies

of other people. Observing actions engages a distributed brain network of parietal, fron-
tal, and temporal sensorimotor brain regions known as the action observation network
(Buccino et al. 2001). An experimental design and analysis technique known as repeti-
tion suppression/​fMRI adaptation (Grill-​Spector et al. 2006) exploits the greater sensitiv-
ity of neural circuits to novel information than repeated information to reveal neural
populations that decode distinct dimensions of a stimulus. During an action observation
task, several dimensions of the action are processed concurrently (e.g., kinematics, goals,
outcomes, intentions, expressive meaning). Using repetition suppression, brain processes
that decode each of these dimensions have been localized to distinct, hierarchically orga-
nized functional modules nested within the larger action observation network (Grafton &
Hamilton 2007; Tipper et  al. 2015). By identifying more precise functional granularity
within functional brain networks, the precision of the measuring sticks we use to assess
brain pathology across of broad range of clinical conditions is greatly increased.
Advances in fMRI study design are made possible in part by an increasing willing-
ness to utilize ecologically valid, complex, dynamic stimuli and tasks that employ video
displays, interactive tasks, physical manipulanda, virtual reality, and wide-​field three-​
dimensional (3D) immersion. As tasks and stimuli better match real-​world conditions,
the richness of available behavioral measures is opening a window onto the significance
of individual variability. The result is a growing appreciation that clever new tools are
needed to quantify this meaningful social, cognitive, and behavioral information to define
nuanced sociocognitive phenotypes, and map them to distinct patterns of brain function.
This new perspective is critical to developing new tools for improving diagnostics and
individualized interventions for numerous neurodevelopmental, neurological, and neu-
ropsychiatric conditions.

Clinical application: Localizing neuropathology in amblyopia

Amblyopia is a common developmental visual disorder that is characterized by reduced
visual acuity in one eye that cannot be immediately corrected with lenses. Based on ani-
mal models, amblyopia is classically attributed to changes in the primary visual cortex
(V1), such as shrinkage of ocular dominance columns driven by the amblyopic eye and
reduction in the number of binocular neurons (Hubel et al. 1977; Crawford & Harwerth
2004). Very high-​resolution fMRI has been used to confirm the shrinkage of ocular dom-
inance columns in humans with amblyopia (Goodyear et  al. 2002)  and fMRI has also
established the involvement of extrastriate visual areas outside of V1 in human amblyo-
pia (Muckli et al. 2006; Lerner et al. 2006; Ho & Giaschi 2009; Thompson et al. 2012).
These studies extend our understanding of the neural basis of amblyopia beyond that
available through animal models (Kiorpes & McKee 1999), and confirm the need for a
revised definition of amblyopia to include a broader range of behavioral deficits (Wong
2012). For example, we used an event-​related, parametric fMRI design to study the neu-
ral correlates of a behavioral deficit in multiple-​object tracking (the ability to use atten-
tion to track several randomly moving targets in a field of moving distractors) (Ho et al.
2006), measurable through both amblyopic and non-​amblyopic eyes. Area MT in lateral
 19

Advances in functional magnetic resonance imaging 19

occipitotemporal cortex, the anterior intraparietal sulcus, and the frontal eye fields, but
not V1, were implicated in the visual deficit (Secen et al. 2011). Other studies used the
subvoxel resolution provided by repetition suppression to confirm the involvement of V1
and extrastriate regions in amblyopia (Li X. et al. 2011a), and to demonstrate abnormal
binocular interactions in these regions (Jurcoane et al. 2009).
Functional MRI is now being used to assess new treatment approaches to amblyopia
aimed at augmenting visual cortex activity. A recent study reported an increase in BOLD
response in visual cortex with amblyopic eye viewing after 30 days of perceptual learning
treatment, but no structural change measurable with DTI (Zhai et al. 2013). In another
study, anodal direct current stimulation was found to improve vision in the amblyopic eye
in some adults with amblyopia; it also equalized the BOLD response of the visual cortex to
inputs from each eye (Spiegel et al. 2013). In a more controversial study, oral administra-
tion of levodopa produced a small improvement in visual acuity in the amblyopic eye and
a correspondingly small increase in V1 activation measured with fMRI (Yang et al. 2003).

From localization to organization

As novel imaging technologies, experimental paradigms, and analytical procedures enable
the investigation of the finer granular substructure within functional brain networks,
there is growing interest in not only mapping the localization of specific brain functions
to specific brain anatomy, but also in quantifying patterns of functional organization of
brain networks. For example, studies using resting state fMRI have reported disrupted
spontaneous activity patterns and/​or reduced functional connectivity between visual and
visuomotor areas in amblyopia (Lin et al. 2012; Ding et al. 2013; Wang T. et al. 2014). One
study used task-​activated fMRI and found reduced effective connectivity involving tha-
lamic, V1, and extrastriate visual areas for both feed-​forward and feedback connections
(Li X. et al. 2011b). Such analytical advancements in data analysis enable a more complete
understanding of the neural basis of amblyopia, which is essential to improving treatment
interventions. More generally, examining how functional brain networks interact under
changing task demands may provide new insights into neuropathology linked to neuro-
developmental, neurological, and neuropsychiatric conditions.
A range of functional connectivity analysis techniques is now available to quantify
brain organization, each taking a slightly different approach. Multivariate techniques
such as constrained principal component analysis for fMRI (fMRI-​CPCA) (Woodward
et al. 2006) reveal distinct functional networks based on coherent patterns of task-​related
variation in whole-​brain activity. Other task-​based approaches include seed-​voxel con-
nectivity maps, which reveal functional brain networks based on correlations in activity
under various task conditions, psychophysiological interaction maps, which reveal dif-
ferences in inter-​regional connectivity associated with the experimental manipulation,
and Granger causality maps, which estimate the direction of information flow through
various regions of a network (Rogers et al. 2007).
Another key advance in characterizing functional brain network organization is the
emerging field of topological network analysis (Bullmore & Bassett 2010). This approach
20  2

20 Emerging neuroimaging technologies

relies upon parcellating a brain network into a set of nodes, computing the functional
relationships between each node-​pair (e.g., activity correlations, coherence, mutual infor-
mation, transfer entropy; Wang H.E. et al. 2014), and then quantifying the overall organi-
zational structure, or architecture, of the network as a whole. A range of graph metrics is
available to quantify properties of brain network organization, such as strength, efficiency,
clustering, modularity, path length, centrality, and assortativity (Rubinov & Sporns 2010).
An important advantage of these metrics is their ability to reveal organizational features
that are unobservable with traditional fMRI analyses. As fMRI is used to characterize
brain pathology linked to heterogeneous symptom profiles that occur with neurodevel-
opmental and neurological disorders, topological network analysis provides a promising
analytical tool (Kaiser 2011).
Topological network metrics can be applied not only to functional brain organiza-
tion, but also to anatomical brain organization based on tractography analyses of diffu-
sion imaging data, which estimates probabilistic measures of white matter connectivity
between brain regions (Basser et al. 2000). Functional and anatomical network metrics
can then be compared to identify structure–​function relationships related to task per-
formance (Hermundstad et al. 2013) and individual variability in how underlying brain
architecture is utilized to achieve particular cognitive states (Hermundstad et al. 2014).
This approach is also being applied to move beyond identifying static patterns of func-
tional organization to reveal dynamic brain changes that unfold over time (Bassett et al.
2011; Betzel et al. 2016). New techniques for characterizing interactions and transitions
between identifiable coherent brain states are providing promising avenues for enabling
distinctions between neurologically healthy and pathological brain function.

Task-​based fMRI signal reliability and validity

Task-​based fMRI data provides well-​localized and compelling heat images depicting brain
activity in response to a wide range of tasks. Typically, brain images depict the magnitude
and reliability of differences of parameter estimates derived from individual conditions.
However, task-​based fMRI data provides richer information than brain activation (e.g.,
difference) images, such as task-​based network information, and network-​level hemo-
dynamic response (HDR) shape estimates that may be informative in terms of under-
standing the cognitive operations driving their shape. The percentage of variance in raw
BOLD signal that is predictable from task timing typically ranges from 5% to 15%, but
this percentage depends on the task design, task timing, and the nature of the task. Even
if the percentage of task-​related signal in the BOLD data is as low as 5%, as long as that
signal can be accurately extracted, it can still be reliable and valid, a concept identical in
principal to the case of true-​score correlations between two tests and unattenuated cor-
relations (Spearman 1904).
In order to determine that reliable and valid task-​related signal is being extracted from
the BOLD signal, we suggest that task-​based fMRI data should meet at least two and ideally
three validity checks, and one reliability check, before being interpreted; namely, spatial,
temporal, and possibly experimental validity, as well as reliability over subjects at the level
 21

Advances in functional magnetic resonance imaging 21

of task-​based networks. Spatial validity requires observation of network configurations

that resemble those well known in the literature, first described as the task-​positive and
-​negative networks (Fox et al. 2005). Temporal validity requires observation of a biologi-
cally plausible HDR shape for each network (Logothetis et al. 2001). Experimental validity
requires observation of HDR shape and magnitude changes with important experimental
manipulations or measured cognitive operations, or both (Friston et al. 1998). Finally, reli-
ability in HDR shape over subjects at the level of whole-​brain networks should be observed
(Metzak et al. 2012; Lavigne et al. 2015b; Woodward et al. 2015). Functional MRI-​CPCA
efficiently meets all of these requirements as part of its standard analysis procedure that
involves two essential steps: (1) constraining variance in BOLD signal to that predictable
from task timing using multivariate multiple regression, and (2) extracting multiple task-​
related functional brain networks using principal component analysis. The percentage
of variance in BOLD signal that can be predicted from task timing is part of the fMRI-​
CPCA output, as is this value for each brain network extracted. Component loadings
are displayed on the brain images, and component scores are combined with the design
matrix to estimate network-​, subject-​, and condition-​specific HDR shape estimates, aver-
aged over trials. For each task-​related functional brain network, observed HDR shapes
can be submitted to repeated-​measures analysis of variance (ANOVA) to test temporal
validity (i.e., the HDR shape is not a random shape that changes between subject) and
experimental validity (i.e., differences in HDR shape between experimental conditions.
This step can also be used to carry out group fMRI-​CPCA, for testing differences between
clinical samples in the HDR shape (Woodward et al. 2015, 2016).

Experimental manipulation/​spatial and temporal replication

If the task-​related BOLD signal displays spatial, temporal, and possibly experimental
validity, as well as reliability in HDR shape over subjects at the level of task-​based net-
works, a very powerful methodology is available through manipulation of functional
brain networks with a variety of different tasks (and/​or task conditions), and comparison
of the nature of the BOLD signal associated with different tasks and/​or task conditions.
We quantify these principles as spatial and temporal replication, and in this section we
outline how these concepts can be harnessed to identify the cognitive function of brain
networks.
In order to assess spatial and temporal replication of network configurations, and take
advantage of spatial replication combined with temporal differences to interpret function
of brain networks, two tasks (or task conditions) can be compared though simultaneous
analysis of two datasets (Lavigne et al. 2015a). When two (or more) experiment versions
elicit the same underlying cognitive operation (e.g., visual attention), spatial and tempo-
ral replication would be observed if HDR shapes for the network in question were not
distinguishable between the two experiment versions, and this should be the case if the
timing elicited by that cognitive operation does not differ between experiments. In con-
trast, spatial but not temporal replication would be observed if HDR shapes were reliably
different between the two experiment versions, and this should be the case if the timing of
2  2

22 Emerging neuroimaging technologies

the cognitive operation differs between experiments. This case (viz., spatial but not tem-
poral replication) provides an important scientific opportunity to use differences between
experiments to help test the theorized timing of cognitive functions of brain networks.
That is to say, if a theorized cognitive function can be manipulated using (for example)
variation in task timing between experiments, it can be determined whether or not the
BOLD signal pattern supports the account of the cognitive operation performed by that
functional brain network, at least for the task in question. This is tested using the ANOVA
method already mentioned above with experiment as a within-​or between-​subject factor.
Finally, if a cognitive operation is elicited by only one version of the experiment but not
the other, the version not eliciting this cognitive operation would show a flat HDR shape
for that functional brain network, and therefore it could be concluded that neither spa-
tial nor temporal replication has been observed. This methodology has been used in past
work to test theoretical accounts of the function of brain networks across closely matched
experiments (Lavigne et al. 2015a).

Future directions
Moving forward, the combination of more nuanced experimental paradigms to assess
complex cognitive functions and characterize individual sociocognitive phenotypes and
more sophisticated analyses of functional and anatomical brain network organization
open up a new frontier for clinical neuroscience research. The potential to improve diag-
nostic and assessment capabilities and enhance individualized care across a range of neu-
rodevelopmental, neurological, and neuropsychiatric conditions is unprecedented.

Advances in functional and biochemical positron emission

tomography imaging
Many brain diseases are known to start well before clinical symptoms become manifest.
The ability to correctly diagnose disease early is expected to enhance the probability of
successful intervention. In this context, the network degeneration hypothesis (Palop et al.
2006), which suggests that initiation and progression of disease-​specific pathological
changes occur within specific brain networks and are mediated by protein misfolding,
inflammation, and impaired cellular energetics coupled to abnormal neurotransmission,
suggests that multiparameter information may lead to significantly enhanced under-
standing of brain function and thus disease. This approach is encouraging development
of novel positron emission tomography (PET) imaging tracers that target abnormal pro-
tein aggregation, multimodality imaging, either sequential or simultaneous, such as that
enabled by hybrid PET/​MRI scanners, and application of analysis methods that are able
to extract relevant features from multiparametric information.
Aggregations of the beta-​amyloid protein, considered a hallmark of Alzheimer’s dis-
ease, are fairly well studied with several established PET tracers (Villemagne 2016).
Imaging of tau aggregation, implicated in Alzheimer’s disease, chronic traumatic enceph-
alopathy, progressive supranuclear palsy, and corticobasal syndrome is more recent; three
 23

Advances in functional and biochemical positron emission tomography imaging 23

promising novel tracers are currently used in human studies, 11C-​PPB3, 18F-​T807 or 18F-​
AV-​1451, and 18F-​THK5351 (Villemagne et al. 2015). The tau tracers are not equivalent in
their ability to detect deposits of different tau isoforms that are selectively associated with
different aspects of neurodegeneration:  the precise relevance of each tracer to specific
diseases is thus still under investigation. Development of PET tracers for other targets of
interest such as alpha-​synuclein, whose aggregations are implicated in the pathogenesis of
Parkinson’s disease, is a very active research area, but no successful candidates have been
developed as yet (Eberling et al. 2013, Kikuchi et al. 2010).
The ability to identify abnormal protein aggregation or alterations in metabolic path-
ways observable with 18F-​FDG, does not always by itself lead to accurate differential diag-
nosis or to improved understanding of pathogenic mechanisms. Informed combination
of data obtained from different imaging modalities has been shown to yield superior
information; for example, a recent study performed on a hybrid PET/​MRI demonstrated
that the combination of regional metabolism, functional connectivity, and gray matter
volume, which were derived from disease characteristic networks, was able to achieve
high classification accuracies for separating patients with different neurodegenerative
syndromes of 77.5% for Alzheimer’s disease versus others, 82.5% for behavioral variant
frontotemporal dementia versus others, 97.5% for semantic dementia versus others, and
87.5% for progressive nonfluent aphasia versus others—​this multimodal classification
was superior to unimodal approaches (Tahmasian et al. 2016). In addition to combing
data from different modalities, novel image analysis approaches for PET images are also
emerging and are proving complementary to the traditional ones based either on kinetic
modeling or radioactivity concentration values. Such approaches include information
about specific tracer distribution patterns within anatomically relevant regions of interest
(Klyuzhin et al. 2016; Liu S. et al. 2016). Combinations of such patterns or features applied
to the analysis of 18F-​FDG data coupled with MRI-​derived information, resulting in the
definition of multiparameter-​based biomarkers, have been shown to be associated with
different aspects of Alzheimer’s disease progression (Liu et al. 2016). Such biomarkers will
be of great relevance when stratifying patients and evaluating mechanisms of action and
effectiveness of emerging treatments.
The hybrid PET/​MRI provides access to novel measurements, such as direct investiga-
tion of the interactions between neurotransmitter activity and brain function either at rest
or as stimulated by a pharmacological or behavioral intervention. This is a very exciting
area of research relevant to many aspects of brain function that will see growth as the
availability of the hybrid PET/​MR scanners increases. For example, it will be possible
to investigate correlations between responses to reward, pain, or treatment in terms of
dopamine release and activation of cognitive networks and how such correlations dif-
fer amongst different subject populations. Ideally, it will be possible to identify imaging-​
based biomarkers that identify subjects at risk and thus promote development of disease
prevention strategies. Optimization of such approaches will drive development of joint
PET/​MRI image processing methods, either in the image reconstruction step or image
analysis step (Sander et al. 2013; Kang et al. 2015). In summary, over the last decade PET
24  2

24 Emerging neuroimaging technologies

imaging has been enhanced by development of novel tracers, technical improvements

that allow simultaneous PET/​MRI data acquisition and novel data processing methods,
thus catalyzing and reflecting the increased recognition of the interactions between neu-
rochemistry and distributed brain networks.

Advances in functional and dynamic magnetoencephalography

imaging
New horizons for mapping spontaneous neuromagnetic
networks
Magnetoencephalography (MEG) offers a direct measure of neural activity, and enables
mapping of neural activity with a combination of spatial and temporal resolution that
is superior to any other noninvasive neuroimaging modality. This makes MEG ideal for
mapping neural oscillations and their coordination among brain areas (Palva & Palva
2012), which has been proposed as a mechanism supporting dynamic functional interac-
tions among neuronal populations to support cognition and perception (Fries 2015). The
theoretical perspective of understanding brain function through neural oscillations and
their inter-​regional synchrony, together with the technical advantages for mapping such
large-​scale brain networks and dynamics provided by MEG, has opened new frontiers for
understanding distributed human brain function, dysfunction, and development.
Like most human functional brain imaging approaches, much initial research in MEG
focused on how the brain responds under various types of sensory stimulation, or cog-
nitive or motor demands. It has been increasingly appreciated that most brain activity
is comprised of spontaneous background fluctuations rather than task or stimulation-​
dependent activation, or both, and that much can be gleaned by mapping intrinsic func-
tional connectivity at rest (Raichle 2015). It is also becoming increasingly clear that the
dynamics of intrinsic connectivity are highly informative regarding the organization of
brain function (Zalesky et al. 2014). This highlights the advantages of MEG, as the timing
accuracy of MEG enables connectivity dynamics to be measured with millisecond preci-
sion and in fast physiological frequency ranges critically relevant for cognition, percep-
tion, and behavior.

Mapping intrinsic neurophysiological amplitude network

correlations and dynamics
Correlations in slow fluctuations in neuromagnetic amplitudes, particularly in beta
and alpha frequency bands, have been shown to recapitulate many of the resting state
networks previously observed using other imaging modalities such as fMRI (Brookes
et al. 2011). These functional networks, expressed at rest, are also modulated by cogni-
tive activity (Brookes et al. 2012). Graph analysis of resting MEG amplitude correlations
also conform to major anatomical divisions of the brain, with global hubs for different
frequency ranges concentrated in different brain loci (Hipp et al. 2012). Inter-​regional
amplitude correlations have been shown to increase with age throughout childhood
 25

Advances in functional and dynamic magnetoencephalography imaging 25

and adolescent development, particularly in beta and alpha frequency ranges (Schäfer
et al. 2014). EEG studies suggest that such increasing spontaneous electrophysiological
connectivity may be associated with the acceleration of the alpha peak (Miskovic et al.
2015), suggesting that acceleration of spontaneous oscillatory connectivity may lead
to the predominant expression of intrinsic connectivity networks in the beta band in
adulthood.
One important advantage MEG has over fMRI is temporal resolution. This allows map-
ping of the dynamics of intrinsic connectivity networks at faster time scales. For exam-
ple, this approach has been useful for exploring the expression of connectivity in these
networks in the time domain, and for elucidating sequential transitions between relative
dominance of specific intrinsic connectivity networks (Baker et al. 2014). For example,
it has been observed that it is much more likely for there to be a transition between a
default mode network (DMN) dominant state and the predominance of another intrin-
sic connectivity network than it is to transition directly between two non-​DMN resting
state networks, and that these internetwork transitions primarily involve inter-​regional
amplitude correlations in the beta frequency range (de Pasquale et al. 2012). This could be
interpreted as indicating that the DMN serves to shift the pattern of inter-​regional com-
munication of the brain between different functional states. For example, beta-​amplitude
correlations involving the DMN could mediate transitions between a motor-​focused state
supported by the motor network and a spatial attention-​focused state supported by the
dorsal attention network. Another advantage conferred by the millisecond timing accu-
racy of MEG network mapping is the ability to determine that certain networks, such as
the motor network, may actually be comprised of a larger number of subnetworks that
serially express periods of relative predominance (O’Neill et al. 2015). Notably, expres-
sion of local neuromagnetic spectral power has been shown to have clinical utility for
detecting and characterizing conditions such as mild traumatic brain injury (Huang et al.
2014). Recent observations that inter-​regional amplitude correlations are altered in mild
traumatic brain injury and associated with cognitive and affective symptoms in this group
(Dunkley et al. 2015) buttresses the hope that this type of connectivity measure may also
hold future clinical applicability.

Spontaneous phase synchrony in neuromagnetic networks and its

alteration in brain disorders
In addition to mapping of amplitude correlations in spontaneous MEG, another domi-
nant approach has been to measure inter-​regional phase locking, which is typically inves-
tigated at faster time scales. It has been proposed that the slower amplitude correlations
are more closely related to underlying structural brain connectivity, whereas phase–​phase
relations encode more transient cognitive and/​ or computation specific information
(Engel et al. 2013). Though much remains to be discovered regarding the relevant roles
of amplitude and phase coherence, it is worth noting that spontaneous phase locking
effects are often observed at high gamma frequencies that are much more spatially refined
(Jerbi et al. 2009) and have been proposed to play a more computational role relative to
26  2

26 Emerging neuroimaging technologies

oscillations at lower frequencies (Fries 2009). Phase and amplitude should not be viewed
as independent in this context, however, as inter-​regional correlations in cross-​frequency
phase amplitude coupling in spontaneous MEG has also been shown to correspond to
resting-​state networks first identified using fMRI (Florin and Baillet 2015).
Spontaneous neuromagnetic phase locking has been particularly successful for cap-
turing atypical connectivity in neurological and neuropsychiatric populations, adding
to the emerging network perspective on neurological disorders (Stam 2014), and add-
ing credence to the notion that brain oscillations and their coherence may constitute a
type of neural syntax for information processing and communication that is critical for
understanding the brain basis for psychiatric disorders (Buzsáki and Watson 2012). For
example, it has been shown that resting-​state MEG synchrony is altered in post-​traumatic
stress disorder (Dunkley et al. 2014). Source mapping of such atypical neural synchrony
has demonstrated that such altered neural synchrony prominently involves areas such
as amygdala and hippocampus, and is associated with symptom severity as well as asso-
ciated cognitive and affective sequelae (Dunkley et  al. 2014). An exhaustive review of
atypical resting MEG phase synchrony is too long for the present chapter, but it appears to
be relevant for a broad array of conditions including neurodegenerative diseases such as
Alzheimer’s disease (de Haan et al. 2012), movement disorders such as Parkinson’s disease
(Berendse & Stam 2007), and epilepsy (Elshahabi et al. 2015), suggesting that such mea-
sures are tapping a fundamental aspect of neuronal communication and its disruptions
in brain disorders.
Electroencephalographic research using a large sample has demonstrated reorganiza-
tion of spontaneous network phase synchrony during child development (Boersma et al.
2011). Clinical child populations have been shown to express characteristic alterations in
spontaneous MEG synchrony. Children with dyslexia have been shown to exhibit atypi-
cal neural synchrony, which was also shown to be associated with language difficulties
(Dimitriadis et al. 2013). Frequency-​and network-​specific resting neuromagnetic phase
synchrony have been reported in adolescents with autism (Ye et  al. 2014), and altered
MEG synchrony has also been reported autistic children (Kikuchi et al. 2015). Such alter-
ations of inter-​regional MEG synchrony have been related to autistic symptomatology
(Kitzbichler et al. 2015). Spontaneous MEG synchrony has been shown to be reduced in
school-​age children born very preterm across multiple physiologically relevant frequency
ranges (Ye et al. 2015), which may be related to well-​characterized alterations in white
matter development in this group (Pannek et al. 2014).

Bright future through big data? Toward quantitative

translational MEG
Increasing emphasis in neuroimaging is being placed on the importance of large sam-
ple sizes to improve the accuracy and reproducibility of findings. This will be aided by
large open source databases of resting state MEG recordings. For example, the Human
Connectome Project will provide hundreds of such scans with accompanying high qual-
ity structural and functional MRI data (Larson-​Prior et  al. 2013). Open source data
 27

Advances in functional and dynamic electroencephalography imaging 27

repositories more explicitly focused on MEG such as “OMEGA” will also help to provide
large samples of MEG data collected across multiple centers (Niso et al. 2016). Hope is
increasing that big data in neuroimaging, combined with techniques such as machine
learning, will provide new translational opportunities for diagnosis and predicting treat-
ment response with sufficient sensitivity and specificity to enable translation (Deco and
Kringelbach 2014). Major future trends in resting MEG network mapping will likely
include mapping normative networks, their development and relation to function,
together with how such refined population data could be used for detection of neural
network abnormalities and to guide treatment and rehabilitation for those suffering from
disorders of the brain.

Advances in functional and dynamic electroencephalography

imaging
From identification of neural sources of electrical activity
to fast neural network dynamics
Functional imaging involves describing how the brain implements sensory, perceptual,
cognitive, motor, and emotional processes at several scales of space and time. Functional
MRI is efficient at doing this at several spatial scales but only at time scales from several
seconds to several minutes; MEG can do a great job at shorter time scales of tens of mil-
liseconds to seconds, and at spatial scales comparable to those of fMRI, but it is expen-
sive and not portable. Arguably the greatest promise for bedside functional imaging is
provided by current and near-​future electroencephalography (EEG) technologies. It is
relatively inexpensive, portable, and operates at time scales of tens of milliseconds. Its
major drawback, spatial inaccuracy, is being addressed by new techniques of data analysis
and recording technology. Here we describe recent advances and promise for this elderly
technology that is being reborn.
Electroencephalography has been used in medicine for diagnosis of epilepsy foci, for
example, for many years. These uses will continue, but EEG is now poised to contribute
significantly to the growing knowledge of the fast dynamics of brain networks and their
vicissitudes in challenged brains. First, new techniques of data analysis allow increasingly
accurate identification of the neural sources of electrical activity recorded at the scalp by
EEG. Independent component analysis (ICA) coupled with single dipole fitting (Delorme
et al. 2012) has successfully recovered specific brain loci, associated with perceptual and
cognitive processing, that have been previously identified by fMRI (e.g., Bedo et al. 2014).
Similarly, beamformer analysis can perform this function well when applied to EEG data
(e.g., Doesburg et al. 2009; Green et al. 2011). Moreover, some of the sources of inaccurate
localization can be removed by using a wearable, dry, rigid electrode array rather than one
that flexes or requires wet electrolytes, or both (e.g., Mullen et al. 2013). The latter paper
also presents evidence that ICA can remove much of the movement-​related artifact that
plagues all neuroimaging techniques. Similarly, ICA also can be used to remove the arti-
facts generated by tiny shivers and so on of the muscles around the eyes, head, and neck
28  2

28 Emerging neuroimaging technologies

(electromyography (EMG)) (Fitzgibbon et  al. 2016). Thus, EEG is becoming a cleaner
neuroimaging technique that can begin to approach the more expensive fMRI and MEG
results, but more flexibly and at much less expense.
Second, the fast time scale at which EEG can be recorded allows the analysis of
moment-​to-​moment dynamics in the neural networks that support cognition, emotion,
and behavior. Two currently available techniques are especially useful in this regard.
Various synchronization indices are available to measure phase synchronization of oscil-
latory neural activity. The first evidence of neural oscillations recorded by EEG was the
alpha wave (around 10 Hz; Berger 1929). Since then oscillatory activity in several fre-
quency bands has been closely associated with perceptual and cognitive processes (e.g.,
Varela, et al. 2001; Ward L.M. 2003). Phase synchronization between oscillations at the
same or different frequencies is an indication of functional coupling between the brain
areas generating the oscillations. Although the most direct evidence for such functional
coupling comes from studies with implanted electrodes (e.g., Lewis et al. 2016), EEG data
treated with advanced analysis techniques can also detect transient functional connectiv-
ity between neural sources at fast time scales of tens of milliseconds (e.g., Doesburg et al.
2009; Bedo et al. 2014) (Figure 2.1). In addition, new techniques of measuring directed
information flow between oscillatory sources, such as transfer entropy (Schreiber 2000;
Vicente et al. 2011; Wibral et al. 2011) and phase transfer entropy (Lobier et al. 2014), can
actually allow us to make (weak, or Granger-​type) causal inferences about interactions
between brain areas, for example, in reading (Bedo et al. 2014). Finally, when there are
competing network topologies or interaction models based on previous data, dynamic
causal modeling can be applied to choose the most useful model (Friston et al. 2003).
There are still significant limitations to be overcome, however. One of the most impor-
tant is the inability of EEG to visualize subcortical areas—​MEG also is not good at this,
but fMRI does it well. Thus, it will be important to develop linkages between fMRI and
EEG/​MEG results to allow inferences of fast dynamics from fMRI when subcortical brain
regions are heavily involved. This is especially important for the thalamus, which is impli-
cated in nearly every brain operation and network (Ward L.M. 2013). Another limita-
tion is the relatively low signal to noise ratio enjoyed by EEG. Measures to increase this,
such as ICA, have been successful, but still more is needed. Synchronization and transfer
entropy analysis suffer particularly from this problem and new methods of filtering out
the noise are needed. But even given what is now available it should be possible to use
EEG both to characterize normal fast dynamics in neural networks, and to discover how
aberrations in these networks can lead to dysfunction. Of course, it will then be neces-
sary to decide what actions to take to ameliorate or rehabilitate these dysfunctions. The
neuroimaging techniques will help point to the necessary treatment foci, and they can
help assess whether the applied treatment has succeeded. But they will not answer the dif-
ficult ethical problems given rise to by the knowledge of the source or extent or cause of
a brain dysfunction, especially if treatment is expensive, risky, or impossible. This is par-
ticularly true for EEG-​facilitated discoveries of residual functions, and even indications
  29
0–100 100–200 200–300 300–400 400–500 500–600 600–700 700–800 800–900
theta

(a) Theta PLVs

(All ROIs)

(b) Theta PLVs

(vOT)

(c) Theta
Transfer
Entropy (vOT)

(d) Gamma
PLVs
(All ROIs)

(e) Gamma
PLVs (vOT)

(e) Gamma
Transfer
Entropy
(vOT)
gamma

Figure 2.1  (See also color plate section.) Example of dynamic EEG synchronization and transfer entropy results from a word reading task. Synchronization
was measured with phase locking value (PLV), and narrow band transfer entropy was measured using an adaptation of the Kullback entropy (for vOT
to/​from other areas only). Theta band is 3–​7 Hz and gamma band is 35–​45 Hz. Black lines (arrows) indicate significant interaction (directed information
flow) between the connected reading-​related brain areas during the time period (ms after stimulus presentation) indicated at the top of the figure. vOT
indicates ventral occipital-​temporal brain region, the putative word-​form area.
Reproduced from Bedo N, Ribary U, and Ward LM. (2014) ‘Fast dynamics of cortical functional and effective connectivity during word reading’, PLoS ONE, Volume 9, Issue 2, e88940,
doi:10.1371/​journal.pone.0088940, Copyright © 2014 Bedo et al. Reproduced under the terms of the Creative Commons Attribution Version 4.0 International (CC BY 4.0), https://​
creativecommons.org/​licenses/​by/​4.0/​.
30  3

30 Emerging neuroimaging technologies

of conscious processes, in severely compromised brains, such as those of patients with

unresponsive wakefulness or minimal consciousness (e.g., Cruse et al. 2011).

Applications and challenges in clinical neuroimaging: Localization

and synchronization
As scientists, we are ethically responsible to conduct the necessary basic research to be
able to take the next steps in conducting clinical research. With the growing interest in
personalized healthcare, we need to provide tools that allow clinicians to make diagnosis
and recommend management options at the individual patient level. Many neuroimag-
ing tools exist (MRI, fMRI, PET, MEG, EEG, near infrared spectroscopy, etc.) and many
are clinically used to screen, diagnose, and/​or prognosticate many types of neurological
diseases and disorders (e.g., epilepsy, schizophrenia, dementia, and dyslexia). Several of
these neuroimaging methods have a long history of clinical use, while other methods have
a more recent history. The literatures on these different neuroimaging methods are exten-
sive and beyond the scope of this brief communication to be able to cover them in any
great depth. Therefore, we very briefly highlight one neuroimaging method, the auditory
event-​related potential (ERP), that is used to assess sensorineural hearing loss and neuro-
logical disorders (e.g., vestibular schwannoma screening). We do this in order to stress the
ethical responsibility of the scientific community to conduct basic and clinical research
on neuroimaging tools that can be easily and effectively used clinically. We then go on to
briefly discuss the importance of thoroughly investigating and validating neuroimaging
methods prior to recommending their use clinically. We provide an example from our
recent methodological work in beamformer source modeling and its role in functional
connectivity imaging to emphasize this point.
Auditory ERPs directly reflect the electrical signal generated from neural responses
in the auditory system and thus can be used as a neuroimaging tool. One example
of an auditory ERP that is used clinically is the auditory brainstem response (ABR).
Testing of ABR has been used for screening and diagnosing sensorineural hearing loss
in infants for many years (see Picton 2011, pp.213–​246, pp.449–​492). This testing is
based on decades of basic research that helped inform clinical researchers to investi-
gate its utility in evaluating hearing function in humans across all ages. The ABR is
commonly used to assess hearing thresholds in infants because infants younger than
8 months old are unable to provide reliable behavioral responses (i.e., raising a hand to a
sound). The reason for using ABR to evaluate infant hearing thresholds is that research
showed that detection of a hearing impairment in infants by 3 months of age and inter-
vention by 6 months of age significantly improves the child’s later language develop-
ment (Yoshinaga-​Itano et al. 1998, 2000). Beginning in the 1990s, another ERP method
called the 80 Hz auditory steady-​state response (ASSR) was suggested to improve hear-
ing diagnostics because they could be a faster, more reliable, and more objective test
of hearing thresholds in infants (see Picton 2011, pp.285–​334). However, this excite-
ment diminished because basic research helped inform the scientific community that
ASSR testing of infant hearing was as reliable as the gold-​standard ABR method but
 31

Advances in functional and dynamic electroencephalography imaging 31

ASSR testing had a noteworthy caveat; artifactual responses could be elicited at high
sound intensities. This would lead to falsely indicating that individuals with profound
sensorineural hearing loss had residual hearing. In other words, ASSRs would show
residual hearing in individuals who were known to have no residual hearing. Although
ASSR testing is not recommended currently for diagnostic hearing threshold testing
in infants, enough basic and clinical research was conducted to provide evidence for
its use as a tertiary-​stage hearing screening tool. In addition, research is continuing
to identify other potential clinical uses of ASSR in evaluating hearing functions (see
Picton 2011, pp.320–​325).
Neurological ABR testing is another auditory ERP method that is used clinically to
screen for vestibular schwannomas (aka acoustic neuromas; Selters & Brackmann 1977;
see also Picton 2011, pp.500–​505). Although neurological ABR testing is not a spatial
neuroimaging method for detecting tumors, it is a useful neuroimaging method for
detecting delayed or disrupted neural communication along the auditory pathway (i.e.,
between the cochlear nerve and brainstem nuclei). There are clear guidelines and norma-
tive data collected in non-​clinical and clinical populations (Stockard et al. 1978; Chiappa
et al. 1979; Campbell et al. 1981). This evidence has informed researchers and clinicians
about the validity of ABR to screen for tumors and brainstem lesions along the audi-
tory pathway. Importantly, clinical research has clearly identified that the sensitivity and
specificity for neurological ABR in detecting 1–​2 cm tumors are 90–​100% and 60–​75%,
respectively (see Picton 2011, p.503). Notably, this performance is based on large samples
of patients. The tumor-​detection performance of the ABR led early researchers to rec-
ommend that it was a good screening tool for discriminating between individuals with
and without retrocochlear pathologies (e.g., vestibular schwannomas). As MRI became a
more prevalent neuroimaging tool and its diagnostic performance was to be superior to
ABR, MRI became the recommended tool for screening and diagnostics. However, the
financial expense of MRI precluded much of its use as a screening tool (until recently)
and when MRI is contraindicated in certain populations (e.g., patients with cardiac pace-
makers). Thus, neurological ABR is still routinely used as a screening tool before using
more expensive MRI diagnostic methods or when MRI is contraindicated. When MRI
testing is available, MRI screening is recommended over ABR screening because of the
added benefits of better sensitivity and better ability to identify the etiology of auditory
pathology (Fortnum et al. 2009). However, a current challenge for using MRI as a screen-
ing tool is that MRI testing facilities typically reside only in major urban areas, which
add barriers and costs to providing healthcare in rural communities. Neurological ABR
testing, on the other hand, is easily performed in any clinical setting with significantly less
expensive equipment as compared to a MRI scanner. Thus, screening in rural communi-
ties using neurological ABR and then referring patients for MRI testing in urban areas
can be more cost-​effective and easier for the patients and healthcare system. The history
of basic and clinical research for using ABR and MRI to diagnose retrocochlear patholo-
gies highlights the importance of initial and continued validation of using neuroimaging
tools for clinical purposes (see Fortnum et al. 2009). This evidence inevitably reduces the
32  3

32 Emerging neuroimaging technologies

uncertainty that clinicians often face when making decisions about diagnoses, prognoses,
and management.
These brief historical accounts of using auditory ERPs showcase some of the basic prin-
ciples that are needed for recommending clinical uses of specific neuroimaging tools.
Some of the basic challenges to the tests are to determine (1) specific validity and reli-
ability relating to technical algorithms used; (2) diagnostic performances relating to the
applications on pathological subpopulations (e.g., sensitivity, specificity, predictive value);
and (3)  cost-​effectiveness and cost-​utility (Medina et  al. 2013, pp.3–​18). The histories
of using auditory ERPs to diagnose hearing loss and screen for tumors are interesting
with respect to how neuroimaging can be used as tools for screening and diagnosing sen-
sory and neurological impairments. These histories are also a reminder of the diligence
required to sufficiently evaluate and validate neuroimaging tools in order to recommend
their use in healthcare at single-​patient and population-​based levels.
Validating the neuroimaging tools from a methodological point of view is essential
before recommending their use for clinical purposes. One major goal of methodological
research in neuroimaging is to improve our ability to confidently identify local and global
brain function. For example, we are investigating the reliability of specific neuroimag-
ing analyses to localize the neural generators underlying EEG and MEG and to identify-
ing the neural communication within the human brain. However, some recent caveats
have come to light that we are currently investigating and attempting to overcome. Here
we highlight one of the major challenges in neural communication analyses of EEG and
MEG data (aka functional connectivity analyses). We briefly present this research here to
illustrate the point that basic methodological research is highly important before using
tools for clinical purposes. A major challenge in functional connectivity analyses is mak-
ing sure that the brain regions (aka, sources) under investigation do not contain activity
from other brain regions because of the inherent physics of the neuroimaging measure
or the mathematics underlying its analyses, or both. When using some neuroimaging
tools and analyses, nearby (<20 mm) brain regions can contain a mixture of signals that
are separately generated from different brain regions. This is known as source mixing
and can lead to false conclusions regarding how these regions are functionally connected
and how they communicate information among themselves (Sekihara & Nagarajan 2015).
Traditional beamforming and minimum-​norm source modeling methods (Van Veen &
Buckley 1988; Hamalainen & Ilmoniemi 1994; Van Veen et al. 1997; see also Sekihara &
Nagarajan 2015, ­figure 2) cannot avoid source mixing where neighboring sources will be
modeled to contain contributions of each other’s activity. Unfortunately, this source mix-
ing can generate deceptively false oscillatory phase-​coherence between sources; thereby
causing misleadingly strong inter-​source connectivities (i.e., type I errors). To overcome
this source-​mixing challenge, different connectivity measures of phase-​coherence (e.g.,
phase-​lag index or imaginary-​phase coherence) (Stam et  al. 2007; Ewald et  al. 2012;
Sekihara and Nagarajan 2015) have been suggested and implemented with some success.
However, these compensatory algorithms become increasingly blinded to identifying true
connectivities as inter-​source phase differences approach zero (type II errors). Another
 3

Advances in functional and dynamic electroencephalography imaging 33

method to overcome the possible type I errors of source mixing is to average across many
participants. However, this often leads to type II errors or spatial smearing of the con-
nectivity maps because individual participant’s inter-​source connection pairs usually do
not exactly line up spatially across participants brains. Moreover, providing personalized
healthcare would require neuroimaging tools to provide reliable connectivity maps at the
individual patient level, not at the population level. Overall, source mixing leads to tra-
ditional beamformers being less sensitive and less specific to detecting true functional
connections in local networks. Thus, to be able to confidently evaluate functional connec-
tivity among locally connected brain regions in individual patients, we need better tools
that minimize or negate source mixing (Figure 2.2).
Multiple constrained minimum-​ variance (MCMV) beamforming (Moiseev et  al.
2011)  is one such neuroimaging method that overcomes source mixing. The MCMV
beamformer technology mathematically constrains the sources to be independent of each
other; thereby, preventing source mixing (see Figure 2.2; for mathematical proofs and
methods see Moiseev et al. 2011 and 2013). Figure 2.3 demonstrates the ability of MCMV-​
connectivity analyses to accurately resolve network connectivity in real EEG data by over-
coming source mixing among nearby brain regions. Phase-​locking connectivity maps
(Lachaux e al. 1999) using traditional LCMV beamformers revealed significantly strong
alpha-​band (9–​10 Hz) synchronization (red lines) among nearby sources in the posterior
left visual network (Figure 2.3, left brain map). However, when analyzed using a MCMV
beamformer, the connectivity map for these nearby sources had significantly larger alpha-​
band desynchronizations (blue lines; Figure 2.3, right brain map). The MCVM results in
Figure 2.3, are likely the more valid result because the EEG data analyzed were from a
visual discrimination task and from a post-​stimulus interval (380 ms) where event-​related
desynchronization in the scalp recordings occurred. In addition, this interval is well
known to contain event-​related desynchronizations over occipital scalp regions. Thus, it
is highly unlikely that the local visual network would be synchronized within this inter-
val as revealed by the traditional LCMV beamformer. Therefore, the LCMV connectivity
map on the left is likely showing false synchronizations among nearby posterior visual
sources due to source mixing. Given the advantage of MCMV beamforming not having
source mixing, we can now be more confident that our results of local functional connec-
tions represent the true underlying functional connectivity. By combining MCMV beam-
forming with functional connectivity measures (such as phase-​locking values (Lachaux
et al. 1999)), we can significantly enhance our ability to image local and global network
connections. This will further improve the validity of our results obtained from network
graph-​theory analysis (Sporns 2003). Overall, thoroughly investigating and validating our
methods will enhance our ability to accurately represent the local and global network
dynamics underlying the EEG and MEG recorded from individual patients.
This brief overview of ABR testing provided examples of how basic research has pro-
vided suitable evidence for using neuroimaging tools for clinical purposes. In addition,
continued research in validating neuroimaging analyses (such as source modeling meth-
ods) is essential so that we can obtain the most confident and accurate depiction of brain
 34
Source waveforms Fast-Fourier Transform
Anterior 25
LCMV

Source Amplitude
50 20 MCMV

Amplitude |y(f)|
16-Hz Mixing

(nAmp)
15
0
10

–50 5

0
0 50 100 150 200 0 10 20 30 40 50 60
Time (ms) Frequency (Hz)
25
LCMV
50 20

Amplitude |y(f)|
MCMV
Amplitude
(nAmp) 15 36-Hz Mixing
0
10

–50 5
LH RH 0
Posterior
0 50 100 150 200 0 10 20 30 40 50 60
Time (ms) Frequency (Hz)
Figure 2.2  (See also color plate section.) EEG localization and connectivity accuracy. Left panel shows a simulated source location (blue square) that
had only a 16-​Hz oscillation and a neighboring (within 15 mm) source location (red square) that had only a 36-​Hz oscillation. Source mixing of 16-​
and 36-​Hz oscillations were clearly visible in the traditional beamformer (LCMV) reconstructed source waveforms (blue and red lines; middle panel).
Amplitude spectra (right panels) showed that both red and blue LCMV sources contained energies at 16 and 36 Hz (i.e., source mixing). Because of
this source mixing, phase-​coherence between the sources existed and functional connectivity was falsely revealed (green line; left panel). Our MCMV
beamformer (black lines), however, prevented source mixing. MCMV sources only had 16-​Hz (lower panels’ black lines) or 36-​Hz oscillations (upper
panels’ black lines). Obviously, false-​connections were not found for the MCMV beamformer.

 3
 35

Advances in brain imaging signal processing 35

Anterior

LH RH

Figure 2.3  (See also color plate section.) Challenge in EEG connectivity maps. Traditional LCMV-​
beamformer connectivity map (left) for alpha-​band (9–​10 Hz) revealed highly synchronized (red
lines) local couplings in visual cortices at 380 ms after letter onset. However, MCMV-​beamformer
connectivity map (right) revealed strongly desynchronized (blue lines) couplings. The MCMV-​
connectivity maps fit better with known event-​related desynchronizations that occur after a visual
stimulus onset for this band and latency. Thus, the MCMV map is likely the real map.

function. It is imperative that basic and clinical researchers work together to provide cli-
nicians with strong evidence that validates new neuroimaging tools in order to improve
patient care.

Advances in brain imaging signal processing

In past years, the main focus of analysis of brain signals was on studying responses of indi-
vidual brain areas, associated with certain functions, to external stimuli. More recently,
however, this focus shifted to investigating interactions between a large number of brain
regions, often functionally connected with each other, in both task-​related environments
and in the case of resting state brain activity. As a consequence, modern processing meth-
ods are more oriented on analysing large sets of correlated and interacting brain sources,
rather than on individual ones.
Such analyses in MEG/​EEG brain imaging, which we broadly call brain network or con-
nectivity analyses, typically involve the following steps. First, an inverse problem must be
solved, which means reconstructing signals from specific locations within the brain, using
data from physical MEG/​EEG sensors, located outside the brain. Second, connectivity
(or interaction) between different areas should be estimated. Third, this connectivity data
should be statistically evaluated, to detect true connections and discard spurious ones. Let
us briefly discuss each step in more detail.
Start with the source reconstruction. There are several methods to solve the inverse
problem, which are popular in MEG/​EEG community (Baillet et  al. 2001). An impor-
tant example that we will consider here is called minimum variance beamformer solution
36  3

36 Emerging neuroimaging technologies

(Van Veen et al.1997; Robinson & Vrba 1999; Sekihara & Nagarajan 2008), but similar
considerations apply to other methods. Technically, the original beamformer solution was
developed assuming that electromagnetic field registered by the sensor array is produced
by a single brain source of interest, plus noise. This is called a single-​source beamformer
approach. Of course in reality even performing very simple tasks engages many brain
areas, and consequently many sources are simultaneously activated. It turned out though
that single-​source beamformer, applied to each source individually, is still quite success-
ful in locating and reconstructing multiple active sources, as long as they are not too
close to each other and their correlations are negligible. However, if sources are close or
they are strongly synchronized, or both, localization accuracy and spatial resolution of
the beamformer degrades. Besides, reconstructed signals become contaminated with arti-
factual contributions from other brain areas. This phenomenon is called source leakage.
To overcome these problems, more advanced multisource beamforming methods were
developed (Dalal et al. 2006; Hui et al. 2010; Moiseev et al. 2011; Moiseev and Herdman
2013). In particular, these methods allow for strong interactions (correlations) between
the sources, and they take care of signal leakage by rejecting any direct contributions from
one reconstructed signal to another.
The next step is estimating connectivity between the brain signals. No matter which
one of many known measures of synchronization between signals is applied (Lachaux
et al. 1999; Palva & Palva 2012; Vinck et al. 2011; Schoffelen & Gross 2009), it is impor-
tant to ensure that such synchronization is not artificial, occurring, for example, due to
the common noise components in the signals, or due to the signal leakage. One possible
way to achieve that is to use connectivity measures that are insensitive to correlations
between signals, which have no time delay. Linear mixing due to leakage involves no
time delay; therefore, measures in question are immune to those artifacts. The flip side of
this approach is that these measures are almost insensitive to connections with time lags
that are small compared to the time period of the signal frequency. Consider an alpha
frequency, for example. Its period is around 100 ms, therefore in the alpha range, connec-
tions with physiologically feasible propagation delays of several or even 10–​20 ms may
not be detected. An alternative way to exclude spurious connectivity due to linear mixing
is to eliminate the leakage at the very beginning—​that is, at source reconstruction step. In
this case, a broader set of connectivity measures, including those sensitive to zero-​delay
connections, can be applied. This is where the multisource beamformers become handy,
because direct leakage from one source to another is rejected.
The third step in the analyses consists of recognizing distinct groups of interacting brain
regions, or brain networks, based on the connectivity data. The difficulty here is that the
number of possible pairwise connections between different regions is usually very large,
while existence of each connection can only be established with certain probability (say,
95%)—​in other words, involves statistical error. It follows then that some of the found
connections will be not real, occurring simply because of random fluctuations. For exam-
ple, suppose we consider locations corresponding to approximately 50 known Brodmann
areas. The number of possible pairwise connections between those is around 1200. If our
 37

Advances in brain imaging processing and visualization 37

statistical error per connection is 5%, then around 5% of all detected connections—​say,
50 or 60 connections—​will be false, and there is no way to distinguish between the real
and spurious connections. The situation we described is called a “multiple-​comparisons
problem” in statistics (Shafer 1995). There is no general way to overcome the multiple
comparison problem. Depending on specific situation, different approaches can be used.
Here we will just mention a few popular ones.
The most straightforward approach is to try to reduce the number of statistical tests
(comparisons) using prior knowledge. For example, if one can limit the number of brain
areas to look at from 50 to 5 based on neurophysiological considerations, the number of
pairwise connections will go down from approximately 1200 to 10. Then by limiting sta-
tistical error for each pair to 0.5%, one can guarantee with 95% certainty that all detected
connections are the true ones. When such reduction of the number of connections is not
possible, another useful approach is to apply statistical tests pertaining to (sub)networks
as a whole rather than to individual connections. For example, one can look at subsets,
or “clusters” of locations with mutual connectivity values above a certain threshold. The
probability of such a cluster to occur by chance can be estimated (Zalesky et al. 2010), and
if it is small enough, one can argue that the locations involved constitute a brain network.
This way, interconnected brain areas can be identified in spite of the curse of multiple
comparisons, even though it might be not possible to make conclusions about individual
pairwise connections within the network. Another method is to consider a set of areas
strongly connected to a single location (a seed point) to form a separate network (Brookes
et al. 2012). Yet another set of approaches involves representing a signal from each loca-
tion as a linear combination of a certain number of uncorrelated or statistically indepen-
dent components (so-​called principal or independent component analysis). When any
such component mostly consists of contributions from a well-​defined, distinct subset of
locations, one can argue that corresponding areas operate synchronously and constitute a
single network (Luckhoo et al. 2012; Whitman et al. 2016).
In summary, we discussed how the focus on interactions and connectivity within the
human brain affected MEG/​EEG analyses of brain signals. We showed that new, more
sophisticated signal processing techniques were developed to deal with the new chal-
lenges. However, this journey is far from over, and we need more novel, even more
advanced techniques to emerge in this field in coming years to further improve the qual-
ity of brain connectivity analysis.

Advances in brain imaging processing and visualization:

Interpretation of diffusion MRI for the brain
As advances have been made in brain imaging techniques, the quantity and complexity of
the outputted images has also increased, leading to data visualization and interpretation
challenges, challenges most prominently seen in the area of diffusion MRI (dMRI) (Booth
& Hamarneh 2015). In dMRI, image sequences are used to measure, non-​invasively and
in vivo, the rates of molecular diffusion in the brain. This diffusion is impeded by cell
38  3

38 Emerging neuroimaging technologies

structure in such a way that fibrous tissue (e.g., white matter) shows a maximal rate of dif-
fusion along the direction of the fibers (Stejskal & Tanner 1965; Le Bihan & Breton 1985).
Uncovering these directions of maximal diffusion—​and therefore the fiber directions—​
requires the use of diffusion-​sensitizing gradient pulses to sample diffusion along tens, or
even hundreds, of directions (as in high angular resolution diffusion imaging, e.g., Q-​ball
imaging) (Tuch 2004). The result is a high-​dimensional 3D image with a (fiber) orienta-
tion distribution function (Tournier et al. 2007) at each voxel—​an image that is difficult
to manually examine and interpret.
Initial attempts to visualize dMRI datasets revolved around reducing their dimension-
ality to a single scalar-​valued image by computing statistics across the sampled diffusion
directions. By computing the mean and variance in diffusion across the sample direc-
tions, we obtain the commonly used mean diffusivity (MD) and fractional anisotropy
(FA) measures (Figure 2.4a, b). The MD is sensitive to the amount of cell structure present
while the FA is sensitive to how fibrous the tissue is. It is also common to see the FA image
color-​coded to show the directions of maximal diffusion, which approximate the fiber
directions (Figure 2.4c). Other scalar measures include radial, axial, and relative diffusiv-
ity; linear, planar, and sphericity measures; mode; and volume ratio (Westin et al. 2002).
Finally, it has also become customary to reduce the dimensionality of a dMRI dataset by
fitting models, at each voxel, to the sampled diffusion measurements. Through the use of
tensors (i.e., DTI) and spherical harmonics (SPHARM) (Basser et al. 1994: Jian & Vemuri
2007), we can reduce the dimensionality of a dMRI dataset, from the number of diffusion
samples to the much lower number of parameters of the model, thus facilitating visualiza-
tion (Figure 2.4d).
More recent work has looked at producing dMRI visualizations that highlight dif-
ferent geometric properties. For example, recent work has led to color visualizations
of dMRI datasets that match the perceptual differences in color to the real differences
in measured diffusion (Figure 2.4e) (Hamarneh et al. 2011). Other works have looked
at extracting regions of interest—​usually axon bundles—​from a dMRI scan through
the use of specially-​designed structure detectors (Figure  2.4f) (Nand et  al. 2011)  or
segmentation techniques (Figure 2.4g) (Hamarneh & Hradsky 2006; Weldeselassie &
Hamarneh 2007; Booth & Hamarneh 2013). Similarly, those regions of interest can
also be detected through the use of image registration. By aligning two dMRI scans
and examining the differences in the image data at the level of individual voxels, we
can flag regions of interest where the scans differ (Figure  2.4h) (Smith et  al. 2006;
Booth et al. 2016). In all of these techniques, the high-​dimensional dMRI scan under-
goes multiple processing steps in order to generate the visualization. As a result, vari-
ous mathematical models have had to be extended to account for the dMRI’s high
dimensionality and to ensure that its measured diffusion values remain positive (Booth
& Hamarneh 2011a). Further, these processing and analysis techniques benefit from
pre-​processing algorithms that remove imaging noise (Hamarneh & Hradsky 2007;
Nand et al. 2012) and ones that capture relations between neighboring voxels (Booth
& Hamarneh 2011b).
 39

Advances in brain imaging processing and visualization 39

Figure 2.4  (See also color plate section.) Examples of visualizations associated with diffusion
MRI (dMRI) data. Some visualizations highlight the brain’s diffusion properties (a–​e), while
others highlight its geometric properties (f–​h), while still others highlight brain connectivity
(i–​l). See the text for a description of each visualization technique: (a) mean diffusivity (MD);
(b) fractional anisotropy (FA); (c) color-​coded FA; (d) ellipsoidal visualization of diffusion tensors;
(e) perceptual color visualization of diffusion tensors; (f) tubular structure detection in dMRI;
(g) dMRI segmentation of corpus callosum (above) and the cingulum (right), visualized in 2D and
3D respectively; (h) dMRI image difference overlaid on MD image; (i) streamline tractography;
(j) visualization of tract confidence regions; (k) a connectome visualized as a circular graph; (l) a
connectome overlaid on a brain silhouette.

The most appealing aspect of dMRI may be its unique ability to examine structural
connectivity within the brain. As dMRI can identify the direction of tissue fibers, in a
process called tractography (Mori & van Zijl 2002; Booth & Hamarneh 2012), we can
trace out 3D curves called streamlines that estimate the location of white matter axonal
40  4

40 Emerging neuroimaging technologies

pathways, thereby uncovering connections between different brain regions. Tractography

techniques range from streamline-​based techniques (Figure  2.4i) to probabilistic tech-
niques that capture the uncertainty in the fiber tract location (Figure 2.4j) (Brown et al.
2013a, 2013b). Recently, groups have begun summarizing the structural connections
tractography uncovers by building networks known as connectomes (Sporns et al. 2005).
In a connectome, nodes are defined as functional regions in the brain (usually identified
by registering a labeled atlas to the dMRI scan under evaluation) and weighted edges are
placed between nodes based on how strongly connected the tractography results show the
regions to be. Visualizing connectomes remains an area of open research, but two com-
mon approaches include the use of circular graphs (Figure 2.4k) and spatially overlaying
the network’s properties onto a brain image (Figure 2.l) (Brown et al. 2014).
While the visualization techniques presented here provide the ability for a human
operator to examine and interpret a high-​dimensional, complicated dMRI dataset, the
value of these visualization techniques can be further strengthened by having comple-
mentary automated computational methods that identify which features or aspects would
be most valuable to visualize. Recently, researchers have begun using machine learning
algorithms (e.g., support vector machines, decision forests, or deep neural networks) to
model relationships between the image data and clinical variables of interest. By coming
up with a model for this relationship, we identify regions in the images, or edges in the
connectomes, that are the most important to the model. We then visualize these image-​
based features using the above techniques. For example, Figure 2.4j shows the presence of
abnormal geometry in a fiber bundle, while Figure 2.4h highlights voxels that are signifi-
cantly different between a subject’s scan and a healthy population, and Figure 2.4k shows
edges in a connectome most predictive of motor outcome in preterm infants (Brown et al.
2015). By using machine-​learning techniques, not only are we able to automatically iden-
tify relevant visualizations, but also seek imaging biomarkers of neurological disorders
(Brown et al. 2015; Booth et al. 2016).

Emerging neurophysiological frameworks for unified

thalamocortical processing
Sensory, motor, and cognitive functions are associated with oscillatory changes within
task-​relevant cortical brain regions, as well as alterations in functional and effective
connectivity between those regions associated with neuronal synchronization (Llinás
& Ribary 1993; Varela et al. 2001; Ward L.M. 2003; Uhlhaas et al. 2009; Wang X.J. 2010;
Ribary et  al. 2014). Recording methodologies with sufficient temporal resolution to
measure fast above 1 Hz neural oscillations, such as EEG and MEG, have shown that
brain dynamics within and between regions often differ markedly across frequencies,
and that brain rhythms often interact across widely separated frequency ranges (Llinás
et  al. 1999; Sauseng et  al. 2008; Doesburg et  al. 2009, 2012; Holz et  al. 2010; Palva
et al. 2010; Palva and Palva 2012). It has further been reported that cross-​frequency
interactions may play an important role in local processing within the thalamus and
 41

Conclusion 41

neocortex, as well as information transfer between them (FitzGerald et  al. 2013).
Strong commonalities in rhythmic network properties have been observed across
recording techniques and task demands, but strong neuroscientific theories to situate
such observations within a unified framework that has direct relevance to the explana-
tion of neuropathologies remain scarce.
Our recent comprehensive review into the animal and human literature indicates
a further thinking beyond synchrony and connectivity and the readiness for more
hypothesis-​driven research and modeling toward unified principles of thalamocorti-
cal processing (Doesburg et al. 2015). We further introduced such a possible emerg-
ing framework:  “the alpha-​theta-​gamma (ATG) switch.” We probed and introduced
this neurophysiological framework to explain how coordinated cross-​frequency and
interregional oscillatory cortical dynamics may underlie typical and atypical brain
activation, and the formation of distributed functional ensembles supporting cortical
networks underpinning sensation and cognition (Doesburg et al. 2015). We also dis-
cussed evidence that alpha-​theta-​gamma dynamics emerging from thalamocortical and
cortico-​cortical interactions may be implicated in cognition across diverse contexts,
and that the disruption of such processes is implicated in numerous neurological and
neuropsychiatric conditions. Moreover, this emerging framework further challenges
the dominant view in current neuroscience on the classical activation of the brain per
se and rather suggests an inhibitory induced dis-​inhibition of intrinsic cortical activity
during sensory and cognitive processing, a novel plausible mechanism to integrating
local and large-​scale brain networks and its related alterations in clinical pathologies
(Doesburg et al. 2015).
Such neuroscientific advances, emerging neurophysiological frameworks, and more
future hypothesis-​driven basic and clinical research and modeling will pose further future
ethical challenges for the implementation of quantitative diagnostic and prognostic strat-
egies into clinical practice according to best practice and the highest ethical standards.

Conclusion
This comprehensive chapter, highlighting advances in multimodal brain imaging,
signal processing, and visualization from related expert perspectives, points to the
next necessary step in cognitive and clinical neuroscience brain imaging, namely to
more basic and clinical research and the quantification of the five-​dimensional human
brain (across 3D space, frequency, and time) in health and disease. In this chapter, we
urge quantification of the biochemical, structural, functional, and dynamic network
connectivity and causality of the brain underlying typical/​atypical sensory and cogni-
tive processing, to establish objective diagnostic neuromarkers for the identification
and better characterization of subtypes of neurological disabilities and pathologies.
In addition, we believe that it is essential to indicate new innovative ways of how
such subtypes can be selectively and optimally targeted with existing or addition-
ally modified neuroscience-​based interventional training programs that exploit brain
42  4

42 Emerging neuroimaging technologies

plasticity with neuropharmacological or neurosurgical interventional strategies, and

that thereby validate and monitor their effectiveness with the highest possible preci-
sion and accuracy across five dimensions. It is incumbent on us, as experts in neuro-
science, and on experts in neuroethics and biomedicine, to proactively consider and
advance the best possible diagnostic evaluation, utilization of criteria, and prediction
of interventional outcome to researchers, educators, clinicians, and healthcare prac-
titioners at large.

Acknowledgments
The co-​authors are listed in chronological order of their contributions:  MacKay and
Rauscher (MRI), Tipper, Giaschi and Woodward (fMRI), Sossi (PET), Doesburg
(MEG), Ward (EEG-​1), Herdmann (EEG-​2), Moiseev (Signal Processing), Hamarneh
and Booth (Processing and Visualization), Ribary, Doesburg and Ward (Emerging
Neurophysiological Frameworks).

References
Baillet, S., Mosher, J.C., and Leahy, R.M. (2001). Electromagnetic brain mapping. IEEE Signal Process
Magazine, 18, 14–​30.
Baker, A.P., Brookes, M.J., Rezek, I.A., et al. (2014). Fast transient networks in spontaneous human
brain activity. Elife, 3, e01867.
Bandettini, P.A., Wong, E.C., Hinks, R.S., Tikofsky, R.S., and Hyde, J.S. (1992). Time course EPI of
human brain function during task activation. Magnetic Resonance in Medicine, 25, 390–​397.
Barth, M., Breuer, F., Koopmans, P.J., Norris, D.G., and Poser, B.A. (2016). Simultaneous multislice
(SMS) imaging techniques. Magnetic Resonance in Medicine, 75, 63–​81.
Basser, P.J., Mattiello, J., and LeBihan, D. (1994). MR diffusion tensor spectroscopy and imaging.
Biophysical Journal, 66, 259–​267.
Basser, P.J., Pajevic, S., Pierpaoli, C., Duda, J., and Aldroubi, A. (2000). In vivo fiber tractography using
DT-​MRI data. Magnetic Resonance in Medicine, 44, 625–​632.
Bassett, D.S., Wymbs, N.F., Porter, M.A., Mucha, P.J., Carlson, J.M., and Grafton, S.T. (2011).
Dynamic reconfiguration of human brain networks during learning. Proceedings of the National
Academy of Sciences of the United States of America, 108, 7641–​7646.
Beaty, R.E., Benedek, M., Silvia, P.J., and Schacter, D.L. (2015). Creative cognition and brain network
dynamics. Trends in Cognitive Sciences, 20, 87–​95.
Beaulieu, C. (2002). The basis of anisotropic water diffusion in the nervous system—​a technical review.
NMR in Biomedicine, 15, 435–​455.
Bedo, N., Ribary, U., and Ward, L.M. (2014). Fast dynamics of cortical functional and effective
connectivity during word reading. PLoS One, 9(2), e88940.
Berendse, H.W. and Stam, C.J. (2007). Stage-​dependent patterns of disturbed neural synchrony in
Parkinson’s disease. Parkinsonism & Related Disorders, 13(Suppl 3), S440–​445.
Berger, H. (1929). Uber das elektrenkephalogramm des menschen. Archiv für Psychiatrie und
Nervenkrankheiten, 87, 527–​570.
Betzel, R.F., Gu, S., Medaglia, J.D., Pasqualetti, F., and Bassett, D.S. (2016). Optimally controlling
the human connectome: the role of network topology. arXiv:1603.05261 [q-​bio.NC]. Available
from: http://​arxiv.org/​abs/​1603.05261 [accessed February 3, 2017].
 43

References 43

Bilgic, B., Pfefferbaum, A., Rohlfing, T., Sullivan, E.V., and Adalsteinsson, E. (2011). MRI estimates
of brain iron concentration in normal aging using quantitative susceptibility mapping. NeuroImage,
59(3), 2625–​2635.
Boersma, M., Smit, D.J., de Bie, H.M., et al. (2011). Network analysis of resting state EEG in the
developing young brain: structure comes with maturation. Human Brain Mapping, 32(3), 413–​425.
Booth, B.G. and Hamarneh, G. (2011a, July). Consistent information content estimation for diffusion
tensor MR images. In Proceedings of IEEE International Conference on Healthcare Informatics,
Imaging and Systems Biology, HISB, 166–​173.
Booth, B.G. and Hamarneh, G. (2011b, April). Exact integration of diffusion orientation distribution
functions for graph-​based diffusion MRI analysis. In: Proceedings/​IEEE International Symposium on
Biomedical Imaging: From Nano to Macro. IEEE International Symposium on Biomedical Imaging,
935–​938.
Booth, B.G. and Hamarneh, G. (2012, January). Multi-​region competitive tractography via graph-​based
random walks. In: 2012 IEEE Workshop on Mathematical Methods in Biomedical Image Analysis
(MMBIA), 73–​78.
Booth, B.G. and Hamarneh, G. (2013). A cross-​sectional piecewise constant model for segmenting
highly curved fiber tracts in diffusion MR images. In: Mori, K., Sakuma, I., Sato, Y., Barillot, C., and
Navab, N. (Eds.) Medical Image Computing and Computer-​Assisted Intervention –​MICCAI 2013
(Lecture Notes in Computer Science Vol. 8151), pp.469–​476. New York: Springer.
Booth, B.G. and Hamarneh, G. (2015). Diffusion MRI for brain connectivity mapping and analysis.
In: Majumdar, A. and Ward, R.K. (Eds.) MRI: Physics, Image Reconstruction, and Analysis, pp.137–​
171. Boca Raton, FL: CRC Press.
Booth, B.G., Miller, S.P., Brown, C.J., et al. (2016). STEAM—​statistical template estimation for
abnormality mapping: a personalized DTI analysis technique with applications to the screening of
preterm infants. NeuroImage, 125, 705–​723.
Borich, M.R., Mackay, A.L., Vavasour, I.M., Rauscher, A., and Boyd, L.A. (2013). Evaluation of white
matter myelin water fraction in chronic stroke. NeuroImage Clinical, 2, 569–​580.
Brookes, M.J., Woolrich, M., Luckhoo, H., et al. (2011). Investigating the electrophysiological basis
of resting state networks using magnetoencephalography. Proceedings of the National Academy of
Sciences of the United States of America, 108(40), 16783–​16788.
Brookes, M.J., Liddle, E.B., Hale, J.R., et al. (2012a). Task induced modulation of neural oscillations in
electrophysiological brain networks. NeuroImage, 63(4), 1918–​1930.
Brookes, M.J., Woolrich, M.W., and Barnes, G.R. (2012b). Measuring functional connectivity in
MEG: a multivariate approach insensitive to linear source leakage. NeuroImage, 63, 910–​920.
Brown, C.J., Booth, B.G., and Hamarneh, G. (2013a, April). K-​confidence: assessing uncertainty
in tractography using k optimal paths. In Proceedings of IEEE International Symposium on
Biomedical Imaging: From Nano to Macro. IEEE International Symposium on Biomedical Imaging,
250–​253.
Brown, C.J., Booth, B.G., and Hamarneh, G. (2013b, January). Uncertainty in tractography via tract
confidence regions. In: Proceedings of Medical Image Computing and Computer-​Assisted Intervention
Workshop on Computational Diffusion MRI (MICCAI CDMRI), 13–​22.
Brown, C.J., Miller, S., Booth, B.G., et al. (2014). Structural network analysis of brain development in
young preterm neonates. NeuroImage, 101, 667–​680.
Brown, C.J., Miller, S., Booth, B.G., et al. (2015, October). Prediction of motor function in very
preterm infants using connectome features and local synthetic instances. In: Proceedings of Medical
Image Computing and Computer Assisted Intervention (MICCAI) 2015, 9349, 69–​76.
Buccino, G., Binkofski, F., Fink, G.R., et al. (2001). Action observation activates premotor and parietal
areas in a somatotopic manner: an fMRI study. European Journal of Neuroscience, 13, 400–​404.
4  4

44 Emerging neuroimaging technologies

Bullmore, E.T. and Bassett, D.S. (2010). Brain graphs: graphical models of the human brain
connectome. Annual Review of Clinical Psychology, 7, 16–​18.
Buzsáki, G. and Watson, B.O. (2012). Brain rhythms and neural syntax: implications for efficient coding
of cognitive content and neuropsychiatric disease. Dialogues in Clinical Neuroscience, 14(4), 345–​367.
Campbell, K.B., Picton, T.W., Wolfe, R.G., Maru, J., Baribeau-​Braun, J., and Braun, C. (1981).
Auditory potentials. Sensus, 1, 21–​31.
Chiappa, K.H., Gladstone, K.J., and Young, R.R. (1979). Brainstem auditory evoked responses: studies
of waveform variations in 50 normal human subjects. Archives of Neurology, 36, 81–​87.
Coluccia, D., Fandino, J., Schwyzer, L., et al. (2014). First noninvasive thermal ablation of a brain tumor
with MR-​guided focused ultrasound. Journal of Therapeutic Ultrasound, 2, 17.
Crawford, M.L. and Harwerth, R.S. (2004). Ocular dominance column width and contrast sensitivity in
monkeys reared with strabismus or anisometropia. Investigative Ophthalmology & Visual Science, 45,
3036–​3042.
Cruse, D., Chennu, S., Chatelle, C., et al. (2011). Bedside detection of awareness in the vegetative
state: a cohort study. The Lancet, 378: 2088–​2094.
Dalal, S., Sekihara, K., and Nagarajan, S. (2006). Modified beamformers for coherent source region
suppression. IEEE Transactions on Biomedical Engineering, 53, 1357–​1363.
Decety, J. and Cacioppo, J. (2010). Frontiers in human neuroscience: the golden triangle and beyond.
Perspectives on Psychological Science, 5, 767–​771.
Deco, G. and Kringelbach, M.L. (2014). Great expectations: using whole-​brain computational
connectomics for understanding neuropsychiatric disorders. Neuron, 84(5), 892–​905.
DeHaan, W., van der Flier, W.M., Wang, H., Van Mieghem, P.F., Scheltens, P., and Stam, C.J. (2012).
Disruption of functional brain networks in Alzheimer’s disease: what can we learn from graph
spectral analysis of resting-​state magnetoencephalography? Brain Connectivity, 2(2), 45–​55.
Ding, K., Liu, Y., Yan, X., Lin, X., and Jiang, T. (2013). Altered functional connectivity of the primary
visual cortex in subjects with amblyopia. Neural Plasticity, 2013, 1–​8.
Delorme, A., Palmer, J., Onton, J., Oostenveld, R., and Makeig, S. (2012). Independent EEG sources
are dipolar. PLoS One, 7, e30135.
DePasquale, F., Della Penna, S., Snyder, A.Z., et al. (2012). A cortical core for dynamic integration of
functional networks in the resting human brain. Neuron, 74(4), 753–​64.
Dimitriadis, S.I., Laskaris, N.A., Simos, P.G., et al. (2013). Altered temporal correlations in resting-​
state connectivity fluctuations in children with reading difficulties detected via MEG. NeuroImage,
83, 307–​317.
Doesburg, S.M., Green, J.J., McDonald, J.J., and Ward, L.M. (2009). Rhythms of
consciousness: binocular rivalry reveals large-​scale oscillatory network dynamics mediating visual
perception. PLoS One, 4(7), e6142.
Doesburg, S.M., Green, J.J., McDonald, J.J., and Ward, L.M. (2012). Theta modulation of inter-​regional
gamma synchronization during auditory attention control. Brain Research, 1431, 77–​85.
Doesburg, S.M., Ward, L.M., and Ribary, U. (2015). The alpha-​theta-​gamma (ATG) switch: toward
unified principles of cortical processing. Current Trends in Neurology, 9, 1–​12.
Dunkley, B.T., Doesburg, S.M., Sedge, P.A., et al. (2014). Resting-​state hippocampal connectivity
correlates with symptom severity in post-​traumatic stress disorder. NeuroImage Clinical, 5, 377–​384.
Dunkley, B.T., Da Costa, L., Bethune, A., et al. (2015). Low-​frequency connectivity is associated with
mild traumatic brain injury. NeuroImage Clinical, 7, 611–​621.
Duyn, J.H., Van Gelderen, B., Li, T.Q., de Zwart, J.A., Koretsky, A.P., and Fukunaga, M. (2007). High-​
field MRI of Brain Cortical Substructure Based on Signal Phase. Proceedings of the National Academy
of Sciences of the United States of America, 104, 11796–​801.
 45

References 45

Eberling, J.L., Dave, K.D., and Frasier, M.A. (2013). Alpha-​synuclein imaging: a critical need for
Parkinson’s disease research. Journal of Parkinson’s Disease, 3, 565–​567.
Elshahabi, A., Klamer, S., Sahib, A.K., Lerche, H., Braun, C., and Focke, N.K. (2015). Magneto-​
encephalography reveals a widespread increase in network connectivity in idiopathic/​genetic
generalized epilepsy. PLoS One, 10(9), e0138119.
Engel, A.K., Gerloff, C., Hilgetag, C.C., and Nolte, G. (2013). Intrinsic coupling modes: multiscale
interactions in ongoing brain activity. Neuron, 80(4), 867–​886.
Ewald, A., Marzetti, L., Zappasodi, F., Meinecke, F.C., and Nolte, G. (2012). Estimating true brain
connectivity from EEG/​MEG data invariant to linear and static transformations in sensor space.
NeuroImage, 60(1), 476–​488.
Fitzgerald, T.H.B., Valentin, A., Selway, R., and Richardson, M.P. (2013). Cross-​frequency coupling
within and between the human thalamus and neocortex. Frontiers in Human Neuroscience, 7, 1–​13.
Fitzgibbon, S.P., DeLosAngeles, D., Lewis, T.W., et al. (2016). Automatic determination of EMG-​
contaminated components and validation of independent components analysis using EEG during
pharmacologic paralysis. Clinical Neurophysiology, 127, 1781–​1793.
Florin, E. and Baillet, S. (2015). The brain’s resting-​state activity is shaped by synchronized cross-​
frequency coupling of neural oscillations. NeuroImage, 111, 26–​35.
Fortnum, H., O’Nei, C., Taylor, R., et al. (2009). The role of magnetic resonance imaging in the
identification of suspected acoustic neuroma: a systematic review of clinical and cost effectiveness
and natural history. Health Technology Assessments, 13, 1–​154.
Fox, M.D., Snyder, A.Z., Vincent, J.L., Corbetta, M., Van Essen, D.C., and Raichle, M.E. (2005). The
human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proceedings
of the National Academy of Sciences of the United States of America, 102, 9673–​9678.
Fries, P. (2009). Neuronal gamma-​band synchronization as a fundamental process in cortical
computation. Annual Review of Neuroscience, 32, 209–​224.
Fries, P. (2015). Rhythms for cognition: communication through coherence. Neuron, 88(1), 220–​235.
Friston, K.J., Fletcher, P., Josephs, O., Holmes, A.P., Rugg, M.D., and Turner, R. (1998). Event-​related
fMRI: characterizing differential responses. NeuroImage, 7, 30–​40.
Friston, K.J., Harrison, L., and Penny, W. (2003). Dynamic causal modelling. NeuroImage, 19,
1273e1302.
Goodyear, B.G., Nicolle, D.A., and Menon, R.S. (2002). High resolution fMRI of ocular dominance
columns within the visual cortex of human amblyopes. Strabismus, 10, 129–​136.
Grafton, S.T. and Hamilton, A.F. (2007). Evidence for a distributed hierarchy of action representation
in the brain. Human Movement Science, 26, 590–​616.
Green, J.J., Doesburg, S.M., Ward, L.M., and McDonald, J.J. (2011). Electrical neuroimaging of
voluntary audio-​spatial attention: evidence for a supramodal attention control network. Journal of
Neuroscience, 31(10), 3560–​3564.
Grill-​Spector, K., Henson, R., and Martin, A. (2006). Repetition and the brain: neural models of
stimulus-​specific effects. Trends in Cognitive Sciences, 10, 14–​23.
Guan, X., Xuan, M., Gu, Q., et al. (2016). Regionally progressive accumulation of iron in Parkinson’s
disease as measured by quantitative susceptibility mapping. NMR in Biomedicine. Advance online
publication. doi:10.1002/​nbm.3489.
Hamalainen, M.S. and Ilmoniemi, R.J. (1994). Interpreting magnetic fields of the brain: Minimum
norm estimates. Medical & Biological Engineering & Computing, 32(1):35–​42.
Hamarneh, G. and Hradsky, J. (2006, August). DTMRI segmentation using DT-​snakes and DT-​livewire.
In: Proceedings of IEEE International Symposium on Signal Processing and Information Technology
(IEEE ISSPIT), 513–​518.
46  4

46 Emerging neuroimaging technologies

Hamarneh, G. and Hradsky, J. (2007). Bilateral filtering of diffusion tensor magnetic resonance images.
IEEE Transactions on Image Processing, 16, 2463–​2475.
Hamarneh, G., McIntosh, C., and Drew, M. (2011). Perception-​based visualization of manifold-​valued
medical images using distance-​preserving dimensionality reduction. IEEE Transactions on Image
Processing, 30, 1314–​1327.
Hermundstad, A.M., Bassett, D.S., Brown, K.S., et al. (2013). Structural foundations of resting-​state
and task-​based functional connectivity in the human brain. Proceedings of the National Academy of
Sciences of the United States of America, 110, 6169–​6174.
Hermundstad, A.M., Brown, K.S., Bassett, D.S., et al. (2014). Structurally-​constrained relationships
between cognitive states in the human brain. PLoS Computational Biology, 10, e1003591.
Hipp, J.F., Hawellek, D.J., Corbetta, M., Siegel, M., and Engel, A.K. (2012). Large-​scale cortical
correlation structure of spontaneous oscillatory activity. Nature Neuroscience, 15(6), 884–​890.
Ho, C.S. and Giaschi, D.E. (2009). Low-​and high-​level motion perception deficits in anisometropic and
strabismic amblyopia: evidence from fMRI. Vision Research, 49, 2891–​2901.
Ho, C.S., Paul, P., Asirvatham, A., Cavanagh, P., Cline, R., and Giaschi, D. (2006). Abnormal spatial
selection and tracking in children with amblyopia. Vision Research, 46, 3274–​3283.
Holz, E.M., Glennon, M., Prendergast, K., andSauseng, P. (2010). Theta-​gamma phase synchronization
during memory matching in visual working memory. NeuroImage, 67:331–​343.
Huang, M.X., Nichols, S., Baker, D.G., et al. (2014). Single-​subject-​based whole-​brain MEG slow-​
wave imaging approach for detecting abnormality in patients with mild traumatic brain injury.
NeuroImage Clinical, 5, 109–​119.
Hubel, D.H., Wiesel, T.N., and LeVay, S. (1977). Plasticity of ocular dominance columns in monkey
striate cortex. Philosophical Transactions of the Royal Society B: Biological Sciences, 278, 377–​409.
Hui, H.B., Pantazis, D., Bressler, S.L. and Leahy, R.M. (2010). Identifying true cortical interactions in
MEG using the nulling beamformer. NeuroImage, 49, 3161–​3174.
Immordino-​Yang, M.H. and Singh, V. (2013). Hippocampal contributions to the processing of social
emotions. Human Brain Mapping, 34, 945–​955.
Jerbi, K., Ossandón, T., Hamamé, C.M., et al. (2009). Task-​related gamma-​band dynamics from
an intracerebral perspective: review and implications for surface EEG and MEG. Human Brain
Mapping, 30(6), 1758–​1771.
Jian, B. and Vemuri, B.C. (2007). A unified computational framework for deconvolution to reconstruct
multiple fibers from diffusion weighted MRI. IEEE Transactions on Medical Image Analysis, 26,
1464–​1471.
Jones, D.K. (2016). Diffusion MRI: Theory, Methods, and Applications. New York: Oxford
University Press.
Jones, D.K., Knösche, T.R., and Turner, R. (2013). White matter integrity, fiber count, and other
fallacies: the do’s and don’ts of diffusion MRI. NeuroImage, 73, 239–​254.
Jurcoane, A., Choubey, B., Mitsieva, D., Muckli, L., and Sireteanu, R. (2009). Interocular transfer of
orientation-​specific fMRI adaptation reveals amblyopia-​related deficits in humans. Vision Research,
49, 1681–​1692.
Kaiser, M. (2011). A tutorial in connectome analysis: Topological and spatial features of brain networks.
NeuroImage, 57, 892–​907.
Kang, J., Gao, Y., Shi, F., Lalush, D.S., Lin, W., and Shen, D. (2015). Prediction of standard-​dose
brain PET image by using MRI and low-​dose brain [18F]FDG PET images. Medical Physics, 42,
5301–​5309.
Kaplan, J.T., Gimbel, S.I., Dehghani, M., et al. (2016). Processing narratives concerning protected
values: a cross-​cultural investigation of neural correlates. Cerebral Cortex. Advance online
publication. doi:10.1093/​cercor/​bhv325
 47

References 47

Kikuchi, A., Takeda, A., Okamura, N., et al. (2010). In vivo visualization of alpha-​synuclein deposition
by carbon-​11-​labelled 2-​[2-​(2-​dimethylaminothiazol-​5-​yl)ethenyl]-​6-​[2-​(fluoro)ethoxy]benzoxazole
positron emission tomography in multiple system atrophy. Brain, 133, 1772–​1778.
Kiorpes, L. and McKee, S.P. (1999). Neural mechanisms underlying amblyopia. Current Opinion in
Neurobiology, 9, 480–​486.
Kitzbichler, M.G., Khan, S., Ganesan, S., et al. (2015). Altered development and multifaceted band-​
specific abnormalities of resting state networks in autism. Biological Psychiatry, 77(9), 794–​804.
Klyuzhin, I.S., Gonzalez, M., Shahinfard, E., Vafai, N., and Sossi, V. (2016). Exploring the use of shape
and texture descriptors of positron emission tomography tracer distribution in imaging studies of
neurodegenerative disease. Journal of Cerebral Blood Flow & Metabolism, 36(6), 1122–​1134.
Kwong, K.K., Belliveau, J.W., Chesler, D.A., et al. (1992). Dynamic magnetic resonance imaging of
human brain activity during primary sensory stimulation. Proceedings of the National Academy of
Sciences of the United States of America, 89, 5675–​5679.
Lachaux, J.P., Rodriguez, E., Martinerie, J., and Varela, F.J. (1999). Measuring phase synchrony in brain
signals. Human Brain Mapping, 8, 194–​208.
Lang, D.J.M., Yip, E., MacKay, A.L., et al. (2014). 48 echo T2 myelin imaging of white matter in first-​
episode schizophrenia: evidence for aberrant myelination. NeuroImage Clinical, 6, 408–​414.
Larson-​Prior, L.J., Oostenveld, R., Della Penna, S., et al. (2013). Adding dynamics to the Human
Connectome Project with MEG. NeuroImage, 80, 190–​201.
Laule, C., Kozlowski, P., Leung, E., Li, D.K.B., MacKay, A.L., and Moore, G.R.W. (2008). Myelin
water imaging of multiple sclerosis at 7 T: correlations with histopathology. NeuroImage, 40,
1575–​1580.
Lavigne, K.M., Metzak, P.D., and Woodward, T.S. (2015a). Functional brain networks underlying
detection and integration of disconfirmatory evidence. NeuroImage, 112, 138–​151.
Lavigne, K.M., Rapin, L.A., Metzak, P.M., et al. (2015b). Left-​dominant temporal-​frontal hypercoupling
in schizophrenia patients with hallucinations during speech perception. Schizophrenia Bulletin, 41,
259–​267.
LeBihan, D. and Breton, E. (1985). Imagerie de diffusion in vivo par résonance magnétique nucléaire.
Compte Rendus de l’Académie de Sciences Paris, 301, 1109–​1112.
Lerner, Y., Hendler, T., Malach, R., et al. (2006). Selective fovea-​related deprived activation in
retinotopic and high-​order visual cortex of human amblyopes. NeuroImage, 33, 169–​179.
Lewis, C.M., Bosman, C.A., Womelsdorf, T., and Fries, P. (2016). Stimulus-​induced visual cortical
networks are recapitulated by spontaneous local and interareal synchronization. Proceedings of the
National Academy of Sciences of the United States of America, 113, E606–​E615.
Li, W., Wu, B., Batrachenko, A., et al. (2014). Differential developmental trajectories of magnetic
susceptibility in human brain gray and white matter over the lifespan. Human Brain Mapping, 35,
2698–​2713.
Li, X., Coyle, D., Maguire, L., McGinnity, T.M., and Hess, R.F. (2011a). Long timescale fMRI neuronal
adaptation effects in human amblyopic cortex. PLoS ONE, 6, e26562.
Li, X., Mullen, K.T., Thompson, B., and Hess, R.F. (2011b). Effective connectivity anomalies in human
amblyopia. NeuroImage, 54, 505–​516.
Li, X., Harrison, D.M., Liu, H., et al. (2015). Magnetic susceptibility contrast variations in multiple
sclerosis lesions. Journal of Magnetic Resonance Imaging, 43(2), 463–​473.
Lin, X., Ding, K., Liu, Y., Yan, X., Song, S., and Jiang, T. (2012). Altered spontaneous activity in
anisometropic amblyopia subjects: revealed by resting-​state fMRI. PLoS ONE, 7, e43373.
Liu, C., Wei, H., Gong, N.J., Cronin, M., Dibb, R., and Decker, K. (2015). Quantitative susceptibility
mapping: contrast mechanisms and clinical applications. Tomography: A Journal for Imaging
Research, 1, 3–​17.
48  4

48 Emerging neuroimaging technologies

Liu, S., Cai, W., Pujol, S., et al. (2016). Cross-​view neuroimage pattern analysis in Alzheimer’s disease
staging. Frontiers in Aging Neuroscience, 8, 23.
Llinás, R. and Ribary, U. (1993). Coherent 40-​Hz oscillation characterizes dream state in humans.
Proceedings of the National Academy of Sciences of the United States of America, 90, 2078–​2081.
Llinás, R., Ribary, U., Jeanmonod, D., Kronberg, E., and Mitra, P.P. (1999). Thalamocortical
dysrhythmia: a neurological and neuropsychiatric syndrome characterized by
magnetoencephalography. Proceedings of the National Academy of Sciences of the United States of
America, 96, 15222–​15227.
Lobier, M., Siebenhühner, F., Palva, S., and Palva, J.M. (2014). Phase transfer entropy: A novel
phase-​based measure for directed connectivity in networks coupled by oscillatory interactions.
NeuroImage, 85, 853–​872.
Lodygensky, G.A., Marques, J.P., Maddage, R., et al. (2011). In vivo assessment of myelination by phase
imaging at high magnetic field. NeuroImage, 59(3), 1979–​1987.
Logothetis, N.K., Pauls, J., Augath, M., Trinath, T., and Oeltermann, A. (2001). Neurophysiological
investigation of the basis of the fMRI signal. Nature, 412, 150–​157.
Luckhoo, H., Hale, J.R., Stokes, M.G., et al. (2012). Inferring task-​related networks using independent
component analysis in magnetoencephalography. NeuroImage, 62, 530–​541.
MacDonald, M.E. and Frayne, R. (2015). Cerebrovascular MRI: a review of state-​of-​the-​art approaches,
methods and techniques. NMR in Biomedicine, 28, 767–​791.
MacKay, A., Whittall, K., Adler, J., Li, D., Paty, D., and Graeb, D. (1994). In vivo visualization of myelin
water in brain by magnetic resonance. Magnetic Resonance in Medicine, 31, 673–​677.
Manogaran, P., Vavasour, I., Borich, M., et al. (2015). Corticospinal Tract Integrity Measured Using
Transcranial Magnetic Stimulation and Magnetic Resonance Imaging in Neuromyelitis Optica and
Multiple Sclerosis. Multiple Sclerosis. Basingstoke, England: Houndmills.
McCall, C., Tipper, C.M., Blascovich, J., and Grafton, S.T. (2012). Attitudes trigger motor behavior
through conditioned associations: neural and behavioral evidence. Social Cognitive and Affective
Neuroscience, 7, 841–​849.
Medina, L.S., Balckmore, C.C., and Applegate, K.E. (2013). Evidence-​based imaging: principles.
In: Medina, L.S., Balckmore, C.C., and Applegate, K.E. (Eds.) Evidence-​Based Imaging: Improving
Quality in Patient Care. New York: Springer.
Metzak, P.D., Riley, J.D., Wang, L., Whitman, J.C., Ngan, E.T.C., and Woodward, T.S. (2012).
Decreased efficiency of task-​positive and task-​negative networks during working memory in
schizophrenia. Schizophrenia Bulletin, 38, 803–​813.
Miskovic, V., Ma, X., Chou, C.A., et al. (2015). Developmental changes in spontaneous electrocortical
activity and network organization from early to late childhood. NeuroImage, 118, 237–​247.
Moiseev, A. and Herdman, A. (2013). Multi-​core beamformers: derivation, limitations and
improvements. NeuroImage, 71, 135–​146.
Moiseev, A., Gaspar, J., Schneider, J., and Herdman, A. (2011). Application of multi-​source minimum
variance beamformers for reconstruction of correlated neural activity. NeuroImage, 58, 481–​496.
Mori, S. and van Zijl, P.C.M. (2002). Fiber tracking: principles and strategies—​a technical review. NMR
in Biomedicine, 15, 468–​480.
Muckli, L., Kieb, S., Tonhausen, N., Singer, W., Goebel, R., and Sireteanu, R. (2006). Cerebral
correlates of impaired grating perception in individual, psychophysically assessed human
amblyopes. Vision Research, 46, 506–​526.
Mullen, T., Kothe, C., Chi, Y.M., et al. (2013, July). Real-​Time Modeling and 3D visualization of Source
Dynamics and Connectivity Using Wearable EEG. Presented at the 35th Annual International
Conference of the IEEE EMBS Osaka, Japan.
 49

References 49

Nand, K.K., Abugharbieh, R., Booth, B.G., and Hamarneh, G. (2011). Detecting structure in diffusion
tensor MR images. International Conference on Medical Image Computing and Computer-​Assisted
Intervention, 14(Pt 2), 90–​97.
Nand, K., Hamarneh, G., and Abugharbieh, R. (2012). Diffusion tensor image processing using
biquaternions. In: Proceedings of 9th IEEE International Symposium on Biomedical Imaging (ISBI)
2012, 538–​541.
Nasrallah, F.A., Pagès, G., Kuchel, P.W., Golay, X., and Chuang, K.H. (2013). Imaging brain
deoxyglucose uptake and Metabolism by glucoCEST MRI. Journal of Cerebral Blood Flow and
Metabolism, 33, 1270–​78.
Niso, G., Rogers, C., Moreau, J.T., et al. (2016). OMEGA: The Open MEG Archive. NeuroImage, 124(Pt
B), 1182–​1187.
Ogawa, S., Tank, D.W., Menon, R., et al. (1992). Intrinsic signal changes accompanying sensory
stimulation: Functional brain mapping with magnetic resonance imaging. Proceedings of the
National Academy of Sciences of the United States of America, 89, 5951–​5955.
O’Neill, G.C., Bauer, M., Woolrich, M.W., et al. (2015). Dynamic recruitment of resting state sub-​
networks. NeuroImage, 115, 85–​95.
Oz, G., Alger, J.R., Barker, P.B., et al. (2014). Clinical proton MR spectroscopy in central nervous
system disorders. Radiology, 270, 658–​679.
Palop, J.J., Chin, J., and Mucke, L. (2006). A network dysfunction perspective on neurodegenerative
diseases. Nature, 443, 768–​773.
Palva, J.M. and Palva, S. (2012). Discovering oscillatory interaction networks with M/​EEG: challenges
and breakthroughs. Trends in Cognitive Science, 16(4), 219–​230.
Palva, J.M., Monto, S., Kulashekhar, S., and Palva, S. (2010). Neuronal synchrony reveals working
memory networks and predicts individual memory capacity. Proceedings of the National Academy of
Sciences of the United States of America, 107, 7580–​7585.
Pannek, K., Scheck, S.M., Colditz, P.B., Boyd, R.N., and Rose, S.E. (2014). Magnetic resonance
diffusion tractography of the preterm infant brain: a systematic review. Developmental Medicine &
Child Neurology, 56(2), 113–​124.
Picton, T.W. (2011). Human Auditory Evoked Potentials. San Diego, CA: Plural Publishing Incorporated.
Poldrack, R.A. (2010). Mapping mental function to brain structure: how can cognitive neuroimaging
succeed? Perspectives on Psychological Science, 5, 753–​761.
Prasloski, T., Rauscher, A., MacKay, A.L., et al. (2012). Rapid whole cerebrum myelin water imaging
using a 3D GRASE sequence. NeuroImage, 63, 533–​539.
Pruessmann, K.P., Weiger, M., Scheidegger, M.B., and Boesiger, P. (1999). SENSE: sensitivity encoding
for fast MRI. Magnetic Resonance in Medicine, 42, 952–​962.
Raichle, M.E. (2015). The restless brain: how intrinsic activity organizes brain function. Philosophical
Transactions of the Royal Society B: Biological Sciences, 370(1668), 20140172.
Rauscher, A., Sedlacik, J., Barth, M., Mentzel, H.J., and Reichenbach, J.R. (2005). Magnetic
susceptibility-​weighted MR phase imaging of the human brain. AJNR. American Journal of
Neuroradiology, 26, 736–​742.
Ribary, U., Doesburg, S.M., and Ward, L.M. (2014). Thalamocortical network dynamics: a
framework for typical/​atypical cortical oscillations and connectivity. In: Supek, S. and Aine,
C.J. (Eds.) Magnetoencephalography—​From Signals to Dynamic Cortical Networks, pp.429–​450.
Heidelberg: Springer Verlag.
Robinson, S. and Vrba, J. (1999). Functional neuroimaging by synthetic aperture magnetometry (SAM).
In: Yoshimoto, Y. (Ed.) Recent Advances in Biomagnetism, pp.302–​305. Sendai, Japan: Tohoku
University Press.
50  5

50 Emerging neuroimaging technologies

Rogers, B.P., Morgan, V.L., Newton, A.T., and Gore, J.C. (2007). Assessing functional connectivity in
the human brain by fMRI. Magnetic Resonance Imaging, 25, 1347–​1357.
Ross, B.D., Bhattacharya, P., Wagner, S., Tran, T., and Sailasuta, N. (2010). Hyperpolarized
MR imaging: neurologic applications of hyperpolarized metabolism. American Journal of
Neuroradiology, 31, 24–​33.
Rubinov, M. and Sporns, O. (2010). Complex network measures of brain connectivity: uses and
interpretations. NeuroImage, 52, 1059–​1069.
Saggar, M., Vrticka, P., and Reiss, A.L. (2016). Understanding the influence of personality on dynamic
social gesture processing: an fMRI study. Neuropsychologia, 80, 71–​78.
Sander, C.Y., Hooker, J.M., Catana, C., et al. (2013). Neurovascular coupling to D2/​D3 dopamine
receptor occupancy using simultaneous PET/​functional MRI. Proceedings of the National Academy
of Sciences of the United States of America, 110, 11169–​11174.
Sauseng, P., Klimesch, W., Gruber, W.R., and Birbaumer, N. (2008). Cross-​frequency phase
synchronization: a brain mechanism of memory matching and attention. NeuroImage, 40, 308–​317.
Schäfer, C.B., Morgan, B.R., Ye, A.X., Taylor, M.J., and Doesburg, S.M. (2014). Oscillations, networks,
and their development: MEG connectivity changes with age. Human Brain Mapping, 35(10),
5249–​5261.
Schoffelen, J.M. and Gross, J. (2009). Source connectivity analysis with MEG and EEG. Human Brain
Mapping, 30, 1857–​1865.
Schreiber, T. (2000). Measuring information transfer. Physical Review Letters, 85, 461e464.
Schweser, F., Deistung, A., Lehr, B.W., and Reichenbach, J.R. (2011). Quantitative imaging of intrinsic
magnetic tissue properties using MRI signal phase: an approach to in vivo brain iron metabolism?
NeuroImage, 54, 2789–​2807.
Schweser, F., Deistung, A., and Reichenbach, J.R. (2016). Foundations of MRI phase imaging and
processing for quantitative susceptibility mapping (QSM). Zeitschrift Für Medizinische Physik,
26, 6–​34.
Secen, J., Culham, J., Ho, C., and Giaschi, D. (2011). Neural correlates of the multiple-​object tracking
deficit in amblyopia. Vision Research, 51, 2517–​2527.
Sekihara, K. and Nagarajan, S. (2008). Adaptive Spatial filters For Electromagnetic Brain Imaging.
Berlin: Springer.
Sekihara, K. and Nagarajan, S.S. (2015). Electromagnetic Brain Imaging: A Bayesian Perspective.
Switzerland: Springer International Publishing.
Selters, W.A. and Brackmann, D.E. (1977). Acoustic tumor detection with brainstem electric response
audiometry. Archives of Otolaryngology, 103, 181–​187.
Shafer, J.P. (1995). Multiple hypothesis testing. Annual Review of Psychology, 46, 561–​584.
Shah, N.J., Worthoff, W.A., and Langen, K.J. (2016). Imaging of sodium in the brain: a brief review.
NMR in Biomedicine, 29, 162–​174.
Smith, S.M., Jenkinson, M., Johansen-​Berg, H., et al. (2006). Tract-​based spatial statistics: voxelwise
analysis of multi-​subject diffusion data, NeuroImage, 31, 1487–​1505.
Spearman, C. (1904). The proof and measurement of association between two things. American Journal
of Psychology, 15, 72–​101.
Spiegel, D.P., Byblow, W.D., Hess, R.F., and Thompson, B. (2013). Anodal transcranial direct current
stimulation transiently improves contrast sensitivity and normalizes visual cortex activation in
individuals with amblyopia. Neurorehabilitation and Neural Repair, 27, 760–​769.
Sporns, O. (2003). Graph theory methods for the analysis of neural connectivity patterns. In: Kötter, R.
(Ed.) Neuroscience Databases: A Practical Guide, pp.171–​185. New York: Springer US.
 51

References 51

Sporns, O., Tononi, G., and Kötter, R. (2005). The human connectome: a structural description of the
human brain. PLoS Computational Biology, 1, e42.
Stam, C.J. (2014). Modern network science of neurological disorders. Nature Reviews Neuroscience,
15(10), 683–​695.
Stam, C.J., Nolte, G., and Daffertshofer, A. (2007). Phase lag index: assessment of functional
connectivity from multi-​channel EEG and MEG with diminished bias from common sources.
Human Brain Mapping, 28(11), 1178–​1193.
Stejskal, E.O. and Tanner, J.E. (1965). Spin diffusion measurements: spin echoes in the presence of a
time-​dependent field gradient. Journal of Chemical Physics, 42, 288–​292.
Stockard, J.J., Stockard, J.E., and Sharbrough, F.W. (1978). Nonpathologic factors influencing
brainstem auditory-​evoked potentials. American Journal of EEG Technology, 18, 177–​193.
Tahmasian, M., Shao, J., Meng, C., et al. (2016). Based on the network degeneration
hypothesis: separating individual patients with different neurodegenerative syndromes in a
preliminary hybrid PET/​MR Study. Journal of Nuclear Medicine, 57, 410–​415.
Thompson, B., Villeneuve, M.Y., Casanova, C., and Hess, R.F. (2012). Abnormal cortical processing of
pattern motion in amblyopia: evidence from fMRI. NeuroImage, 60, 1307–​1315.
Tipper, C.M., Handy, T.C., Giesbrecht, B., and Kingstone, A. (2008). Brain responses to biological
relevance. Journal of Cognitive Neuroscience, 20, 879–​891.
Tipper, C.M., Signorini, G., and Grafton, S.T. (2015). Body language in the brain : constructing
meaning from expressive movement. Frontiers in Human Neuroscience, 9, 450.
Tournier, J.D., Calamante, F., and Connelly, A. (2007). Robust determination of the fibre orientation
distribution in diffusion MRI: non-​negativity constrained super-​resolved spherical deconvolution.
NeuroImage, 35, 1459–​1472.
Tuch, D.S. (2004). Q-​ball imaging. Magnetic Resonance in Medicine, 52, 1358–​1372.
Uhlhaas, P.J., Pipa, G., Lima, B., et al. (2009). Neural synchrony in cortical networks: history, concept
and current status. Frontiers in Integrative Neuroscience, 3(17), 1–​19.
Van Veen, B.D. and Buckley, K.M. (1988). Beamforming: a versatile approach to spatial filtering. IEEE
Transactions on Signal Processing, 5, 4–​24.
Van Veen, B.D., van Drongelen, W., Yuchtman, M., and Suzuki, A. (1997). Localization of brain
electrical activity via linearly constrained minimum variance spatial filtering. IEEE Transactions on
Biomedical Engineering, 44, 867–​880.
Varela, F., Lachaux, J.P., Rodriguez, E., and Martinerie, J. (2001). The brainweb: phase synchronization
and large-​scale integration. Nature Reviews Neuroscience, 2(4), 229–​239.
Varma, G., Duhamel, G., de Bazelaire, C., and Alsop, D.C. (2015). Magnetization transfer from
inhomogeneously broadened lines: a potential marker for myelin. Magnetic Resonance in Medicine,
73, 614–​622.
Vavasour, I.M., Laule, C., Li, D.K.B., et al. (2009). Longitudinal changes in myelin water fraction in two
MS patients with active disease. Journal of the Neurological Sciences, 276, 49–​53.
Vicente, R., Wibral, M., Lindner, M., and Pipa, G. (2011). Transfer entropy-​a model-​free measure of
effective connectivity for the neurosciences. Journal of Computational Neuroscience, 30, 45–​67.
Villemagne, V.L. (2016). Amyloid imaging: past, present and future perspectives. Ageing Research
Reviews, 30, 95–​106.
Villemagne, V.L., Fodero-​Tavoletti, M.T., Masters, C.L., and Rowe, C.C. (2015). Tau imaging: early
progress and future directions. The Lancet Neurology, 14, 114–​124.
Vinck, M., Oostenveld, R., van Wingerden, M., Battaglia, F., and Pennartz, C. (2011). An improved
index of phase-​synchronization for electrophysiological data in the presence of volume-​conduction,
noise and sample-​size bias. NeuroImage, 55, 1548–​1565.
52  5

52 Emerging neuroimaging technologies

Wang, H.E., Bénar, C.G., Quilichini, P.P., Friston, K.J., Jirsa, V.K., and Bernard, C. (2014). A
systematic framework for functional connectivity measures. Frontiers in Neuroscience, 8, 1–​22.
Wang, T., Li, Q., Guo, M., et al. (2014). Abnormal functional connectivity density in children with
anisometropic amblyopia at resting-​state. Brain Research, 1563, 41–​51.
Wang, X.J. (2010). Neurophysiological and computational principles of cortical rhythms in cognition.
Physiological Reviews, 90, 1195–​1268.
Wang, Y., Wang, Q., Haldar, J.P., et al. (2011). Quantification of increased cellularity during
inflammatory demyelination. Brain, 134, 3590–​3601.
Ward, K.M., Aletras, A.H., and Balaban, R.S. (2000). A new class of contrast agents for MRI based on
proton chemical exchange dependent saturation transfer (CEST). Journal of Magnetic Resonance,
143, 79–​87.
Ward, L.M. (2003). Synchronous neural oscillations and cognitive processes. Trends in Cognitive
Science, 7, 553–​559.
Ward, L.M. (2013). The thalamus: gateway to the mind. Wiley Interdisciplinary Reviews Cognitive
Science, 4(6), 609–​622
Weldeselassie, Y. and Hamarneh, G. (2007). DT-​MRI segmentation using graph cuts. SPIE Medical
Imaging, 6512–​1K, 1–​9.
Westin, C.F., Maier, S.E., Mamata, H., Nabavi, A., Jolesz, F.A., and Kikinis, R. (2002). Processing and
visualization for diffusion tensor MRI. Medical Image Analysis, 6, 93–​108.
Whitman, J.C., Takane, Y., Cheung, T.P.L., et al. (2016). Acceptance of evidence-​supported hypotheses
generates a stronger signal from an underlying functionally-​connected network. NeuroImage, 127,
215–​226.
Wibral, M., Rahm, B., Rieder, M., Lindner, M., Vicente, R., and Kaiser, J. (2011). Transfer entropy in
magnetoencephalographic data: quantifying information flow in cortical and cerebellar networks.
Progress in Biophysics and Molecular Biology, 105, 80–​97.
Wiggermann, V., Torres, E.H., Vavasour, I.M., et al. (2013). Magnetic resonance frequency shifts
during acute MS lesion formation. Neurology, 81, 211–​218.
Wong, A.M. (2012). New concepts concerning the neural mechanisms of amblyopia and their clinical
implications. Canadian Journal of Ophthalmology, 47, 399–​409.
Woodward, T.S., Cairo, T.A., Ruff, C.C., Takane, Y., Hunter, M.A., and Ngan, E.T.C. (2006). Functional
connectivity reveals load dependent neural systems underlying encoding and maintenance in verbal
working memory. Neuroscience, 139, 317–​325.
Woodward, T.S., Tipper, C., Leung, A., Lavigne, K.M., Sanford, N., and Metzak, P.D. (2015). Reduced
functional connectivity during controlled semantic integration in schizophrenia: a multivariate
approach. Human Brain Mapping, 36, 2949–​2964.
Woodward, T.S., Leong, K., Sanford, N., Tipper, C.M., and Lavigne, K. M. (2016). Altered balance of
functional brain networks in schizophrenia. Psychiatry Research, 248, 94–​104.
Wright, A.D., Jarrett, M., Vavasour, I., et al. (2016). Myelin water fraction is transiently reduced after
a single mild traumatic brain injury—​a prospective cohort study in collegiate hockey players. PloS
One 11(2), e0150215.
Yang, C.I., Uang, M.L., Huang, J.C., Wan, Y.L., Tsai, R.J.F., Wai, Y.Y., and Liu, H.L. (2003). Functional
MRI of amblyopia before and after levodopa. Neuroscience Letters, 339, 49–​52.
Ye, A.X., Leung, R.C., Schäfer, C.B., Taylor, M.J., and Doesburg, S.M. (2014). Atypical resting
synchrony in autism spectrum disorder. Human Brain Mapping, 35(12), 6049–​6066.
Ye, A.X., AuCoin-​Power, M., Taylor, M.J., and Doesburg, S.M. (2015). Disconnected neuromagnetic
networks in children born very preterm. NeuroImage Clinical, 9, 376–​384.
 53

References 53

Yoshinaga-​Itano, C., Sedey, A.L., Coulter, D.K., and Mehl, A.L. (1998). Language of early-​and later-​
identified children with hearing loss. Pediatrics, 102, 1161–​1171.
Yoshinaga-​Itano, C., Coulter, D.K., and Thomson, V. (2000). The Colorado newborn hearing screening
project: effects on speech and language development for children with hearing loss. Journal of
Perinatology, 20(8 Pt 2), S132–​137.
Zalesky, A., Fornitoa, A., and Bullmorec, E.T. (2010). Network-​based statistic: Identifying differences
in brain networks. NeuroImage, 53, 1197–​1207.
Zalesky, A., Fornito, A., Cocchi, L., Gollo, L.L., and Breakspear, M. (2014). Time-​resolved resting-​state
brain networks. Proceedings of the National Academy of Sciences of the United States of America,
111(28), 10341–​10346.
Zhai, J., Chen, M., Liu, L., Zhao, X., Zhang, H., Luo, X., and Gao, J. (2013). Perceptual learning
treatment in patients with anisometropic amblyopia: a neuroimaging study. British Journal of
Ophthalmology, 97, 1420–​1424.
54  5

Chapter 3

Incidental findings: Current ethical

debates and future challenges
in advanced neuroimaging
Lorna M. Gibson, Cathie L.M. Sudlow,
and Joanna M. Wardlaw

Introduction
Incidental findings (IFs) on neuroimaging are the subject of widespread debates, and with
the increase in use of imaging across research, clinical, and commercial sectors, there is
a pressing need to address knowledge gaps to inform the development of appropriate
strategies for their management.
Incidental findings may be defined as “observations of potential clinical significance
unexpectedly discovered in healthy subjects or in patients recruited to any imaging
research study, and unrelated to the purpose or variables of the study” (Illes et  al.
2006). However, with the recent surge of interest in and experience of managing par-
ticipants with IFs, IFs can no longer be deemed unexpected, and should be antici-
pated (Medical Research Council & Wellcome Trust 2014; Bunnik & Vernooij 2016).
Instead, an IF may be defined as “a finding concerning an individual research par-
ticipant that has potential health or reproductive importance and is discovered in the
course of conducting research but is beyond the aims of the study” (Wolf et al. 2008).
The increasing use of imaging as a research tool, a clinical diagnostic tool, and within
the commercial sector increases the likelihood of detecting IFs, and necessitates the
development of a robust evidence base to inform policies for detecting, classifying,
and feeding back information on IFs to individuals, and evaluation of the feasibility
and impact of those policies.
In this chapter, we will describe the scale of the problem of IFs; summarize current
knowledge on the prevalence and determinants of prevalence of IFs, the impact of IFs on
key stakeholders, and the expectations of the public; and highlight gaps in the evidence
that will inform debates on the management of IFs. While we focus on IFs detected dur-
ing research imaging, we also highlight issues related to the management of IFs detected
during clinical and commercial imaging.
 5

Scale of the problem of incidental findings 55

Scale of the problem of incidental findings

Our understanding of the scale of the problem of IFs is informed by reports of recent and
ongoing large imaging research studies, and studies of the prevalence of IFs.

Large imaging research projects

Population-​based research projects are underway that include imaging of large subsets
of their participants. Two of the largest projects are the UK Biobank and the German
National Cohort. The UK Biobank is a cohort of 500,000 British adults aged 40–​69 years
at the time of recruitment that began in 2006 and ended in 2010. The cohort partici-
pants have been extensively characterized using data from questionnaires, blood samples,
physical measurements, and cognitive tests, and data on health-​related outcomes will also
be generated via linkage to health records (Sudlow et  al. 2015). The UK Biobank data
resource will image 100,000 of its participants using brain, cardiac, and abdominal mag-
netic resonance imaging (MRI), carotid ultrasound, and dual-​energy X-​ray absorptiom-
etry (Matthews & Sudlow 2015), and will generate the world’s largest multimodal imaging
dataset. The German National Cohort is collecting questionnaire and medical examina-
tion data and biological samples from 200,000 population-​based participants aged 20–​
69  years, and will perform whole-​body MRI in a subset of 30,000 of these individuals
(German National Cohort (GNC) Consortium 2014).
Whole-​body MRI has already been completed in 2500 population-​based Study of
Health in Pomerania participants (Hegenscheid et  al. 2013), and multiple large-​scale,
population-​based, neuroimaging-​only initiatives are also complete (Ikram et  al. 2011;
Wardlaw et al. 2011; Smith et al. 2015; Stephan et al. 2015). The population-​based, lon-
gitudinal Rotterdam Study introduced neuroimaging for all participants in 2005. It per-
formed imaging in random subsets in 1995 and in 1999, and had obtained 5886 brain
MRI scans as of January 2011(Ikram et al. 2011). Brain MRI was performed in 803 out of
10,455 participants enrolled in the Canadian Prospective Urban Rural Epidemiological
(PURE) study in order to investigate associations between small vessel disease and cog-
nition (Smith et al. 2015). Brain MRI was also performed in 1923 participants from the
Three City Study, a French longitudinal cohort study that recruited participants in 1999–​
2001 and was designed to investigate dementia and cognitive impairment and vascular
risk factors (Stephan et  al. 2015). The Lothian Birth Cohort 1936 includes 1091 indi-
viduals who reside in Edinburgh, were born in 1936, and underwent the Scottish Mental
Survey general intelligence test in 1947 (Deary et al. 2007). The age 70 years cohort under-
went medical interviews, physical examination, fitness testing, and cognitive testing, and
answered questionnaires on personality, quality of life, and diet (Deary et al. 2007). Three
years later, surviving members of the cohort were invited for retesting and brain MRI
in order to provide imaging data that could be used to investigate associations between
structural brain variables and cognitive function (Wardlaw et al. 2011).
56  5

56 Incidental findings

Prevalence of incidental findings on neuroimaging

Current knowledge about the prevalence and types of IFs on brain imaging conducted
in asymptomatic populations is informed by a recent systematic review. From a meta-​
analysis of 16 studies of 19,559 apparently asymptomatic people, the pooled prevalence of
neoplastic IFs on brain MRI was 0.7% (95% confidence interval (CI) 0.5–​1.0%), and in 15
studies of 15,559 people the pooled estimate of non-​neoplastic IFs was 2.0% (95% CI 1.1–​
3.1%) (Morris et al. 2009). Additional data from 2000 participants from the Rotterdam
Scan Study estimated that 94.6% of 45–​59-​year-​olds and 98.9% of people aged 75 and
over had white matter hyperintensities, and 7.2% of the total cohort had silent infarcts
(Vernooij et al. 2007).
In contrast, our knowledge of the prevalence of IFs on neuroimaging in patient cohorts
is relatively limited. Estimates of IFs on brain MRI performed in patients is informed
by small (range n  =  12–​931, mean n  =  274) single-​center studies using either 1.5 or
3.0 Tesla scanners, with estimates ranging from 7.9% to 62.5% (Wahlund et  al. 1989;
Lubman et al. 2002; Papanikolaou et al. 2010; Powell & Choa 2010; Koppelmans et al.
2011; Parker et al. 2011; Jaremko et al. 2012; Khandanpour et al. 2013; Proctor et al. 2013;
Winston et al. 2013; Trufyn et al. 2014). While MRI is the most commonly used modal-
ity for performing brain imaging in research, computed tomography (CT) remains the
workhorse of clinical brain imaging. A retrospective study of 3000 CT brain examina-
tions performed in trauma patients identified 30 cases with IFs, which included 11 with
tumors (of which three were benign meningiomas and three lipomas, the remainder
being malignant) (Eskandary et al. 2005). Of 2195 cases who underwent cranial CT angi-
ography for neurological symptoms, trauma, or known intracranial lesions, 39 (1.8%)
had incidental unruptured intracranial aneurysms, who went on either to treatment or
annual surveillance (Agarwal et al. 2014).
Estimates of the prevalence of IFs on spinal MRI also vary widely, from 8.4% to
99.1% (Cheung et al. 2009; Kamath et al. 2009; Park et al. 2011; Quattrocchi et al. 2013;
Cieszanowski et al. 2014). The prevalence of suspected malignant lesions on spinal MRI
in a population-​based sample of 666 participants was 0.4% (Cieszanowski et al. 2014).
Lumbar spine MRI in 1043 population-​based participants in China demonstrated lum-
bar disc degenerative changes in 42% of participants aged 18–​30 years, rising to 88% in
participants aged 50–​55 years (Cheung et al. 2009). Such a high prevalence of IFs in this
population-​based sample raises the question of which IFs could be deemed normal.
The wide ranges in estimates of prevalence of IFs on brain and spine imaging may be
partly explained by variation in investigators’ case definitions and sources of data for IFs.
Prevalence estimates may be influenced by different decisions to classify normal variants
as IFs, such as mega cisterna magna (Khandanpour et al. 2013), or to exclude lesions that
were not deemed clinically relevant (Koppelmans et al. 2011). Data on IFs may be sourced
from IFs documented in available reports, or by dedicated review of images to identify
IFs, and use of these different data sources likely also affects estimates of the prevalence of
IFs. For example, the prevalence of extra-​spinal IFs described in clinical reports of 3000
lumbar spine MRI examinations performed in patients aged 16–​91 years (mean age 59.3,
 57

Scale of the problem of incidental findings 57

1453 (48.4%) men) was 7.2% (217/​3000), which rose almost by a factor of ten (68.7%,
2060/​3000) on dedicated review of images to identify IFs. The lower prevalence in clinical
reports may partly be explained by a lack of reporting of nonserious IFs in clinical prac-
tice, such as diverticulosis (330/​351 unreported), renal cysts (702/​732 unreported), or
postsurgical appearances (13/​16 unreported), but also lack of reporting of a smaller num-
ber of potentially clinically significant IFs that could be reasonably expected to be well
characterized, including abdominal aortic aneurysms (10/​11 unreported), and enlarged
lymph nodes (36/​38 unreported) (Quattrocchi et al. 2013).

Potentially clinically significant incidental findings

A meaningful and useful definition of IFs should include a statement about clinical signif-
icance, or potential health importance (Wolf et al. 2008). Data on the prevalence of poten-
tially clinically significant IFs could be used to inform potential research participants’
decisions about enrolling in neuroimaging research, and to inform the design of study
policies for detecting, handling, and feeding back information about IFs to participants
and their healthcare providers. Some findings, such as sinus opacification, are common
and of little or no clinical significance (Katzman et al 1999; Alphs et al. 2006). It could be
argued that IFs should only be fed back to individuals if they are clinically significant, or
if feedback will provide a strong net benefit (Wolf et al. 2008). These might include IFs
likely to be life-​threatening, where adverse consequences could be avoided or treated, or
that could inform reproductive decision-​making (Wolf et al. 2008). Therefore, accurate
data on the prevalence of clinically significant IFs is paramount.
However, the clinical significance of an IF cannot always be accurately determined.
Research imaging protocols are designed to optimize the collection of data relevant to the
study’s particular question or questions. In contrast, clinical imaging is optimized to dem-
onstrate a suspected diagnosis. Given the range of potential IF diagnoses, optimization
to detect each of these would not be practical, affordable, or, due to the duration of scan
time, tolerable to participants. There have been some calls for the addition of clinical-​
type imaging sequences in research imaging protocols as standard (Milstein 2008), which
should reduce both the rate of false positives (Hegenscheid et al. 2013) (i.e., IFs that are
finally diagnosed as nonserious conditions, artifacts, already known conditions, or are not
confirmed on follow-​up) and the necessity for public healthcare systems to meet the costs
of further investigation and diagnosis. However, adding additional sequences to research
protocols may yield significant extra cost to the study and be impractical to implement,
for example, if scanning time within a center is simply not available, or by lengthening
scan time beyond that which is tolerable to participants (Booth et al. 2010). Indeed, add-
ing clinical standard imaging sequences to research protocols may be perceived as screen-
ing. This would generally be deemed inappropriate given the potential range of IFs that
may be detected, with their differing clinical consequences, variation in the necessity for
or availability of treatment options, and limited evidence that such treatments positively
benefit morbidity or mortality (Zealley 2015).
58  5

58 Incidental findings

The difficulty of handling IFs of potential clinical significance is that lack of a firm
diagnosis is likely to prompt further investigations. There is limited reporting of system-
atic follow-​up of participants with indeterminate IFs. At the very least, potential imaging
research participants should be made aware of the possibility of demonstrating an IF and
that further tests and referrals may be required to accurately characterize it (Illes et al.
2006, 2008). In the event that an IF is finally diagnosed as not clinically significant, in
retrospect, any follow-​up that occurred may be deemed unnecessary. Such unnecessary
follow-​up may have exposed the individual to harm, for example, through the use of ion-
izing radiation for further imaging, or an invasive procedure, without clinical benefit to
the individual. Unnecessary follow-​up may also impact resources of individuals and soci-
ety, in terms of incurring costs of unnecessary healthcare, unnecessary use of healthcare
services, and time away from employment.
The clinical significance of some IFs is currently uncertain due to lack of data on their
natural history. A  systematic review of the clinical significance of white matter hyper-
intensities found associations with risk of incident stroke in six studies of the general
population (hazard ratio 3.1, 95% CI 2.3–​4.1) and with risk of incident dementia in three
studies of the general population (hazard ratio 2.9, 95% CI 1.3–​6.3), leading the authors
to conclude that the identification of white matter hyperintensities should prompt assess-
ment for other risk factors for stroke and dementia in such individuals (Debette & Markus
2010). However, the methods of measuring white matter hyperintensities varied between
studies and risk of incident stroke and dementia with varying volumes was not presented.
Whether it is the presence versus absence, or a particular proportion of white matter
affected by hyperintensities that is associated with increased risk of incident disease
remains unclear. In addition, there is limited evidence of effective preventive therapies for
stroke and dementia in people with white matter hyperintensities. With further research,
judgment of the clinical significance of these and many other IFs is likely to evolve.
In contrast to lesions that can be detected by visual assessment of images, abnormali-
ties of brain tissue volumes, which require segmentation and computation, tend not to
be considered as IFs. Recent studies suggest an association between small hippocampal
volumes with a first episode of major depressive disorder (Cole et al. 2011), and with
genetic risk for Alzheimer disease (Lupton et al. 2016), but there is not enough evidence
yet to support advising assessment for depressive symptoms or cognitive impairment in
participants identified to have hippocampal volumes below a particular level. A small
hippocampal volume may not be readily apparent on visual assessment of images, and
measuring hippocampal volume seems to have a more “active” nature of seeking IFs com-
pared to visual assessment alone. However, it is not clear how performing measurements
on imaging to identify IFs differs from the act of, for example, calculating a cognitive test
score, on which a low score on a clinically validated instrument may also be deemed an
IF. Researchers should consider how to handle abnormal results generated by any data
collection activity or measure that may have clinical implications.
Further studies of the natural history of different IFs and robust evidence for benefits
of treatment are needed. In the meantime, for IFs in which the clinical significance and
 59

Determinants of prevalence 59

benefit of treatments is not known, the usefulness of disclosing information on these to

participants is likely limited. Care must be taken with using current estimates of preva-
lence of IFs, as variability of case definitions will affect any overall prevalence, and instead,
data on the prevalence of potentially clinically significant IFs should guide designs of poli-
cies to handle IFs, and inform potential participants of the likelihood of identifying IFs.
Judgments of the clinical significance of IFs should be informed by empirical data gener-
ated from long-​term follow-​up and studies of the natural history of findings.

Determinants of prevalence
With better understanding of the subject, imaging, and image reader characteristics that
affect prevalence of potentially serious IFs, better predictions will be possible about the
likely prevalence of IFs generated by newly planned studies. Such estimates could then
inform the design of appropriate consent materials and policies for detecting, classifying,
and feeding back IFs in imaging studies, which are now mandated by major funding bod-
ies including the Medical Research Council and the Wellcome Trust (Farrar & Savill 2014;
Medical Research Council & Wellcome Trust 2014).
Subject characteristics, such as age and sex, may affect the prevalence of IFs. Such char-
acteristics are selection criteria likely to be considered at study planning stage, therefore
data on the prevalence of IFs in different groups will inform future studies’ estimates
of the likely prevalence of IFs they will generate, and help them to design appropri-
ate consent materials and policies to handle IFs. Data from the Rotterdam Scan Study
participants show that the prevalence of asymptomatic brain infarcts increases with age,
from 30/​750 (4.0%) in those aged 45–​59, to 47/​257 (18.3%) in those aged 75–​97. Median
volume of white matter lesions also increased, from 1.8 mL in those aged 45–​59 years,
3.1 mL in those aged 60–​74 years, to 7.7 mL in those aged 75–​97 years (Vernooij et al.
2007). In contrast, the prevalence of intracranial aneurysms did not differ significantly
between participants within these age groups (Vernooij et al. 2007).
The prevalence of IFs may vary between men and women. In the Lothian Birth Cohort,
brain imaging of 700 adults aged 73 years (SD 1.5 years) found that the prevalence of IFs
was higher in men (134/​368, 36.4% of men versus 89/​332, 26.8% of women, p = 0.007)
(Sandeman et  al. 2013). However, these prevalence estimates include IFs that may not
be clinically significant, such as arachnoid cysts. Of 1113 consecutively imaged healthy
adults aged 22–​84 years, no significant difference in distribution of men and women was
observed between groups with and those without IFs (Hoggard et al. 2009).
Less is known about the influence of imaging and imaging reader characteristics
on the prevalence of IFs. Sequences and combinations of sequences may influence
the perceptibility and characterization, and therefore the frequency and diagnostic
certainty, of IFs. T2-​weighted sequences are helpful in distinguishing between solid
and liquid lesions, and the use of a contrast agent can make some lesions more con-
spicuous, or demonstrate the extent of a lesion more completely. The volume of tissue
coverage and the resolution of images will also likely increase the prevalence of IFs
60  6

60 Incidental findings

(Maxwell et al. 2015). In one study, there was no difference in the prevalence of IFs in
healthy volunteers imaged on a 1.5 T (31/​374) compared to a 3.0 T (15/​151, p = 0.6)
MRI scanner (Hoggard et al. 2009).
The effect of reader experience on the prevalence of IFs is not known. Reader expe-
rience is likely to affect prevalence for two reasons: first, perception of a demonstrable
lesion may increase with experience; second, interpretation of the clinical significance of
a demonstrated lesion may be more accurate by people with medical, or more specifically,
radiological training. For these reasons, it is natural to assume that consultant radiologists
would be the most appropriate readers of imaging for IFs, being doctors who are highly
trained in perception and interpretation of images. However, there is a lack of evidence
to inform this view. While radiologists may detect many IFs, the proportion of these that
turn out to be serious is not known, and the sensitivity and specificity of radiologists
for detecting potentially clinically serious IFs on nonoptimized, nondiagnostic-​grade
research imaging is not known. Logistically, given the shortage of staff in clinical prac-
tice (The Royal College of Radiologists 2011), it is not feasible for radiologists to report
all research imaging, particularly now that much larger imaging studies are being con-
ducted. One solution may be a network of local reporting radiologists although, where
reported, there appears to have been limited uptake of such services by local researchers
(Cramer et al. 2011). While inexperienced readers may be expected to fail to perceive or
misinterpret some IFs, this is not always the case. For example, correct classification of
a set of 14 CT brain scans, performed in patients with suspected stroke documented in
the European Co-​operative Acute Stroke Study trial book that details imaging findings as
normal or abnormal did not differ significantly between observers classed as experienced
(consultant neuroradiologists, consultant neurologists with an interest in stroke, consul-
tant stroke physicians), and those classed as inexperienced (consultant neurologists, gen-
eral practitioners, trainee physicians) (68% correctly classified compared to 63%, p = 0.3)
(Wardlaw et al. 1999). To date, there have been no published head-​to-​head comparisons
of detection of IFs, or those which are finally diagnosed as serious, between readers of
differing experience, such as trainee radiologists, radiographers, or nonmedically trained
scientists, to inform study policies on the detection of IFs.
Research is needed on participant, imaging, and reader-​ related determinants of
prevalence, to inform estimates of the likely prevalence of potentially serious IFs when
planning new neuroimaging studies. Such data could be generated from prespecified sub-
group analyses of participants, head-​to-​head comparisons between different neuroimag-
ing studies, or between different types of readers within the same study.

The impact of incidental findings

Incidental findings have the potential to impact participants, health services, researchers,
and the wider scientific community. Data are needed on the extent of these impacts, and
on how impact may vary between different methods of handling IFs, to inform the design
of appropriate policies and participant consent materials.
 61

The impact of incidental findings 61

Feedback of an IF could potentially impact an individual’s emotional well-​being and

financial situation, by affecting their employment and ability to obtain and the cost of var-
ious forms of insurance. The Study of Health in Pomerania surveyed 471 participants who
received notification of an IF, with data returned from 405 respondents. Of these, 46.9%
(190/​405) reported some distress while waiting for potential notification of an IF, with
9.9% reporting strong distress during this period (Schmidt et al. 2013). Nondisclosure of
an IF to an insurer would likely render the insurance void (Apold & Downie 2011), with
similar issues being faced by patients and participants undergoing genetic tests (Thomson
1998; Raeburn 2002). However, robust data on the actual impact of receiving feedback
of an IF on insurance and employment are not available, or how these different types of
impact may vary by age, gender, or employment status.
Neuroimaging IFs have the potential to impact the use of a variety of services and
generate associated costs. These include clinic attendance at family doctor and specialist
hospital clinics; additional investigations such as blood tests, further imaging, and inva-
sive diagnostic procedures; medical and surgical interventions; and hospital admissions.
Arranged follow-​up may vary by availability across different health services and health-
care systems, and by the diagnostic certainty of the IFs generated from research imaging.
For example, a study that includes sequences close to diagnostic standard may reasonably
detect an uncomplicated arachnoid cyst and confidently advise that further imaging is
not required. However, an intracranial mass is unlikely to be characterized to the extent
required for clinical management without dedicated, optimized, post-​contrast, clinical
diagnostic imaging, clinical review of the participant, and discussion between doctors
from multiple clinical specialties. Use of gadolinium-​based MRI contrast agents is not
without risk, with 0.2–​3.3 per 1000 injections resulting in an immediate adverse reaction,
and a risk of severe reaction, such as cardiac arrest, in approximately 1 in 40,000 injec-
tions (Prince et al. 2011). Although rare, the risk of such severe reactions to MRI contrast
is offset by the benefits of diagnostic information in patient settings, but given the lack
of benefit to research participants, MRI contrast is generally not used in research stud-
ies, particularly in healthy volunteers. Given the potential costs, feedback of IFs should
perhaps only occur when there is potential benefit for the individual, to minimize unnec-
essary use of resources, particularly within publicly funded healthcare systems (Medical
Research Council & Wellcome Trust 2014).
No published assessment of the service use and cost of follow-​up of IFs takes into
account all of the potential sources described previously. However, particular types of IFs
may lend themselves to standardized clinical management pathways, the costs of which
may be assessed. For example, at the University of Utah Hospital, Salt Lake City, United
States, follow-​up of patients with an incidentally detected nonfunctioning microadenoma
includes blood tests, repeat MRI after 1  year with radiologist report, and consultation
with a physician, at a total estimated cost of $6062—​$6215 USD per patient (Randall et al.
2010). Decision analytical modeling has also been used to estimate costs of follow-​up of
IFs. In a decision analysis study of different strategies for handling incidentally detected
intracranial aneurysms on functional MRI (fMRI), cost-​effectiveness was found to vary
62  6

62 Incidental findings

with patient sex and family history, and experience of reporter (Sadatsafavi et al. 2010).
For example, imaging review by a nonspecialist, such as a nonmedical postdoctoral fel-
low, with confirmation or refutation of detected abnormalities by a radiologist, was not
deemed cost-​effective (Sadatsafavi et  al. 2010). However, decision analytical modeling
is limited by the availability of data to inform the model, and in this case the sensitivity
and specificity of detection of incidental aneurysms of a variety of sizes by a nonspecialist
reader was informed by expert opinion rather than empirical data.
It is extremely difficult to estimate the cost of follow-​up and any cost-​benefit of detect-
ing IFs given the variety of possible detected IFs, variation in clinical practice between
centers, necessity to tailor management to the patient, and differences in costs incurred
between countries and even between different institutions within those countries. The
magnitude of increase of service use and cost by people who receive feedback of an IF,
compared to people of similar age, sex, and comorbidities, might usefully inform our
understanding of the cost and service use impact on healthcare systems, but to our knowl-
edge, such comparisons have not been published.
The impact of IFs on a particular research study and on the wider scientific commu-
nity, in terms of cost of administering an IFs handling policy, and the impact on public
trust and involvement in research, is also unknown. Procedures for handling IFs vary
widely among research imaging centers (The Royal College of Radiologists 2011). Recent
guidance and funding bodies have forced researchers to develop policies to handle IFs
that must be submitted during the application for funding (Medical Research Council
& Wellcome Trust 2014). It is emphasized that such plans be appropriate, in terms of
time and cost (Medical Research Council & Wellcome Trust 2014), but there is currently
little guidance or training to assist researchers with the development and administration
of IFs policies (Wardlaw et al. 2015). Methods and descriptions of the results of current
policies for handling IFs have been published (Hegenscheid et al. 2013; Sandeman et al.
2013; Boutet et al. 2016), but head-​to-​head comparisons of different methods of handling
IFs, the time and cost they take to administer, and their impacts, have not. Appropriate
handling of IFs and clear communication with participants is particularly important for
longitudinal cohort studies, where attrition of the cohort could seriously bias the results
of research arising from the study. In the burgeoning era of big data and biobanking,
research data, including biobanked images, are generated for and are being used by sec-
ondary researchers, that is, those not involved in the process of the data collection. Such
“secondary research” on biobanked images may yield IFs, potentially some years after
the initial data collection. Researchers must consider how to handle IFs detected during
secondary research (Richardson & Cho 2012), and the implications for consent processes.
Biobank participants may give broad consent at the time of data collection for their bio-
banked data to be used for as-​yet-​unspecified future projects, or alternatively, participants
may be contacted to give repeat consent to use their biobanked data at the start of each
new project, so-​called dynamic consent (Steinsbekk et al. 2013). Either way, the implica-
tions for participants and the financial and reputational costs to studies of detecting an IF
months or even years after imaging should be considered.
 63

Public expectations 63

Future financial and reputational costs relating to IFs should be considered by any
research imaging study, not just biobanks. Months or years after imaging, participants
may be diagnosed with conditions and may return to study investigators wanting to
know whether those conditions were in fact visible on their research scan. While there
are no documented cases of this within the literature, the scenario is not unrealistic,
and in such a case a participant may seek legal action or financial compensation, or
both, for a clinically significant finding if it was deemed to have been missed on a
research scan.
To inform the design of future neuroimaging studies, further data are needed on the
impact of IFs, and how these may vary between different policies to handle IFs. Studies of
neuroimaging could build in robust data collection on the impact of IFs on a participant’s
emotional well-​being, employment and finances, clinical follow-​up, and final diagnoses
in order to generate evidence that will help inform future potential research participants’
consent. Data on the impact on health service use and cost of different policies of han-
dling IFs would inform future policymaking. It is in the interests of science that processes
for handling IFs are sensible, appropriate, and clearly communicated to potential and
actual research participants, and to their healthcare providers, in order to maintain trust
in and cooperation with researchers and the wider scientific community.

Public expectations
Maintaining trust in research is paramount as the progress of clinical science depends on
the participation of human volunteers. However, several studies show that participants’
expectations of research may be unrealistic, with research imaging being associated with
clinical diagnosis, and consequently raising expectations that such images will be assessed
by a competent, clinical professional (The Royal College of Radiologists 2011).
The National Child Development Study is a longitudinal cohort study of approximately
17,000 people born during 1 week of 1958 in England, Scotland, and Wales. In 2010,
133 of the participants living in and around Cambridge were invited to complete further
cognitive assessments, of whom assessments were conducted in 45 people, and of these,
7 had previously undergone MRI for clinical diagnosis, and none for research. A qualita-
tive interviewer explained the idea that taking part in a fMRI study “could reveal some-
thing that suggests that there could be a more serious problem […] in about one in 40
scans.” The researcher explained people may have different views on the feedback that
they would like or expect, and offered the 45 respondents five options: not to take part in
a fMRI research study; take part regardless of the provision or not of feedback; take part
only if all potential problems were fed back; take part only if serious, treatable problems
were fed back; or take part only if the study provided no feedback. Of 45 potential imag-
ing research participants, 40.9% reported that they would only participate in a study that
provided feedback on all IFs, with a minority (11.4%) responding that they would only
participate in a study that fed back only IFs that were considered serious and treatable
(Brown & Knight 2010).
64  6

64 Incidental findings

Findings were similar in participants who had already undergone neuroimaging for
research. Participants were invited to complete a web-​based questionnaire about IFs
on neuroimaging if they had acted as healthy controls for fMRI research studies at one
of two imaging facilities in the United States. Over 90% of 104 respondents (mean age
25 years, 76/​104 (73.1%) were undergraduate or postgraduate students) who had under-
gone research brain imaging wished to be informed of any IFs, regardless of its clinical
significance, and 94% wished to be informed by a member of the research team, and 54%
expected any abnormality present to be detected although 84% did not expect images to
be reviewed by a doctor (Kirschen et al. 2006). These expectations would be extremely
costly to meet, particularly in large studies, both in terms of researchers’ time and study
costs. Furthermore, given the range of the definition of IFs by some investigators to
include postsurgical appearances (Sandeman et  al. 2013), and normal variants such as
cavum septum pellucidum (Lubman et al. 2002), this approach is likely to be of limited
benefit to participants. While many potential research participants might anticipate that
their research imaging would be reviewed by a competent professional, the provision
for review of images varies considerably throughout centers, ranging from full review of
images by radiologists, to no review of images by radiologists at all (The Royal College of
Radiologists 2011).
Members of the public perceive the benefits of receiving feedback on IFs to outweigh
potential disadvantages. Detecting a condition before symptoms arise is seen as advanta-
geous by potential research participants as it may allow early intervention, decision-​making
around family planning, or prompt screening for conditions in relatives (Wellcome Trust
et al. 2012). This may be founded on the belief that to detect a disease before it becomes
symptomatic must confer a survival benefit, a concept introduced to the public domain by
widespread public health messages related to screening programs (McCaffery et al. 2016).
As discussed previously, research imaging is not a substitute for clinical assessment and
diagnostic imaging, therefore IFs demonstrated on research imaging may be incompletely
characterized, and may require clinical follow-​up and generate anxiety. However, despite
considering that feedback of IFs may generate shock and worry, and that this may be
unnecessary if an IF turned out to be a false positive (i.e., a nonserious condition, artifact,
condition which turns out already to be known, or a finding which is not confirmed on
follow-​up investigations), there remains overwhelming support from the UK public to
receive feedback on IFs (Wellcome Trust et al. 2012).
People who have health problems but are unable to afford healthcare within a private
healthcare system might view research as an opportunity to have a free scan (Wardlaw
et al. 2015). Not only would such participants be at risk of failing to understand consent,
researchers may find themselves handling more potentially serious IFs than expected.
A  variation of “research tourism” may also exist within publicly funded healthcare sys-
tems, whereby participants may view research imaging either as a faster means to access
health services in order to investigate specific health concerns, or as an opportunity to gain
peace of mind, which would not warrant investigation within such publicly funded health
services (Townsend & Cox 2013). Within developing countries, participation in research
 65

References 65

may be driven by either therapeutic misconception, defined as the mistaken belief by par-
ticipants that they are receiving clinical care, or in order to access treatments and health
services as ancillary care, whereby being a research participant enables them to access
free treatments or diagnostic services for problems unrelated to the purposes of the study
(Mfutso-​Bengo et al. 2008). However, participants may also recognize the potential detri-
mental effects of receiving health-​related information from research studies. For example,
research participants in private healthcare settings in the United States have raised con-
cerns that disclosure of results of genetic research may impact health insurance cover-
age (Murphy & Thompson 2009). To our knowledge, there are no data on the association
of participants’ motivation to take part in neuroimaging and prevalence of IFs, or direct
comparisons of the prevalence of IFs in studies performed within different healthcare sys-
tems. Researchers should consider participants’ existing access to healthcare and potential
motivations for participating in research when preparing information materials and when
obtaining consent and managing participants’ expectations about handling of IFs.
When developing policies for handling IFs, researchers should consider balancing fea-
sibility, in terms of cost and time of administration, with the potential impacts of IFs, and
with participants’ expectations. Such expectations may need to be managed during the
consent process, and evaluation of understanding consent is needed to ensure this process
is adequate.

Looking to the future
Despite the progress to date, difficult issues around handling IFs remain, due to the com-
plex and variable nature of IFs and the lack of robust, empirical data to inform practice.
The usefulness of current estimates of the prevalence of IFs on neuroimaging is limited
by variability in case definitions, methods of determining clinical significance, and lack
of information on natural history. Research on participant, imaging, and reader-​related
determinants of prevalence are also needed to inform our understanding of the likely
prevalence of potentially serious IFs in any new neuroimaging study. Data are needed on
the extent of the impact of IFs on individuals, health services, and the scientific commu-
nity, and how impact may vary between different methods of handling IFs. Together, such
data would build an evidence base to inform the design of feasible policies for handling
and feeding back IFs that do not unduly encumber individual research studies or health
services and that are acceptable to the multiple stakeholders. Such an evidence base would
also facilitate informed consent of participants prior to participating in neuroimaging
research studies while managing their expectations and preserving public trust in medi-
cal research.

References
Agarwal, N., Gala, N.B., Choudhry, O.J., et al. (2014). Prevalence of asymptomatic incidental
aneurysms: a review of 2685 computed tomographic angiograms. World Neurosurgery, 82(6),
1086–​1090.
6  6

66 Incidental findings

Alphs, H.H., Schwartz, B.S., Stewart, W.F., and Yousem, D.M. (2006). Findings on brain MRI
from research studies of occupational exposure to known neurotoxicants. American Journal of
Roentgenology, 187(4), 1043–​1047.
Apold, V.S. and Downie, J. (2011). Bad news about bad news: the disclosure of risks to insurability in
research consent processes. Accountability in Research, 18(1), 31–​44.
Booth, T.C., Jackson, A., Wardlaw, J.M., Taylor, S.A., and Waldman, A.D. (2010). Incidental findings
found in “healthy” volunteers during imaging performed for research: current legal and ethical
implications. British Journal of Radiology, 83(990), 456–​465.
Boutet, C., Vassal, F., Celle, S., et al. (2016). Incidental findings on brain magnetic resonance imaging in
the elderly: the PROOF study. Brain Imaging and Behavior. Advance online publication. doi:10.1007/​
s11682-​016-​9519-​4
Brown, M.A. and Knight, H.M. (2010). Attitudes Towards Participating in fMRI Studies Amongst
Participants in a Birth Cohort Study. CLS Working Paper 2010/​8. Available from: http://​www.cls.ioe.
ac.uk/​library-​media/​documents/​CLS_​WP_​2010_​8_​.pdf [accessed January 30, 2017].
Bunnik, E.M. and Vernooij, M.W. (2016). Incidental findings in population imaging revisited. European
Journal of Epidemiology, 31(1), 1–​4.
Cheung, K., Chan, D., Song, Y., et al. (2009). Prevalence and pattern of lumbar magnetic resonance
imaging changes in a population study of one thousand forty-​three individuals. Spine, 34(9), 934–​940.
Cieszanowski, A., Maj, E., Kulisiewicz, P., et al. (2014). Non-​contrast-​enhanced whole-​body magnetic
resonance imaging in the general population: the incidence of abnormal findings in patients
50 years old and younger compared to older subjects. PLoS One, 9(9), e107840.
Cole, J., Costafreda, S.G., McGuffin, P., and Fu, C.H.Y. (2011). Hippocampal atrophy in first episode
depression: a meta-​analysis of magnetic resonance imaging studies. Journal of Affective Disorders,
134(1–​3), 483–​487.
Cramer, S.C., Wu, J., Hanson, J.A., et al. (2011). A system for addressing incidental findings in
neuroimaging research. NeuroImage, 55(3), 1020–​1023.
Deary, I.J., Gow, A.J., Taylor, M.D., et al. (2007). The Lothian Birth Cohort 1936: a study to examine
influences on cognitive ageing from age 11 to age 70 and beyond. BMC Geriatrics, 7, 28.
Debette, S. and Markus, H.S. (2010). The clinical importance of white matter hyperintensities on brain
magnetic resonance imaging: systematic review and meta-​analysis. BMJ, 341, p. c3666.
Eskandary, H., Sabba, M., Khajehpour, F., and Eskandari, M. (2005). Incidental findings in brain
computed tomography scans of 3000 head trauma patients. Surgical Neurology, 63(6), 550–​553.
Farrar, J. and Savill, J. (2014). UK funders’ framework for health-​related findings in research. The
Lancet, 383(9933), 1954–​1955.
German National Cohort (GNC) Consortium (2014). The German National Cohort: aims, study
design and organization. European Journal of Epidemiology, 29(5), 371–​382.
Hegenscheid, K., Seipel, R., Schmidt, C.O., et al. (2013). Potentially relevant incidental findings on
research whole-​body MRI in the general adult population: frequencies and management. European
Radiology, 23(3), 816–​826.
Hoggard, N., Darwent, G., Capener, D., Wilkinson, I.D., and Griffiths, P.D. (2009). The high
incidence and bioethics of findings on magnetic resonance brain imaging of normal volunteers for
neuroscience research. Journal of Medical Ethics, 35(3), 194–​199.
Ikram, M.A., van der Lugt, A., Niessen, W.J., et al. (2011). The Rotterdam Scan Study: design and
update up to 2012. European Journal of Epidemiology, 26(10), 811–​824.
Illes, J., Kirschen, M.P., Edwards, E., et al. (2006). Incidental findings in brain imaging research.
Science, 311(5762), 783–​784.
Illes, J., Kirschen, M.P., Edwards, E., et al. (2008). Practical approaches to incidental findings in brain
imaging research. Neurology, 70(5), 384–​390.
 67

References 67

Jaremko, J.L., MacMahon, P.J., Torriani, M., et al. (2012). Whole-​body MRI in neurofibromatosis:
incidental findings and prevalence of scoliosis. Skeletal Radiology, 41(8), 917–​923.
Kamath, S., Jain, N., Goyal, N., Mansour, R., and Mukherjee, K. (2009). Incidental findings on MRI of
the spine. Clinical Radiology, 64(4), 353–​361.
Katzman, G.L., Dagher, A.P., and Patronas, N.J. (1999). Incidental findings on brain magnetic
resonance imaging from 1000 asymptomatic volunteers. JAMA, 282(1), 36–​39.
Khandanpour, N., Hoggard, N., and Connolly, D.J. (2013). The role of MRI and CT of the brain in first
episodes of psychosis. Clinical Radiology, 68(3), 245–​250.
Kirschen, M.P., Jaworska, A., and Illes, J. (2006). Subjects’ expectations in neuroimaging research.
Journal of Magnetic Resonance Imaging, 23(2), 205–​209.
Koppelmans, V., Schagen, S.B., Poels, M.M., et al. (2011). Incidental findings on brain magnetic
resonance imaging in long-​term survivors of breast cancer treated with adjuvant chemotherapy.
European Journal of Cancer, 47(17), 2531–​2536.
Lubman, D.I., Velakoulis, D., McGorry, P.D., et al. (2002). Incidental radiological findings on brain
magnetic resonance imaging in first-​episode psychosis and chronic schizophrenia. Acta Psychiatrica
Scandinavica, 106(5), 331–​336.
Lupton, M.K., Strike, L., Hansell, N.K., et al. (2016). The effect of increased genetic risk for Alzheimer’s
disease on hippocampal and amygdala volume. Neurobiology of Aging, 40), 68–​77.
Matthews, P.M. and Sudlow, C. (2015). The UK Biobank. Brain, 138(12), 3463–​3465.
Maxwell, A.W.P., Keating, D.P., and Nickerson, J.P. (2015). Incidental abdominopelvic findings on
expanded field-​of-​view lumbar spinal MRI: frequency, clinical importance, and concordance
in interpretation by neuroimaging and body imaging radiologists. Clinical Radiology, 70(2),
161–​167.
McCaffery, K.J., Jansen, J., Scherer, L.D., et al. (2016). Walking the tightrope: communicating
overdiagnosis in modern healthcare. BMJ, 352, p. i348.
Medical Research Council and Wellcome Trust (2014). Framework on the Feedback of Health-​
Related Findings in Research. Available from: https://​www.mrc.ac.uk/​documents/​pdf/​mrc-​
wellcome-​trust-​framework-​on-​the-​feedback-​of-​health-​related-​findings-​in-​researchpdf/​
[accessed January 30, 2017].
Mfutso-​Bengo, J., Ndebele, P., Jumbe, V., et al. (2008). Why do individuals agree to enrol in clinical
trials? A qualitative study of health research participation in Blantyre, Malawi. Malawi Medical
Journal, 20(2), 37–​41.
Milstein, A.C. (2008). Research malpractice and the issue of incidental findings. Journal of Law,
Medicine and Ethics, 36(2), 356–​360.
Morris, Z., Whiteley, W.N., Longstreth, W.T., et al. (2009). Incidental findings on brain magnetic
resonance imaging: systematic review and meta-​analysis. BMJ, 339, b3016.
Murphy, E. and Thompson, A. (2009). An exploration of attitudes among black Americans towards
psychiatric genetic research. Psychiatry, 72(2), 177–​194.
Papanikolaou, V., Khan, M.H., and Keogh, I.J. (2010). Incidental findings on MRI scans of patients
presenting with audiovestibular symptoms. BMC Ear, Nose and Throat Disorders, 10, 6.
Park, H.-​J., Jeon, Y.-​H., Rho, M.-​H., et al. (2011). Incidental findings of the lumbar spine at MRI
during herniated intervertebral disk disease evaluation. American Journal of Roentgenology, 196(5),
1151–​1155.
Parker, J., Wolansky, L.J., Khatry, D., Geba, G.P., and Molfino, N.A. (2011). Brain magnetic resonance
imaging in adults with asthma. Contemporary Clinical Trials, 32(1), 86–​89.
Powell, H.F. and Choa, D. (2010). Should all patients referred for magnetic resonance imaging scans
of their internal auditory meatus be followed up in ENT clinics? European Archives of Oto-​Rhino-​
Laryngology, 267(9), 1361–​1366.
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68 Incidental findings

Prince, M.R., Zhang, H., Zou, Z., Staron, R.B., and Brill, P.W. (2011). Incidence of immediate
gadolinium contrast media reactions. American Journal of Roentgenology, 196(2), W138–​W143.
Proctor, R.D., Gawne-​Cain, M.L., Eyles, J., Mitchell, T.E., and Batty, V.B. (2013). MRI during cochlear
implant assessment: should we image the whole brain? Cochlear Implants International, 14(1), 2–​6.
Quattrocchi, C., Giona, A., Di Martino, A., et al. (2013). Extra-​spinal incidental findings at lumbar
spine MRI in the general population: a large cohort study. Insights into Imaging, 4(3), 301–​308.
Raeburn, S. (2002). Implications of genetic testing for the insurance industry: the UK example.
Community Genetics, 5(2), 102–​109.
Randall, B., Kraus, K., Simard, M., and Couldwell, W. (2010). Cost of evaluation of patients with
pituitary incidentaloma. Pituitary, 13(4), 383–​384.
Richardson, H.S. and Cho, M.K. (2012). Secondary researchers’ duties to return incidental findings and
individual research results: a partial-​entrustment account. Genetics in Medicine, 14(4), 467–​472.
Sadatsafavi, M., Marra, C., Li, D., and Illes, J. (2010). An ounce of prevention is worth a pound of
cure: a cost-​effectiveness analysis of incidentally detected aneurysms in functional MRI research.
Value in Health, 13(6), 761–​769.
Sandeman, E.M., Hernandez, M.D.C.V., Morris, Z., et al. (2013). Incidental findings on brain MR
imaging in older community-​dwelling subjects are common but serious medical consequences are
rare: a cohort study. PLoS One, 8(8), e71467.
Schmidt, C.O., Hegenscheid, K., Erdmann, P., et al. (2013). Psychosocial consequences and severity
of disclosed incidental findings from whole-​body MRI in a general population study. European
Radiology, 23(5), 1343–​1351.
Smith, E.E., O’ Donnell, M., Dagenais, G., et al. (2015). Early cerebral small vessel disease and brain
volume, cognition, and gait. Annals of Neurology, 77(2), 251–​261.
Steinsbekk, K.S., Kare Myskja, B., and Solberg, B. (2013). Broad consent versus dynamic consent in
biobank research: is passive participation an ethical problem? European Journal of Human Genetics,
21(9), 897–​902.
Stephan, B.C.M., Tzourio, C., Auriacombe, S., et al. (2015). Usefulness of data from magnetic
resonance imaging to improve prediction of dementia: population based cohort study. BMJ, 350,
p. h2863.
Sudlow, C., Gallacher, J., Allen, N., et al. (2015). UK Biobank: an open access resource for identifying
the causes of a wide range of complex diseases of middle and old age. PLoS Medicine, 12(3),
e1001779.
The Royal College of Radiologists (2011). Management of Incidental Findings Detected During Research
Imaging. London: The Royal College of Radiologists.
Thomson, B. (1998). Time for reassessment of use of all medical information by UK insurers. The
Lancet, 352(9135), 1216–​1218.
Townsend, A. and Cox, S.M. (2013). Accessing health services through the back door: a qualitative
interview study investigating reasons why people participate in health research in Canada. BMC
Medical Ethics, 14, 40.
Trufyn, J., Hill, M.D., Scott, J.N., et al. (2014). The prevalence of incidental findings in multiple
sclerosis patients. Canadian Journal of Neurological Sciences, 41(1), 49–​52.
Vernooij, M.W., Ikram, M.A., Tanghe, H.L., et al. (2007). Incidental findings on brain MRI in the
general population. New England Journal of Medicine, 357(18), 1821–​1828.
Wahlund, L.O., Agartz, I., Saaf, J., Wetterberg, L., and Marions, O. (1989). Magnetic resonance
tomography in psychiatry-​clear benefits for health care services. Lakartidningen, 86(46),
3991–​3994.
 69

References 69

Wardlaw, J.M., Dorman, P.J., Lewis, S.C., and Sandercock, P.A. (1999). Can stroke physicians
and neuroradiologists identify signs of early cerebral infarction on CT? Journal of Neurology,
Neurosurgery and Psychiatry, 67(5), 651–​653.
Wardlaw, J.M., Bastin, M.E., Valdes Hernandez, M.C., et al. (2011). Brain aging, cognition in youth and
old age and vascular disease in the Lothian Birth Cohort 1936: rationale, design and methodology of
the imaging protocol. International Journal of Stroke, 6(6), 547–​559.
Wardlaw, J.M., Davies, H., Booth, T.C., et al. (2015). Acting on incidental findings in research imaging.
BMJ, 351, h5190.
Wellcome Trust, Medical Research Council, and Opinion Leader (2012). Assessing Public Attitudes to
Health Related Findings in Research. London: Opinion Leader.
Winston, G.P., Micallef, C., Kendell, B.E., et al. (2013). The value of repeat neuroimaging for epilepsy at
a tertiary referral centre: 16 years of experience. Epilepsy Research, 105(3), 349–​355.
Wolf, S.M., Lawrenz, F.P., Nelson, C.A., et al. (2008). Managing incidental findings in human
subjects research: analysis and recommendations. Journal of Law, Medicine and Ethics, 36(2),
219–​248.
Zealley, I.A. (2015). Re: Incidental abdominopelvic findings on expanded field-​of-​view lumbar spinal
MRI: frequency, clinical importance, and concordance in interpretation by neuroimaging and body
imaging radiologists. Clinical Radiology, 70(6), 679.
70  7

Chapter 4

Vulnerability, youth, and

homelessness: Ethical considerations
on the roles of technology in the lives
of adolescents and young adults
Niranjan S. Karnik

Adolescence and digital culture

Case scenario: Justin1 is a 14-​year-​old male with a prior history of attention deficit hyperactivity
disorder. He has been managed on low-​dose stimulants for some time, and is emotionally stable and
doing well academically. He is social, joins sports, and enjoys spending time with his friends. To this
point, his parents have limited his use of social media and Justin does not own a smartphone but is
eager to have one like his friends. His parents are consulting his physician to ascertain whether giving
him a smartphone is wise at this age, and they are debating whether to allow him to start using social
media. They express fears about cyberbullying, online stalkers, and other elements that they have read
and heard about in regards to social media and teens.

There is understandable anxiety about the nature of technology and its impacts on the lives
of young people. Over 90% of adolescents now use social media with a significant num-
ber using it on a regular basis and a marked subset reporting nearly constant connection
(Lenhart 2015). Prior to the development of social media and mobile technologies, television
and radio were triggers for similar waves of anxiety. It may be true that every new societal
technology change prompts concern for the impact on adolescents and young people. Much
of this might be traced to a developmental truism—​that young people seek to differenti-
ate themselves from the prior generation. All children go through a phase of development
wherein they seek to establish themselves as autonomous individuals. One requisite to estab-
lish an individual’s identity is to differentiate and separate from other adults to whom an
individual has been connected up to this point in life. For most children, this process of
individuation involves creating separation from parents or guardians. Technology is often an
easy way to achieve this goal. Young people often claim a cultural space in new technology,
and this space can be difficult for parents and other adults to enter. Adults have less incentive
to use these spaces for their everyday needs as they have already established patterns of work,
communication, cultural meaning, and social interaction with their peers. Youth are not only
early adopters of technology for the desire to be in novel spaces, but also precisely due to the
fact that their parents and other adults are less likely to be on these media.
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Adolescence and digital culture 71

When I present talks on social media and adolescence, I often take an informal poll
of the providers in the room to see which platforms they prefer. Facebook, Twitter, and
Instagram often lead the current line-​up. I then assure the audience that if they are on
these platforms their cool factor is likely diminishing and their youngsters are likely now
moving to Snapchat and other newer and more advanced media.
Nevertheless, there are certain heuristics that are useful in considering how adolescents
use new social media. One notion that is important to dispel is the traditional distinction
between “real” and “virtual.” For people who grew up prior to the advent of social media,
the separation between the real world—​that space where they live, work, and have social
interactions—​feels very different from the virtual world built within social media plat-
forms. For adolescents who have grown up in the period of an omnipresent social media
landscape, these worlds are not necessarily separate: they are continuous—​the physical
world connecting with new social media in a rather seamless way. The communications
that they have in the presence of other people feel very much parallel to those online.
Hence, why it is easy to observe young people sending text messages and links to one
another while physically being in the same space.
One of the issues that youth, generally, are apt to not consider is that in the virtual space
people may not be who or what they seem. They see this space as a means to connect with
their peers and friends. As youth emerge from childhood which is traditionally in contact
with friends and family that are relatively narrowly circumscribed by their schools and
families’ social lives, they are then in a developmentally sensitive period of time where
they trust others around them to be like their prior contacts. The virtual space of social
media introduces the potential for people to represent themselves in an alternative way.
Briefly, they may not be who they say they are, and can instead create a character.
This fluidity of expression and projection of self presents a risk for adolescents in that
other adolescents or adults might pose as peers or age-​appropriate friends online when
in fact they may be different. The stories of these types of behaviors have been told many
times in news stories across multiple platforms and need not be repeated here. The coun-
ter to this nefarious behavior is to give adolescents an opportunity to explore themselves.
Adolescents can alter and change their hobbies, interests, gender identity, and even claim
a different sexual orientation within the space of social media. Such exploration can hap-
pen under their own name or handle, or could be created with another pseudonym. While
individuals interacting with a somewhat fictionalized character might justifiably claim
that they are being misled, the youth projecting the character could be learning what their
choices might engender in terms of relationships, people, and connections. They may be
learning the types of people that share their interests and may be using the experience as
a chance for personal growth.
Clinically, I often liken virtual spaces for adolescents and young people to extensions of
their rooms. The computer or smartphone is a portal into their lives and their communi-
cation with others is often taking place in the privacy of their rooms or other unobserved
venues. This leads to a situation where young people often believe they have privacy and
in fact can interact in ways that expose them very publically. Social media creates a new
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72 Vulnerability, youth, and homelessness

form of public space or commons. Many people believe that when they post text, video,
or photos that only their friends can see this. The degree to which these communiques
are limited to a small group is directly related to the degree to which privacy settings
have been enabled. For many adolescents, privacy is not a key concern, especially when
weighed against peer acceptance and social popularity. Hence, young people are more
likely to unknowingly take risks in the space and be unaware of the ways in which their
private information might be used or misused.
Digital literacy—​the education and teaching about the ways that digital media work and
impact our lives—​is an absent part of present educational practices. Society desperately
needs a pedagogical approach to digital culture that starts at an early age because we can
easily witness children as young as 2 or 3 years of age interacting with iPads and iPhones.

Mental health, adolescence, and social media

Case scenario: Debbie is a 16-​year-​old female who presents to her therapist with significant anxiety
and depressive symptoms. She is presently entering her junior year in high school and admits that her
academic performance has suffered over the past year. She has had increasing difficulties getting along
with a group of popular girls in her class. Debbie is unsure as to why she has become a target but notes
that they regularly post comments, taunts, and threats about her on Facebook and other social media.
She is dysphoric and tearful as she describes the ongoing patterns, and notes that she has largely kept
this information to herself and a few friends. She has not yet informed her parents or her teachers who
rarely use these media sources.

The data on the use of online social media and development of mental health problems
is a vexed area. While many popular commentators like the actor Wentworth Miller have
argued for a link between depression, suicide, and other behavioral problems, and the
online environment (Grant 2016), the academic research in this area is more subtle and
less clear. One of the few reviews of this literature concluded that the methods and time
lags for this field lead to an inability to draw conclusions on the direct impact of social
media on mental health (Pantic 2014). While the majority of studies reviewed did find
correlations between amount of time spent on social media and symptoms of depression,
low self-​esteem, and online addiction, the directionality of these relationships is unclear.
A recent study by Lin and colleagues examined 1787 young adults and determined that
there appeared to be a relationship between the amount of social media use and degree of
depressive symptoms (Lin et al. 2016). Nevertheless, the authors were unable, using their
methodology, to assess the directionality of this effect. They speculate that there is a dose
relationship to this effect but a number of questions remain. For example, does use of
social media lead to mental health and behavioral issues or is the mental health problem
driving the youth toward social media use? Correlational studies are unable to assess the
directionality due to their cross-​sectional nature. A set of longitudinal studies is needed
to better understand the nature of these relationships.
One issue that has emerged is cyberbullying. This form of bullying has become an issue
of deep concern for child mental health professionals (Sivashanker 2013) because of the
 73

Autism spectrum disorders and social media 73

multiple impacts that it has on youth in terms of depression and suicidal ideation (Pham &
Adesman 2015; Mitchell et al. 2016; Ranney et al. 2016). In contrast to the broad impacts
of social media on mental health, the specific impact of cyberbullying has been well docu-
mented as being at least as potent as in-​person bullying or even more toxic because of the
extent and remoteness of the attacks. In other words, while social media mitigates the
physical component of bullying, the psychological component may become more toxic
because of the frequency of attacks and the often relative isolation of the victim.
Cyberbullying of teens and adolescents emerges largely from the social context of edu-
cation and peer relationships. The study of social relationships in schools and the sociol-
ogy of education have been significant parts of the social science canon. The introduction
of social media has likely changed this milieu but it also offers a new opportunity to study
and understand adolescent social relationships. These connections or social networks
may be adaptive and promote self-​esteem or resiliency, and they might also be maladap-
tive as in the case of cyberbullying.
Ethically, studying adolescent social relationships is hard. Traditionally, these youth can-
not provide consent because they lack adult decision-​making capabilities. Most scholars
in this area are required to obtain informed consent from the parents or guardians of ado-
lescents, and then the adolescent may be allowed to opt out by virtue of an assent process.
The challenge arises in that the youth who are most at risk of, or being, victimized may
be the least likely to share their true experiences. As in the case outlined at the beginning
of this section, Debbie has yet to inform adults. Is there a scenario where she is going to
be willing to work with researchers who, depending on jurisdiction, may be required to
report the bullying to authorities? Such disclosure would require that her parents learn
about the ongoing issues. While this disclosure may be necessary and even therapeutic, the
researcher is caught in a dilemma of facing likely refusal from the teen and also failing to
capture the realities of what is happening in this context. Based on these structural issues,
studies of adolescence and social media likely overestimate positive outcomes and under-
estimate negative effects. This observation bias cannot be easily overcome under current
research ethics standards. Even anonymous online surveys that are used may suffer from
a degree of observation bias and they are likely at risk for other types of bias due to their
low response rates.

Autism spectrum disorders and social media

Case scenario: James is a 13-​year-​old boy with high-​functioning autism. He attends regular classes
at the local school and has a special education plan that provides additional support. He has been a
victim of bullying in the past due to his autism but seems to have found a good circle of peers that
are protective of him. He generally spends several hours per day online and lately has been spending
time connecting with other youth with autism using online social media and chat forums. He tells his
counselor that he prefers to talk through the computer because it produces less anxiety than talking to
people directly.

Youth with autism often face a variety of challenges. The core illness is character-
ized by difficulties in social communication, stereotypic or repetitive behaviors, lack
74  7

74 Vulnerability, youth, and homelessness

of emotional reciprocity, and, in extreme cases, difficulties in language development.

Autism is now seen as a spectrum illness with youth having significant variation from
mild to severe presentations. Recent data from the US Centers for Disease Control and
Prevention suggest that approximately 1 in 150 children are on the autism spectrum
(Kuehn 2007). This estimate was a marked change from prior studies of autism and some
degree of alarm was sounded about an epidemic of autism. Most clinicians in the field
believe that this trend reflects better assessment methods and education about the disor-
der, and a near-​universal screening that is now undertaken by primary care physicians.
As with most populations, technology and social media use for adolescents with autism
is a two-​sided experience. On the one side, it can be a source of empowerment, connection,
and support from other youth and families similarly impacted. In contrast, it can also be
a space of further isolation and reduction of interaction, and a space where social growth
is not as essential as in other spaces with people present. Current research indicates that
youth with autism spectrum disorders spend the majority of their time watching television
or playing video games, while a minority (13.2%) spend time on social media (Mazurek
et al. 2012). Similarly, a study by Kuo and colleagues found that nearly 80% of adolescents
with autism spectrum disorders report that they watch television for an average of 2 hours
per day (Kuo et al. 2014). In addition, the authors found that 98% of adolescents in their
sample used computers for an average of 5 hours per day. Kuo and colleagues also noted
that they most frequently watched cartoons, played computer or video games, or visited
websites that are about video games. They found that adolescents who visited social net-
working websites or received emails from friends reported more positive friendships (Kuo
et al. 2014). Based on this research, it appears that a minority of youth with autism spec-
trum disorders use social media to connect with friends while a majority of these youth
spend a significant amount of time watching television and playing games on the Internet.
Studying the use of social media by youth with autism is clearly a challenging sub-
field and an area worthy of further investigation. There is some potential in this area to
develop interventions keyed to the social network and Internet environments that could
help young people on the spectrum to develop better social skills, and reduce the impact
of autism in their lives. The challenge will be balancing the autonomy that should be
accorded to adolescents who are mildly impacted by autism, and their ability to make
decisions for themselves or with minimal support from their parents or guardians, against
the need to protect more significantly impacted youth who may be more vulnerable to
risk in social networks. Consent and assent processes for these youth need to follow the
patterns for adolescents more generally, but further consideration may need to be given
to the particularities of subgroups of youth with autism.

Lesbian, gay, bisexual, and transgender youth and social media

Case scenario: Amy is a 17-​year-​old, male-​to-​female (MTF) transgendered youth who began her
transition about 3 years ago. She was supported by her mother and encountered significant resistance
 75

Lesbian, gay, bisexual, and transgender youth and social media 75

from her father who continues to refuse to acknowledge her new gender identity. She has been meet-
ing young men to date via a social networking profile. She practices safer sex inconsistently and is
often pressured by her partners to have unprotected sex. As her primary care physician, you are now
giving some consideration to prescribing pre-​exposure prophylaxis to better protect her against HIV
transmission.

Lesbian, gay, bisexual, and transgender (LGBT) youth are a subgroup of adolescents
and young adults who deserve special attention. LGBT youth face multiple challenges
including rejection or violence in the coming out process, increased risk of mental health
and substance use disorders, and, depending on the LGBT subgroup, increased risk of
sexually transmitted infections (STIs).
Mustanski and colleagues have published a series of papers on the ethics of research
with LGBT youth (Mustanski 2011; Fisher & Mustanski 2014; Ybarra et al. 2016). They
generally argue that the health disparities facing these populations merit a change of
approach to ethical standards for considering studies in this area. They note multiple
challenges for investigators in this field including heightened perceptions of risk, cum-
bersome requirements for parental consent, and a lack of expertise concerning this pop-
ulation on IRBs.
Elements of Mustanski’s critique are accurate especially in regard to the lack of experi-
enced investigators in this subfield who are willing to serve on institutional review boards
(IRBs). The lack of knowledgeable researchers who are willing to expend time and effort
to serve on an IRB is likely a result of the small size of this field. In addition, Mustanski
accurately outlines why adolescents under the age of 18 would potentially be at greater
risk in the event of inadvertent disclosure to parents and others who may not be aware of
the youth’s sexual orientation or gender identity.
Mustanski’s analysis of risk estimation for LGBT youth is more problematic. He and
his colleagues argue in the absence of evidence that subjective estimates of suicide, sub-
stance use, and HIV/​STI risks are overestimated and that most research should be con-
sidered minimal risk because of the techniques used by social and behavioral scientists.
The difficulty with this risk analysis is that it ignores several lines of research that indicate
higher risks of mental health issues, substance use, suicidality, and HIV/​STI transmission.
In order to mitigate these risks, researchers need to develop clear assessment plans for
addressing mental health and substance use disorders. In regards to LGBT youth, it would
be prudent to involve clinicians who routinely work with patients. Many researchers have
clinical credentials but do not have active clinics or lead clinical teams. In the conduct of
research with LGBT youth, attention needs to be paid to providing care to patients when
the need is clear or the risks are high. This approach is more likely to create a safer pro-
tocol for LGBT youth, and also maximize the potential for advancement of the research
without having adverse events. Such an approach will likely also better address concerns
that IRBs may raise and serve to convince reviewers who only see risk, that the research
teams have protocols for working with these youth that acknowledge risks and address
them directly.
76  7

76 Vulnerability, youth, and homelessness

Homeless youth
Case scenario: Gene is a 15-​year-​old male who was kicked out of his home when he was age 13 and
announced to his family that he was gay. He ran away from his rural environment in a southern US
state and hitchhiked his way to Chicago. He lived on the streets for several months, and survived by
engaging in the sex trade and sex work. He would often sleep with people in exchange for a night in a
bed, and a shower. Some of these people would sometimes give him money, and he often found himself
using drugs with them, especially alcohol, marijuana, and methamphetamines. He comes to the home-
less drop-​in shelter at times to meet with a case manager as he is hoping to get clean and go to college.

Homeless youth are a major social problem with estimates varying in the range of 1.6 to
2 million youth annually experiencing homelessness (Edidin et al. 2011). The social forces
that drive youth on to the streets include domestic violence, perceived LGBT identity, and
economic instability or poverty. All of the groups described earlier in this chapter includ-
ing youth with mental health issues, autistic youth, and LGBT youth are at disproportion-
ately higher risk of becoming homeless. Most homeless youth in the US come out of the
fractured foster care system where young people who turn age 18 “age-​out” and are ineli-
gible to remain in their foster homes or receive ongoing state support. This transition has
been identified repeatedly as an ongoing source of homeless youth and small programs
have been established to stem this trend but none of these have achieved the growth and
coverage that are needed to reduce youth homelessness.
In this section I will review some of the homelessness research I have pursued with
an interdisciplinary team across three institutions. In this manner, I hope to highlight
practices we have developed or used to underpin our research from a strong ethically
informed perspective. Our research team has been working with homeless youth for
the past 7 years in Chicago and 2 years before that in San Francisco. We initially started
by chronicling the mental health and substance use challenges faced by this popula-
tion (Quimby et al. 2012; Castro et al. 2014). These studies demonstrated that this was
a population in high need. Our research also began to show that many homeless youth
use the Internet and social media at high rates (Goldberg et al. 2013). This finding was in
line with our colleague Eric Rice and his team’s findings in Los Angeles-​based homeless
youth (Rice et al. 2011).
We sought to develop an intervention based on cell phones that would enable us to
better reach these youth and to intervene at an earlier time point. We discussed our proj-
ect with staff members at several of the community-​based organizations with which we
have partnered with in the past, and also undertook some qualitative research to guide
our work (Goldberg et  al. 2013). As we assembled our research protocol we initially
thought we would deliver a trauma-​informed sleep intervention using cell phones that we
would give homeless youth. We then launched a series of five focus groups with shelter-​
based youth (Kaiser et al. in press). The youth in the focus groups urged us to change the
approach to our study. They agreed that sleep and trauma are major issues but they felt
that their more pressing issues related to anxiety and depression. They advised us to direct
our treatment toward these symptoms.
 7

Homeless youth 77

In the course of our protocol creation we heard questions from various individuals
about three issues including (1) distribution of high-​quality smartphones, (2) appropri-
ate amount of compensation, and (3) monitoring youth using tracking software. First, we
opted to give these youth the best smartphones we could afford to buy or have donated.
This logic was challenged because many observers assume that homeless youth will use
any technology that is given or donated to them. Our experience was different in that
we discovered that homeless youth value the best and most current technology, and will
go to great lengths to direct funds that they get toward their phone or obtaining cell/​
data time. The rationale is simple—​when you lack a permanent physical address, a virtual
one is even more essential and important. Homeless youth live through their phones and
use them as means to search for resources, keep connected to friends and family, and to
entertain themselves. Thus, from our perspective, giving a high-​quality smartphone was
an important part of our study.
Compensation for underserved or impoverished populations is always a point of con-
cern for review committees. The balance point is to give compensation that is not coer-
cive and yet acknowledges the time and effort that the youth put into working with our
research team. While our distribution of a smartphone and 6 months of data plan are a
major part of the compensation, we also knew that the measures we were asking youth to
complete for follow-​up require time and effort on their part. We opted to give gift cards to
a local store where they could obtain food or clothing.
When considering compensation, there is also a justice issue that arises. It would be
ethically inappropriate to give an impoverished youth less compensation than a wealthier
youth who was participating in the same study or the same type of study. This issue arises
even though the power to coerce may be greater for the impoverished youth. One of the
issues that my team has debated repeatedly is how to value time in a research study that
is spent completing measures or other questionnaires. There is no easy answer and hence
why I have avoided specifying amounts—​the answers to these questions will vary by the
study, the topics under investigation, the time required, and locality. We work closely with
our community-​based partners to define appropriate compensation levels. We believe
that it is important to repeatedly visit these issues, and consider them at regular intervals
and in tandem with local human subject protection committees.
Our study makes use of novel software from Northwestern University’s Center for
Behavior Intervention Technologies (CBITs) called Purple Robot. This software is able to
send comprehensive user data from the phone and tell us locations, contacts, texts, emails,
and which apps are used. There are also algorithms that the CBITs teams have developed
using smartphone sensor data to estimate factors like sleep and mobility. All of these
capabilities give the appearance of a very invasive study. In the course of our focus groups,
we reviewed the use of this software with the homeless youth. They asked good questions
about what the data would be used for, and also requested that the software be removed
at the end of the study period. The focus groups supported the use of this approach if the
findings would help other homeless youth. We included specifics about the monitoring
element of the study in our consent forms that all study participants sign.
78  7

78 Vulnerability, youth, and homelessness

Our study is presently in progress and to this point our team has not faced any major
problems with the consent process. We are providing telephone-​based brief psycho-
therapy to homeless youth and also enabling them to contact their study therapist via a
custom-​designed text messaging interface. We hope that these interventions will increase
the likelihood of homeless youth engaging in mental health services.

Conclusion
Vulnerable youth and social media is a new area of research. In our experience work-
ing with homeless youth, there has been an exploration of appropriate research practices
and approaches which we tried to define within existing standards and in tandem with
community-​based stakeholders. Further research is needed in developing appropriate
ethics standards for research in this population. In particular, it is clear that adolescents
and youth have a different view of privacy than prior generations. They are more apt to
share deeply personal elements of themselves on social media and do so in a way that
they see as empowering. Further research should examine the intersection of privacy and
social media for young people in order to understand this space better and to develop
appropriate standards for researchers to follow.
Finally, IRBs are advised to undertake to educate their members about the needs of
these youth populations so as to be better positioned to judge protocols in this subfield.
Knowledge about adolescents, LGBT youth, the impact of homelessness and trauma on
brain development, and technology are all presently lacking on most IRBs. These com-
mittees should also seek external consultation when protocols fall outside of their areas of
expertise and draw from individuals who have worked in these subfields.

Note
1. All clinical examples in this chapter are created for educational purposes only and do not reflect any
patients directly.

References
Castro, A.L., Gustafson, E.L., Ford, A.E., et al. (2014). Psychiatric disorders, high-​risk behaviors, and
chronicity of episodes among predominantly African American homeless Chicago youth. Journal of
Health Care for the Poor and Underserved, 25(3), 1201–​1216.
Edidin, J.P., Ganim, Z., Hunter, S.J., and Karnik, N.S. (2011). The mental and physical health of
homeless youth: a literature review. Child Psychiatry and Human Development, 43(3), 354–​375.
Fisher, C.B. and Mustanski, B. (2014). Reducing health disparities and enhancing the responsible
conduct of research involving LGBT youth. The Hastings Center Report, 44(Suppl 4), S28–​31.
Goldberg, S., Karnik, N.S., and Hunter, S.J. (2013, October). Technology Usage and Social Support in
a Population of Inner-​City Homeless Youth. Presented at the 60th Annual Meeting of the American
Academy of Child & Adolescent Psychiatry, Orlando, Florida.
Grant, S. (2016, March 29). Wentworth Miller opens up about depression and suicidal thoughts
in candid Facebook post. MTV News. Available from: http://​www.mtv.com/​news/​2858392/​
wentworth-​miller-​facebook-​weight-​gain-​memes-​depression-​suicide-​the-​lad-​bible/​
 79

References 79

Kaiser, E., Zalta, A.K., Boley, R.A., Glover, A., Karnik, N.S., and Schueller, S.M. (in press). Exploring
the potential of technology-​based mental health services for homeless youth: a qualitative study.
Psychological Services.
Kuehn, B.M. (2007). CDC: autism spectrum disorders common. JAMA, 297(9), 940.
Kuo, M.H., Orsmond, G.I., Coster, W.J., and Cohn, E.S. (2014). Media use among adolescents with
autism spectrum disorder. Autism, 18(8), 914–​923.
Lenhart, A. (2015). Teens, Social Media & Technology Overview 2015. Washington, DC: Pew Research
Center.
Lin, L.Y., Sidani, J.E., Shensa, A., et al. (2016). Association between social media use and depression
among U.S. young adults. Depression and Anxiety, 33(4), 323–​331.
Mazurek, M.O., Shattuck, P.T., Wagner, M., and Cooper, B.P. (2012). Prevalence and correlates of
screen-​based media use among youths with autism spectrum disorders. Journal of Autism and
Developmental Disorders, 42(8), 1757–​1767.
Mitchell, S.M., Seegan, P.L., Roush, J.F., Brown, S.L., Sustaíta, M.A., and Cukrowicz, K.C. (2016).
Retrospective cyberbullying and suicide ideation: the mediating roles of depressive symptoms,
perceived burdensomeness, and thwarted belongingness. Journal of Interpersonal Violence. Advance
online publication. doi:10.1177/​0886260516628291
Mustanski, B. (2011). Ethical and regulatory issues with conducting sexuality research with LGBT
adolescents: a call to action for a scientifically informed approach. Archives of Sexual Behavior,
40(4), 673–​686.
Pantic, I. (2014). Online social networking and mental health. Cyberpsychology, Behavior and Social
Networking, 17(10), 652–​657.
Pham, T. and Adesman, A. (2015). Teen victimization: prevalence and consequences of traditional and
cyberbullying. Current Opinion in Pediatrics, 27(6), 748–​756.
Quimby, E.G., Edidin, J.P., Ganim, Z., Gustafson, E., Hunter, S.J., and Karnik, N.S. (2012). Psychiatric
disorders and substance use in homeless youth: a preliminary comparison of San Francisco and
Chicago. Behavioral Sciences, 2(3), 186–​194.
Ranney, M.L., Patena, J.V., Nugent, N., et al. (2016). PTSD, cyberbullying and peer violence: prevalence
and correlates among adolescent emergency department patients. General Hospital Psychiatry,
39, 32–​38.
Rice, E., Lee, A., and Taitt, S. (2011). Cell phone use among homeless youth: potential for new health
interventions and research. Journal of Urban Health, 88(6), 1175–​1182.
Sivashanker, K. (2013). Cyberbullying and the digital self. Journal of the American Academy of Child
and Adolescent Psychiatry, 52(2), 113–​115.
Ybarra, M.L., Prescott, T.L., Phillips, G.L. 2nd, Parsons, J.T., Bull, S.S., and Mustanski B. (2016).
Ethical considerations in recruiting online and implementing a text messaging-​based HIV
prevention program with gay, bisexual, and queer adolescent males. Journal of Adolescent Health,
59(1), 44–​49.
80  8

Chapter 5

The neuroethical future of wearable

and mobile health technology
Karola V. Kreitmair and Mildred K. Cho

Introduction
Imagine you come home to your apartment after a long day at work. It is a comfort-
able  72ºF (22ºC), just as you like it, because your smart phone has alerted your smart
thermostat to your impending arrival and activated the heating in time for you to walk
through the door. Your wrist-​worn heart rate monitor, the size of a wrist watch, which
also functions as an activity tracker, GPS device, and pulse monitor, detects a slightly
elevated heart rate, and the sweat-​sensing fabric of your smart shirt measures cortisol in
your sweat. These data are sent wirelessly to your sound system, which chimes in with
a soothing Chopin Nocturne. You just now remember that you had run out of almond
milk this morning, but fortunately your smart fridge has ordered some online and it is
now sitting in a little box in front of your door. Also waiting for you is your salmon din-
ner, delivered from the local Italian restaurant. Your blood nutrient wearable device, a
noninvasive Band-​Aid-​like patch that continuously measures your glucose, iron, elec-
trolytes, and proteins in your blood, has deduced that your high-​density lipoprotein is
low, but that your glucose is high. The computer in your smart phone matched this infor-
mation with all nearby delivery-​enabled restaurants, cross-​referenced it with your taste
preferences—​which it learned via machine learning from accumulated data from your
smart plates—​then deprioritized recently consumed meals to ensure an element of nov-
elty and made the optimal choice. After you finish your dinner the cortisol levels in your
sweat decline and the smart music serenades you with a more vigorous Bach as you use
your smart tooth brush to apply precisely the right amount of pressure during your 2-​
minute teeth cleaning. Tooth brushing movements, times, and patterns are also relayed to
your designated smart phone app, where they are displayed in graphic format. Finally, you
sink into your bed, which is fully enabled via your smart mattress pad to track your heart
rate and sleep cycles, and offset disturbing light levels or detected noise pollution with
soothing orange melatonin-​activating light and lullabies of circadian rhythm-​mimicking
frequencies.
Of course, you need not imagine it, since (almost) all of this technology already exists.1
Wearable and mobile technology, along with the Internet of Things (IoT), has firmly estab-
lished its foothold in virtually every arena of twenty-​first century Western life. In addition to
 81

Introduction 81

the near ubiquitous activity trackers (such as Fitbit®, Jawbone®, and Misfit®) that are esti-
mated to constitute an over $5 billion USD industry by the year 2019 (Lamkin 2015), there
is a huge array of other wearable technology on both the consumer and industrial markets,
with new modalities seemingly appearing on a weekly basis. This technology includes smart
clothing, headphones, shoes, wristbands, ski goggles, and jewelry, as well as smart mouth
guards, ovulation trackers, personal trainers, and asthma monitors (Wearable Technologies
2016). Devices may be unobtrusive patches worn on the skin, sensors woven into clothing,
or even ingestible sensors swallowed inside pills (Belknap et al. 2013; Banerjee et al. 2015;
Lehmkuhle et al. 2015). Technologies can mine location, activity, breathing rate and volume,
sleep patterns, heart rate, sweat, blood chemistry, and even brain waves for biometric data
(Lupton 2013).
Furthermore, these wearable devices are inextricably connected with mobile technol-
ogy, smartphones, smart watches, tablets, and personal computers in intelligent ways.
Through mobile apps and mobile platforms that allow the integration of data from mul-
tiple apps, biometric data is stored, processed, and represented in colorful visual formats.
The data can be shared online and on social platforms; one’s performance can even be
used to compete in games or as part of an employer wellness incentive.
Healthcare emerges as a natural target for wearable and mobile technology. Indeed
thousands of wearable devices and mobile apps have been developed and are in use
for healthcare purposes (Zheng et al. 2014). Health-​related platforms, such as Apple’s
Health Kit (Apple Inc. 2016), allow for the integration of health and fitness data from
different mobile apps as well as wearable technologies. Furthermore, Apple’s Research
Kit permits the creation and roll out of medical research apps, for example, Stanford’s
My Heart Counts (Apple Inc. 2015; Stanford Medicine 2016). Proponents for the use of
this technology in healthcare see a future in which medically relevant data are wirelessly
relayed to one’s physician or electronic health record on a continuous basis, obviating
the need for cumbersome in-​office visits and patients’ subjective logging (Lupton 2013).
Many of the same ethical issues that arise with wearable and mobile technology in gen-
eral are exacerbated when the technology enters the domain of neuroscience, neurology,
and mental health. Technology here runs the gamut from transcranial magnetic stimula-
tion (TMS) systems designed for the casual user, such as the neuro-​stimulating wearable
Thync® (Zinko 2015), to seizure monitoring devices for epileptics, such as the EEG Patch™
(Lehmkuhle 2015), to mobile apps intended to provide nontraditional modes of mental
healthcare (see “A case study: Mental health apps”).
In this chapter, we conduct an exploration into some of the neuroethical issues associ-
ated with wearable and mobile technology. In “Classifications,” we classify neuro-​and
mental health wearable and mobile technology according to a number of ethically rel-
evant criteria, including the purpose, functionalities, and user profiles of the technology.
In “Ethical considerations,” we consider the accuracy and reliability of these technologies,
and address the issue of privacy and confidentiality. We also provide a discussion of new
opportunities and issues with informed consent. We then broaden the angle to see how
this technology factors into the deprofessionalization trend in healthcare in general and
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82 The neuroethical future of wearable and mobile health technology

introduce a particular case of nontraditional technology-​enhanced mental healthcare. We

use the example of the company 7 Cups of Tea, as it is for us, a case study for many of the
ethical promises and concerns of this new technology. Finally, we conduct an analysis of
the possible effect of wearable and mobile technology to our conception of self and our
authentic experiencing of life.

Classifications
The concept of wearable devices eludes simple definition, so in this section we provide the
parameters of what falls within this category. As already stated, any discussion of wearables
must recognize that such technology is inextricably linked with the mobile technology,
usually smartphones, that support it. Consequently, we cannot in any principled way sepa-
rate wearable from mobile technology. In the arena of healthcare in particular, the mobile
health aspects relevant to our discussion cut across mobile platforms and wearable devices.
Indeed, in many ways the smartphone is itself a wearable device. It accompanies individu-
als almost everywhere, including during exercise and sleep, and can be used as an activity
tracker, as well as a means to measure an array of other biometric and behavioral dimen-
sions (Bonnington 2014). It is not feasible, therefore, to distinguish sharply between tech-
nology that is worn on the body, such as a wristband or a patch, and a smartphone. In this
chapter we are thus looking at an inclusive class of technologies that covers mobile tech-
nology and devices traditionally thought of as wearables. In fact, some forms of wearables
are not worn at all, but are ingested or inserted. For the purposes of brevity, we will refer to
all members of this class as technology*. Roughly, we can think of the class of technology*
as encompassing technology that is worn, adhered to, ingested, or inserted in the body, or
that is contained on mobile computing platforms, that provides and/​or manipulates data
generated by the physiological, behavioral, and environmental features of an individual’s
quotidian activities. We delineate the parameters of this technology* in what follows.
It is useful to make categorizations along three dimensions: purpose, functionality, and
usage profile. Purpose refers to the goal or aim of the particular technology in a given con-
text. Functionality refers to the method by which that technology operates. Usage profile
describes the kind of user using the technology.

Purposes
We have identified five general purposes of this technology*.2 These are:
◆ education
◆ diagnosis
◆ treatment
◆ crisis management
◆ research.
 83

Classifications 83

A brief description of these five purposes is as follows:

Education: Technology* can be used to educate the user and to deliver customized infor-
mation in easy, immediate fashion. For this purpose, technology* is not categorically
different than traditional online sources of information, with the exception that the
information is mobile and accessible in a way that PC-​based access of online informa-
tion is not.
Diagnosis: Technology* can be used as a diagnostic tool for neurological and mental
health issues. Technology* can be employed to determine whether an individual is
afflicted with a particular neurological condition or is suffering from a given mental
health problem. The technology* may even be used to identify from which neurologi-
cal or mental health problem the user is suffering.3
Treatment: Treatment can also be a purpose of this technology*. The notion of “treat-
ment” is complicated, as it lies on a spectrum. In its strictest form, a “treatment”
requires that it be applied to a “disease.” However, here we mean “treatment” in a more
inclusive sense. For instance, we can think of a glass of warm milk as a “treatment”
for sleeplessness. This does not imply that sleeplessness is, in general, a condition that
qualifies as a disease, or that a glass of warm milk is a proven method of alleviating
this condition. Rather we use the idea here merely in the sense that the technology*
considered to be a “treatment,” is intended and/​or used as a means of intervening with
or addressing a state that is found to be undesirable. Thanks to the mobility of smart
phones and the worn/​embedded nature of wearables, devices can be used to adminis-
ter anything from soothing words and sounds, to doses of nicotine or other drugs, to
electronic stimulation, to virtual reality set-​ups that are intended to reprogram one’s
thoughts (Luxton et al. 2011; Leonard 2014; Alba 2015b; Loria 2016). It should be
noted that the notion of treatment, as we use it here, in no way implies that the means
thus described are effective.
Crisis management: Though arguably a subset of treatment, the purpose of crisis
management distinguishes itself by being a generally short-​term use, intended for
immediate effect, that the user employs in states of high mental distress or an acute
neurological event (Samson 2015). Technology* used for crisis management tends
to be either direct interventions of the technology, such as when the technology is
used for a one-​off calming effect or administering of medication, or a method for
alerting relevant persons or authorities in the case of a crisis (Luxton et al. 2011).
Diagnosis: Finally, technology* may also be used to record data of a population with-
out the intent of treatment. This constitutes the research purpose of this technology*.
Research is also distinguished from clinical applications such as diagnosis and treat-
ment, in that data are generally de-​identified. Research, conducted either by medical
researchers, or the technology provider, or even lay people, may often be occurring in
parallel with one or more of the other purposes.
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84 The neuroethical future of wearable and mobile health technology

Functionalities
Having outlined the five purposes of this technology, let us now turn to the functionalities
with which these purposes are to be achieved. Some of the most common functionalities
of this technology are:
Tracking: First and foremost, this technology allows individuals to track a variety of
bodily, mental, and environmental dimensions. Some of the most important ones are
as follows:
Sleep—​One of the most obvious ways in which technology* interacts with neurologi-
cal and mental health issues is through the tracking of sleep. There is a wide array of
sleep trackers available. Many are wrist-​worn, such as Fitbit®, Jawbone®, and Misfit®
(S­tables 2016). These mainly use motion sensors to monitor sleep and sleep cycles,
displaying a large array of data to one’s smartphone or other mobile device. But
there are also sensors that are placed in the bed and connect to a smartphone via
Bluetooth®, for example, Sense® and Beddit®, or body-​sized sensors that are placed
under the bed sheets, track sleep patterns and are connected to lamps that acti-
vate to wake the sleeper during the lightest part of her sleep, for example, Withings
Aura™ (Haslam 2015). Of course, smartphones also have sleep tracking apps, though
purpose-​built technologies appear to be more accurate (Winter 2014).
Activity and location—​Besides their use for measuring fitness, which also has effects
on mental health (Folkins & Sime 1981), activity trackers are used for detecting
specific neurological or mental health conditions (Banerjee et al. 2015). There are
apps that track activity for the purpose of monitoring an individual’s bipolar disor-
der as reduced activity indicates a depressive phase, such as Mood Rhythm™ (Voida
et al. 2013). There are sensors (worn on the wrist or elsewhere on the body) that are
used to monitor the activity and whereabouts of individuals with dementia, such as
9Solutions products (9Solutions n.d.). Wearable clothing (e.g., LifeShirt™) is used to
research behavior and activity in people with schizophrenia (Miniassian et al. 2010).
Many such devices and technologies are also equipped with alarm systems that alert
the user or a designated care giver when either the user’s location or her activity is
outside of pre-​set values (Samson 2015).
Electroencephalogram (EEG)—​Continuous EEG monitoring, such as EEG Patch™
(Lehmkuhle 2015), uses small, waterproof wearable patches that are placed on the
scalp of a person suffering from epilepsy and enables continuous seizure tracking.
Electromyography (EMG)—​Convulsive seizure detection and warning systems, such
as Brain Sentinel® (Cavazos et al. 2015), are being developed. They are worn on the
biceps and measure skeletal muscle electrical activity.
Electrocardiogram (ECG)—​ECG tracking, for instance in wearable vests and shirts
such as those produced by Hexoskin™ (Banerjee et al. 2015), allows for monitoring
ECG which can be used in the diagnosis of dementia.
 85

Classifications 85

Breathing volume—​Smart clothing, such as Hexoskin™, can also track breathing

volume that may be correlated with mental and neurological events (Banerjee
et al. 2015).
Heart rate (HR)—​HR is also measured more simply by the smartphone itself using its
camera, for example with ReachOut Breathe™ (iTunes App Store 2016b). This may
be used to combat the physical symptoms of stress.
Sweat composition—​The composition of an individual’s sweat may be tracked via con-
tinuous sweat sensors. The user can measure glucose, lactate, sodium, potassium,
and skin temperature using, for example, UC Berkeley’s wearable sweat sensor
(Geddes 2016). In future, sweat analysis of further chemicals is likely, giving insight
into an individual’s stress, hydration, and exertion levels.
Blood-​alcohol levels—​Alcohol levels can be tracked transdermally using, for example,
the University of Washington’s Vive (Jeffrey 2014). This may be useful in the moni-
toring of substance abuse.
Ingestion—​Tiny ingestible sensors that are placed inside of pills transmit information
about time and dosage of ingestion to a patch worn on the body, which transmits
information via Bluetooth® to a mobile device, using, for example, Proteus Health
(Belknap et al. 2013). This allows for the monitoring of adherence to medication
schedules.
Logging:  There are a plethora of mobile apps that allow an individual to log different
aspects of their mental and physical ongoing. There are apps for logging daily mood,
eating patterns, sleep patterns, and social interactions. These are in service of providing
more insight into an individual’s mental health problems such as anxiety, depression,
post-​traumatic stress disorder (PTSD), eating disorder, and substance abuse disorders.
Logging differs from tracking in that it is requires active entering of information by the
user, rather than the passive tracking that can occur without the user’s ongoing active
participation (Luxton et al. 2011).
Vocal analysis: By recording and analyzing short snippets of phone calls, mobile apps can
detect speech patterns associated with bipolar disorder; Priori™ (Walker 2015) is one
example.
Video and photography: Mobile and wearable technology allows users and healthcare
provider to exchange video and photos (Luxton et al. 2011).
Communication:  While this may seem like a fairly traditional use of this technology,
the expansion of online messaging into the mental healthcare arena has allowed for
more continuous access of a patient to her provider, for example, Breakthrough™ and
Talkspace™ (Lamas 2014).
Information delivery: Many mobile mental health apps primarily provide the user with
specialized information. These resource services are often combined with one or more
of the other functionalities, such as PTSD Coach™ (Luxton et al. 2011).
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86 The neuroethical future of wearable and mobile health technology

Quizzes and questionnaires: Apps such as What’s my M3™ (iTunes App Store 2016c) are
designed both to diagnose and to provide ongoing progress reports on conditions such
as mood disorders.
Activity tasks: Some mobile apps provide tasks that users have to complete for diagnostic
purposes. These include tapping and breathing tasks, for example, ReachOut Breathe™
(iTunes App Store 2016b).
Games: Gamification is one way in which this technology* has made an impact on men-
tal healthcare. Users can use values “achieved” on their technologies* to compete
against others or themselves. SuperBetter™ (Roepke et al. 2015) is one example of this
technology.
Medication delivery:  Some technologies*, for example, Chrono Therapeutics (Alba
2015b), deliver treatment such as nicotine replacement therapy, and then tailor
the coaching recommendations on the app to the amount of nicotine replacement
consumed.
Augmented reality: While virtual reality headsets are not typically thought of as “wear-
able” technology*, developers are beginning to use this functionality as part of addic-
tion treatment, by recreating trigger situations for the addict, and then providing
cognitive skills for the patient to avoid succumbing to her addiction (e.g., University
of Houston Virtual Reality Lab, Loria 2016). Moreover, augmented reality, such as
Google Glass™, that overlays information onto reality and thereby reminds or nudges a
user about relevant information, may be useful in addressing neurological and mental
health issues.

Usage profiles
Technologies* can also be categorized based on the type of user. We have identified four
relevant usage profiles:
Direct-​to-​consumer use: This category comprises the technology* that is commercially
available, that consumers can purchase directly, and that is not mediated by a health-
care provider or other professional.
Provider-​mediated clinical use: Technology* in this category may be either commer-
cially available or not. However, it differs from the previous category in that it is
administered and monitored by a healthcare professional, such as a neurologist or a
mental healthcare provider.
Provider-​mediated research use: Research may be conducted with this technology*, in
which case it is monitored by a researcher. Research uses differ from the previous two
use profiles in that they have no clinical (diagnostic or therapeutic) intent.
Third-​party use: Although this practice is not yet common with neuro-​and mental health
wearable and mobile health technology, technology* may be used by employers as part
of a wellness incentive, by universities and schools to encourage healthy behavior, by
 87

Ethical considerations 87

the military and hospitals to track the practices of soldiers/​physicians, and by insur-
ance companies to learn more about their subscribers.
We have thus identified the various purposes, functionalities, and usage profiles that
are implicated in the generation of ethical issues of this technology*. As we will see, the
ethical issues that arise, arise out of a combination of these three dimensions. In “A case
study: Mental health apps,” for example, we find that the purpose of treatment as pursued
by the direct-​to-​the-​consumer user emerges as particularly precarious. Having laid the
groundwork we now move on to delineate the various ethical issues.

Ethical considerations
Accuracy and reliability
A primary consideration with this technology*, indeed all technologies involved in a
person’s well-​being and healthcare, is accuracy and reliability. Here, the extent to which
accuracy and reliability matters depends both on the usage profile as well as the pur-
pose. Technology* that is used for clinical purposes and is provider mediated demands a
high level of accuracy and reliability. In treating epilepsy, a clinician may base her treat-
ment plan on the readings from an EEG patch—​a small patch worn on the scalp that
continually tracks seizures over the course of multiple days (Lehmkuhle 2015)—​and in
dealing with bipolar disorder, schizophrenia, or dementia, on the data of a wearable sleep
and activity tracking sensors (Alba 2015a; Banerjee 2015). Any medical device that is
used in clinical decision-​making in the United States must conform with Food and Drug
Administration (FDA) regulations for medical devices (FDA 2014). This ensures a certain
degree of sensitivity and specificity of the device, which is obviously necessary to prevent
harmful medical advice.
In general, the FDA’s approach to regulation is risk-​based, that is, dependent on a con-
sideration of the potential risks of the technology not working as intended, as well as based
on the specific health-​related claims the developer makes about the product (FDA 2013).
However, technology* may not always be used as specified or intended. Commercially
available devices that are not regulated by the FDA can also be used by healthcare provid-
ers for clinical purposes (Sutner 2016). Here, accuracy and reliability are not regulated
and devices have been found to be inaccurate (Geddes 2015; Cipriani 2016). This presents
a problem when clinicians rely on such devices for the purposes of diagnosis or treatment.
Naturally, accuracy and reliability is also critical for the purpose of research. Often
researchers have to rely on participants correctly employing the technology*, since it is
used remotely and researcher have little to no oversight. A subject that is being tracked
for dementia might forget to put on or activate her device and consequently is recorded
as having been stationary all day. Moreover, the identity of the person who is wearing the
device could also be at issue. This, however, becomes less of a concern when the technol-
ogy* includes devices that are implanted, inserted, or even ingested.
An issue for research applications of this technology* may arise when it is intended for
dual use. For example, some vocal analysis platforms are intended both for researching
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88 The neuroethical future of wearable and mobile health technology

speech patterns associated with conditions such as depression or bipolar disorder and
are simultaneously being used by insurance companies to evaluate their policy hold-
ers (Walker 2015).4 Given this dual purpose of both research and diagnosis, incentives
may not be aligned for the user, and data may be inaccurate as a result. For example,
when an individual uses technology* to participate in a corporate wellness program, the
researcher’s goal of obtaining accurate data, may not be those of the user, who is trying to
do well in a competitive, and possibly remunerated, setting. Moreover, given the remote
nature of this technology*, which is of course touted as one of its benefits (e.g., perform-
ing EEG readings on-​the-​go rather than in-​office), correct use is not always easy to ensure
in research contexts.
Prima facie, technology* that is used directly by the consumer and is commercially
available may seem to have the least stringent requirements for accuracy and reliability.
Casual usage of an activity tracker, for example, even if the measurements are inaccurate,
seems unlikely to have a major detrimental impact on a person’s health and behavior.
After all, if the idea is to motivate an individual to participate in healthier behavior, being
off by a few percentage points should not matter too much. However, individuals are
increasingly using this technology* in ways that amount to treatment, in the sense speci-
fied earlier of mental health problems, enabling individuals to address conditions such
depression, anxiety, obsessive–​compulsive disorder, eating disorders, and PTSD (Luxton
et al. 2011). Technology* used in this arena (mainly mobile or online services) are largely
unregulated, and are therefore not legally required to meet minimum accuracy, reliability,
safety, or efficacy standards.
With the presence of the internet in every facet of modern life and the spread of technol-
ogy* advancing at a staggering pace, individuals are increasingly empowered with respect
to their psychological health, taking treatment into their own hands. Traditional mental
healthcare is often inaccessible particularly for young people (Melnyk 2007). Moreover,
a do-​it-​yourself attitude toward healthcare, along with patient advocacy and citizen sci-
ence groups, is gaining prominence (Sarasohn-​Kahn 2008; Greene 2016). In the time of
Uber and Airbnb, individuals are moving away from professional providers of services
and toward the soliciting of services from technology* enthusiasts or financially moti-
vated lay people. Individuals are replacing psychotherapy with online services in which
anonymous “listeners” provide support. Accuracy and reliability matter to the extent
that users are employing this technology* for diagnostic and treatment purposes, which
indeed seems to be the case (Jacobson 2014). While some individuals may be helped in
their mental healthcare by technology* that is accessible and cheap, or free, and provided
by altruistic or well-​meaning outlets, the lack of oversight of technology* used in this cat-
egory, either through government regulation, legislation, or professional self-​regulation,
means that inaccurate and unreliable information is a serious risk.5

Privacy and confidentiality

Wearable and mobile health app technology used for neurological and mental health pur-
poses also raises new concerns with respect to privacy and confidentiality of data. Much
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Ethical considerations 89

of the data involved in mental health is sensitive and it is not clear that this technol-
ogy* has the requisite precautions in place to deal with data of this sort. In the direct-​to-​
consumer category, for instance, the mobile, wearable nature of this technology* makes
it easy for users to share sensitive information about themselves in a non-​private, non-​
confidential way. Of course, voluntary sharing of identified sensitive medical information
on social media, on platforms like PatientsLikeMe, or in games is always problematic.
However, neurological and mental health information from wearable devices is arguably
more sensitive to the extent that it can be coupled with GPS-​tracked location and other
information that gives unprecedented insight into an individual’s behavior. This can make
her vulnerable to criminal activity, social discrimination, and employer retaliation.
Users of this technology*, especially children, may not be aware just how accessible
their data are, or what the potential effects of a loss of privacy may be. However, providers
of the technology* arguably have a duty to apprise users of the non-​confidentiality of their
data. Given the lack of comprehension that is present when users click through usage
agreements, it is not clear that this duty is being satisfied (Felt et al. 2012). In the United
States, in the direct-​to-​consumer category, devices and apps that are not considered to
be medical devices by the FDA are under no obligation to comply with Health Insurance
Portability and Accountability Act (HIPAA). Individuals are likely to underestimate the
accessibility of this information, which suggests greater efforts must be made to empha-
size the non-​private status of this information, as well as possible negative consequences.
A further concern is simply the security of data. Medically sensitive data is stored
on personal devices, such as smart phones, that are not HIPAA compliant and security
breaches both there and on the servers of the technology* developers who are receiv-
ing the data are unavoidable (McNeal 2015). Moreover, hackers may actually hijack the
device itself and track the user or issue malicious guidance (Leavitt 2011), which would
not only endanger the data, but could have dangerous consequences for the user’s health
and safety.
Users’ privacy may also be at risk in the provider-​mediated clinical category. When a
user receives an alert or a signal from her technology*, this may be more intrusive than
receiving an email or phone call. The likelihood of a bystander noticing a buzzing or flash-
ing wearable device is high and might result in socially uncomfortable situations. This
indicates both the promise of this technology*, since messages can be relayed to patients
in a more time-​sensitive manner than ever before, and the peril, since these messages may
be less private than is desirable.
Third parties may also be employing this technology* in ways that are worrisome from
a privacy standpoint. Insurance companies (e.g., Aetna and Humana) are using voice
analysis during phone calls to detect whether a person may be exhibiting speech patterns
that are indicative of depression (Hodson 2014; Walker 2015). The purpose is to monitor
whether that person is engaged with “activities like physical therapy or taking the right
kinds of medications” in an effort to ensure that individuals on short-​term disability ben-
efits return to work sooner (Sanicola 2015). Often, individuals are not even informed that
their voices are being analyzed, because of the risk that that might cause the individual to
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90 The neuroethical future of wearable and mobile health technology

modify his speech patterns.6 Technology* that conducts this kind of voice analysis may
be administered remotely or be installed directly on the user’s smartphone. When voice
data is being recorded for the purpose of monitoring smartphone users, privacy and con-
fidentiality may not be regulated by HIPAA or other regulation, and there is a risk that the
individual’s privacy is not being adequately respected.
Finally, data security and privacy laws vary internationally, but technology* and smart
phones move across borders. Europe, for instance, has strict, centrally mandated privacy
laws that allows users to remove personal information about them from online searches
as well as prevent the transfer of data between companies or across borders (European
Union 1995), while such laws are nonexistent in the United States. Since European laws
apply not only to hardware physically located in Europe, but similarly to all data accessed
through search engines in Europe (European Commission 2014), this might mean that
while an individual located in the United States has no recourse to prevent her employer
from recording data pertaining to her practices, the same individual when travelling in
Europe does, raising issues of justice and fairness.

Consent
Medical consent forms are notorious for being difficult to understand, and indeed mis-
understood (Akkad et al. 2006). Given that consent with this technology*, in particular
in the direct-​to-​consumer category, is usually indicated by a tap on a mobile screen, it
is likely that users’ comprehension of data usage, sharing, privacy, security, and other
important issues may be similarly low (Felt et al. 2012). Users may believe they own or
have control over the sharing of their data, while the app developer collecting the data is
bound, in fact, only by the voluntary terms set forth in the poorly understood consent
agreement (Rosner 2014). Users may be unaware that the data they generate may be sold
for commercial gain (Kaye 2014). In addition, the context of a smart phone app may elicit
less than rigorous consideration, due to an app being viewed not as a serious medical
intervention. Moreover, should the development company go out of business—​a com-
monplace occurrence in the fast-​paced start-​up world—​the data may be bought by a dif-
ferent company with no obligation to honor the terms of the original consent.
Consent is a particular concern for technologies* that offer unregulated online or
mobile mental health services. Users and participants as young as 15 or 13 years old are
permitted to use these services and even here very little effort is made to verify the age or
identity of the user (7 Cups of Tea 2016e). In fact, many technologies* stress the anony-
mous nature of their services and actively discourage users from revealing any identifying
information, which raises concerns of a lack of accountability on the part of the provider.
It is unlikely that such young individuals understand the complexities of consenting to
releasing sensitive information about themselves and more protections probably ought
to be in place.7
At the same time, the potential for two-​way interaction between technology* users and
researchers or clinicians presents an opportunity for novel approaches that may be more
effective than existing, traditional means of obtaining consent. Early developers of some
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Ethical considerations 91

medical research apps, including ResearchKit, utilize multimedia and animation, and
require research participants to go through a set of screens that explain the research prior
to consent being obtained (Stanford Medicine 2016).
In the provider-​mediated clinical use category, users also may not understand that
while the primary goal of data generated will be clinical, physicians are permitted to
share data for research purposes (US Department of Health and Human Services 2003).
Electronic health records that have been de-​identified, but linked to identifiable informa-
tion have been consistently used in research settings without explicit informed consent,
even though there is evidence that patients expect and prefer to be asked for such consent
(Cho et al. 2015). Despite such research not being considered human subject research in
the United States, it may nonetheless be a violation of patient autonomy and the principle
of respect. This issue may be exacerbated when the correlated data include locations fre-
quented, phone calls made, items purchased, or websites visited (Rothstein 2010).
In the instances where there is a lack of explicit informed consent with research con-
ducted on technology*-​generated data, the issue of incidental findings is also complicated
(Illes et  al. 2008). For instance, data gleaned from this technology*, intended to study
something unrelated, might reveal that a particular user exhibits a pattern highly corre-
lated with dementia—​maybe going back in and out of the same room, or dialing a number
wrong multiple times. Should the user be alerted to this? In the absence of an explicit
directive, as may be the case with de-​identified research data, the researcher cannot know
whether the user wants to be informed of a finding that suggests she may have a poten-
tially serious medical condition. Moreover, the participant will likely not have appropriate
expectations for such findings, as her intentions may have been more casual; she may have
worn the technology* or downloaded the app as light-​hearted entertainment.

Democratization of healthcare
Technology* in this area lends itself to individuals taking both clinical decision-​making
and mental health research into their own hands. We look more closely at how this tech-
nology* is influencing traditional mental healthcare in the next section; here we con-
sider some general features of how this technology* contributes to the democratization
of healthcare.
Within the category of research, wearable and mobile technology in neurological and
mental health area allows users to track large amounts of data about themselves. This
copious amount of data has the potential to be mined either individually, or in conjunc-
tion with other users, outside of the umbrella of professional research teams or academic
institutions. While there may not yet be a publicly accessible repository of wearable and
mobile technology* data for neurological or mental conditions, models for such data-
bases exist in Harvard’s Personal Genome Project (Church 2005) and the American Gut
Microbiome Project (Garbarino & Mason 2016). Moreover, individuals who are invested
in the medical research for particular conditions are finding a voice on patient advocacy
and data collection sites such as PatientsLikeMe, where they share data with each other, as
well as with commercial entities (PatientsLikeMe n.d.).
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92 The neuroethical future of wearable and mobile health technology

Increasingly, the roles of patient, provider, subject, and researcher are becoming blurred.
Big data projects where self-​trackers contribute clinical data, which nonprofessional
data scientists analyze, are becoming more widespread (Sarasohn-​Kahn 2008; Kelty &
Panofsky 2014). This raises issues regarding the roles and responsibilities of the actors
engaged in this “citizen science.” Since this research is typically not publicly funded and
since individuals engaged in this research are generally not associated with academic or
research institutions, the regulations and norms that usually apply to healthcare research
may not apply. So far we have not seen massive citizen science endeavors in neurology
or mental health arenas, as we have seen with genomic data, but it seems only a matter
of time that data consolidated from this technology* become subject to big data analysis
projects. It is thus important to determine whether in addition to general duties of non-​
maleficence to others, lay researchers possess any special duties, for example, duties of
veracity, confidentiality, and data sharing, associated with scientific research.
Similarly, in the clinical category, nonprofessional individuals are taking on roles hith-
erto reserved for trained professionals (see “A case study: Mental health apps”). While this
offers the promise of fillings gaps in clinical care, little is known so far about the kinds of
responsibilities implicated in this kind of democratization of healthcare. Do nonprofes-
sional treatment providers have the same duties of care as professionals? If not, is this a
function of a difference in role, or a difference in training? Or is this difference in respon-
sibilities due to a different set of intentions or aims inherent in the definition of a lay per-
son healthcare provider? Does it matter what the expectations of the individuals seeking
treatment are? And if the responsibilities of a professional and a lay person healthcare
provider are similar, are these responsibilities being effectively discharged by such “citizen
clinicians”? We address some of these questions in the case study we consider in the next
section.

A case study: Mental health apps

In this chapter we have already pointed to some of the issues with accuracy, privacy, con-
sent, and the democratization of healthcare involving this technology*. We now take a
closer look at these issues with respect to a particular application of mental healthcare
technology*. To this end, we look at 7 Cups of Tea as a case study for the issues we are
considering. 7 Cups of Tea is an online and mobile service intended to help individuals
cope with their emotional and mental health concerns. Launched as a start-​up by psy-
chologist Glen Moriarty in 2014, his vision is one of a democratized, nonprofessional
mental healthcare counterpart of such sharing economy services as Uber and Airbnb. The
service connects individuals seeking relief from mental health concerns, such as alcohol
and drug abuse, bullying, anxiety, bipolar disorders, domestic violence, eating disorders,
depression, and self-​harm, with nonprofessional, volunteer listeners who provide emo-
tional support and counselling (Google Play 2016; iTunes App Store 2016a).8 Both users
and listeners are anonymous. The simplest version of the service is free, while the cost for
the premium version, offering a personalized progression path, ranges from $6.24 USD
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Ethical considerations 93

per month with a 2-​year subscription to a lifetime subscription for $419.95 USD (7 Cups
of Tea 2016f).
Given the recent advisory by the US Preventive Services Task Force (USPSTF) to screen
the general adult population, including pregnant and postpartum women, for depression
(Siu et al. 2016), and the fact that the USPSTF is poised to recommend similar screen-
ing in 12-​to 18-​year-​old adolescents (Siu & US Preventive Services Task Force 2016) it
stands to reason that a greater incidence of diagnosis and treatment will be in demand,
which traditional mental health services, already overextended, will struggle to fulfill
(Melnyk 2007). Moreover, it is likely that adolescents in particular will increasingly seek
out cheap or free, nontraditional, readily-​available treatment options, such as mobile apps
and online services.
Let us thus take a closer look at such technologies*. There are indeed online therapy
services that operate with licensed therapists and adhere to professional guidelines and
regulations, utilizing the communication and information functionalities listed discussed
previously. These services show considerable promise for patients dealing with affective
disorders (Wagner et al. 2014) and include examples such as the US Veterans Affairs
telemedicine service, but also private providers such as Talkspace™ and Breakthrough™.
Additionally, other mobile and online technologies function as self-​help guides and refer-
ence sources for mental wellness concerns. These technologies* utilize the information,
quizzes, and questionnaires, and sometimes activity task functionalities. Such resources
can provide useful information to individuals who may wish to enhance their well-​being
through approaches such as mindfulness or meditation, or learn about cognitive behav-
ioral or dialectic behavioral therapy.
A third category of services, comprising technologies* such as 7 Cups of Tea, can rea-
sonably be taken to offer something akin to therapy; they offer the advice or commentary
of concerned but nonprofessional lay people, fellow sufferers, or both. This may look like
a form of peer counseling, but it is problematic, as it intimates the guise of traditional
therapy. For example, 7 Cups of Tea advertises that these listeners are specialized in issues
“ranging from panic attacks and bullying to eating disorders, surviving a breakup, and
more” (Google Play 2016a; iTunes App store 2016a).
Employing the categories of purposes, functionalities, and usage profiles we introduced
earlier, we find that the purposes involved here are primarily education and treatment.
Users seek out this technology* to learn more about the particular mental health issue
they perceive themselves to be experiencing, and they aim to treat these issues by talk-
ing them through with and receiving guidance from nonprofessional listeners, as well as
progressing along the games, quizzes, and activity tasks that constitute their progression
paths. At the same time, research is occurring in the background with this technology*
(Baumel 2015). Finally, while crisis management is explicitly a purpose 7 Cups of Tea
rejects as being one of its applications, there are likely instances where this technology*
is employed for the purpose of seeking out psychological help in times of critical mental
health need.
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94 The neuroethical future of wearable and mobile health technology

The usage profile implicated in this technology* is direct-​to-​consumer. This technol-

ogy* is not mediated by healthcare providers, and individuals mostly seek out these kinds
of services at their own discretion. Of note is that with this technology* the providers that
are implicated are themselves not professionals, but rather unpaid volunteers, who pro-
vide services and whose reputation is built on user reviews, or as the case may be ‘cheers’,
‘badges’, and ‘compassion hearts’ (7 Cups of Tea 2016c).
Ethical issues arise if services such as 7 Cups of Tea may reasonably be taken to be offer-
ing therapy or counseling. We ask, therefore, whether a reasonable individual could per-
ceive 7 Cups of Tea and similar services as offering therapy. 7 Cups of Tea explicitly states
that listeners are not psychiatrists or psychologists, and that it does not intend to establish a
professional–​patient relationship, or diagnose, test, treat, or recommend a course of treat-
ment (7 Cups of Tea 2016b). However, there are at least three reasons why people may
reasonably have the expectation that the company is offering a service akin to counseling.
First, the kinds of conditions that 7 Cups of Tea markets target fall within the pur-
view of mental health therapy. Depression, anxiety, PTSD, eating disorders, bipolar
disorder, and substance abuse are all conditions recognized by psychiatric associations
around the world (World Health Organization 1992; American Psychiatric Association
2013). Such disorders have serious consequences for individuals and considerable time
and effort have been expended to develop therapeutic and pharmaceutical treatments.
Second, the kind of listener–​user relationship 7 Cups of Tea is seeking to engender is
one characterized by emotional support and (in some cases) a deeper ongoing rela-
tionship (Google Play 2016; iTunes App Store 2016a). These are similarly features of
a healthy therapist–​patient relationship, so to draw a comparison between the two is
not unreasonable. Third, the motivations 7 Cups of Tea suggests for making use of
its service are ones that seek to favorably compare this technology* with traditional
therapy. Glen Moriarty, the founder of 7 Cups of Tea, states that travel to and from the
therapist is cumbersome and that therapists tend to judge their patients—​both unde-
sirable aspects of traditional therapy that are absent from this technology* (Lufkin
2014). Moreover, traditional therapy is “expensive and carries an unfortunate stigma”
(7 Cups of Tea 2016a). This technology* thus presents itself as pursuing similar aims as
mental health therapy, while fulfilling desiderata that such traditional means cannot.
Given that the above-​mentioned considerations provide sufficient cause to believe that
a reasonable person might view this technology* to have aims similar to those of tradi-
tional mental health counseling or therapy, we ask whether the technology* meets those
aims. If not, and if the failure of meeting these goals carries undesirable ethical implica-
tions with it, we may conclude that this technology* ought not to be permitted in its pres-
ent form. The ethical issues that arise with this technology* are specific instances of issues
we discuss in the aforementioned sections of this chapter.

Accuracy and reliability

One major ethical concern for this technology* is a lack of accuracy and reliability. Leaving
aside the question of what the legal responsibilities of service providers like 7 Cups of Tea
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Ethical considerations 95

may be, the combination of minimal training of the nonprofessional listeners combined
with the gravity of some of the conditions for which this service is advertised, increases
the risk of harmful or misguided medical advice. We also worry that this technology*
may be conveying a false sense of therapeutic efficacy. The problem here is not merely
that these mobile or online services are not providing effective treatment, but that users
are eschewing actual effective treatment for the sake of these services under the mistaken
belief that these services provide effective interventions. Since users on a site like 7 Cups
of Tea can be as young as 13 years—​with parental consent, though this consent is not
confirmed ​it is likely that users may believe that they are effectively treating their mental
health issues, when in reality they are not.
In a recent study, Baumel (2015) finds that individuals who engaged both in sessions on
7 Cups of Tea and with a real-​life psychotherapist, rated the support provided by online
nonprofessional listeners as equally or more helpful than that of the professionals. This,
Baumel argues, is because individuals find online listeners to be more genuine. But of
course, whether an individual finds the therapist to be genuine is not the true measure of
the efficacy of the intervention. The efficacy of nonprofessional listener services must be
assessed according to actual medical outcomes rather than user satisfaction. Moreover,
the perceived genuineness of listeners may actually exacerbate the false sense of therapeu-
tic efficacy this technology* is providing.
While the efficacy of technology* in this third category is an important question that
must be studied empirically, it is worth noting that nonprofessional listeners are not
trained to handle individuals in situations of crisis with serious and potentially life-​
threatening conditions. As already noted, 7 Cups of Tea does state that its service is not
intended for crisis situations (7 Cups of Tea 2016e). However, while such a disclaimer
may be legally exculpating, we argue that 7 Cups of Tea nonetheless has an ethical obliga-
tion toward individuals in states of great mental distress. Particularly if users have strong
expectations that listeners can provide assistance in critical situations, this technology*
has some duty to offer precisely such assistance. It is a real concern to us that listeners
may provide inaccurate and inadequate medical advice in such critical situations. Further
exacerbating this concern is that there seems to be a large turnover amongst listeners, sug-
gesting not only that there is little consistency or opportunity to build up expertise, but
that accountability is also limited.

Privacy and confidentiality

As is the case with other mental health and neuro technology*, privacy and confidential-
ity considerations also arise with services such as 7 Cups of Tea. Since such technolo-
gies* do not technically constitute mental health counseling, official privacy regulations
are not in place. This means that, for example in the United States, listeners and service
providers such as 7 Cups of Tea are not bound by HIPAA privacy regulations that limit
the extent to which psychiatrists and therapists may discuss medical information about
their patients with third parties (US Department of Health and Human Services 2003).9
Of course, technologies* like 7 Cups of Tea may have their own privacy agreements, but
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96 The neuroethical future of wearable and mobile health technology

these are not legally mandated. As a private company, it is within its rights to pass on user
data to third parties for the purposes of marketing or consumer research, which 7 Cups of
Tea explicitly states it does (7 Cups of Tea 2016e). Listeners of course face similar privacy
concerns as any information they reveal about themselves, either toward 7 Cups of Tea or
a particular user, is also not legally protected. For both listener and user, this highlights
precisely the concern we stressed above. Moreover, communications between listeners
and users on 7 Cups of Tea are not encrypted and are thus under considerable threat of
unauthorized interception and monitoring (7 Cups of Tea 2016b).

Democratization of healthcare
Having looked at issues with this technology* including accuracy and reliability, privacy
and confidentiality, we now consider how this technology* illustrates the concerns dis-
cussed in “Democratization of healthcare.” As we have already argued, technology* such
as 7 Cups of Tea seeks to augment and possibly replace traditional mental healthcare with
accessible, democratized, and nonprofessional avenues of counseling and therapy. We can
now consider what sorts of responsibilities this might generate for the nonprofessional
treatment providers—​where treatment is intended in the sense discussed in “Purposes”
in the “Classifications” section—​who populate such sites.
Individuals who operate as listeners complete a multiple choice training guide (7
Cups of Tea 2016a). This training consists of clicking through a small number of
screens featuring scenarios that the listener might encounter. Still, this does not equip
them to respond to serious mental health issues that users might be experiencing;
and, 7 Cups of Tea explicitly states that dealing with critical mental health situations
is not the responsibility of the listener (7 Cups of Tea 2016g). For example, listeners
are instructed that if a user appears to be in a state of crisis, they are immediately to
interrupt the session, direct the user to an emergency resource, and terminate the
interaction.
However, given that as we have already argued, a user can have a justifiable expectation
of receiving mental healthcare, the question arises whether a given listener truly has no
ethical responsibilities toward the struggling user with whom she is communicating. If we
believe that responsibilities are generated by the kind of role that an individual occupies,
and if this role shares some of the features of that of a professional mental healthcare
provider, then the listener may well have at least some of the ethical responsibilities that
a professional therapist or counselor has. For instance, it is worth considering whether
listeners, as is the case with counselors and therapists, have a duty to report evidence of
child, partner, or elder abuse (US Department of Health and Human Services 2009). Even
though listeners may not have legal responsibilities in this arena, the role they assume
may engender such ethical duties.
While professional mental healthcare providers are well-​positioned to discharge such
duties of care thanks to their training, it is not clear that nonprofessional listeners are
similarly well-​apportioned. Consider the instruction to cut off communication with
a user who exhibits signs of severe mental anguish. As a listener, one may have been
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Ethical considerations 97

conversing with this user for many hours and have gotten a sense that one is providing
vital support to a troubled person. In abruptly terminating the conversation with such
an individual in what may be a moment of dire need, the user may feel abandoned.
Moreover, due to the anonymous nature of the technology*, unless that user reaches out
to the same listener again, the listener will have no way of knowing whether the user
did seek professional services or, troublingly, acted on emotionally distressed impulses.
In contrast, professional mental healthcare providers are both trained to deal with and
support patients through crises, and in general are privy to a patient’s mental health
developments.
Similarly, many listeners are themselves individuals who are currently or have in the
past struggled with mental health issues. Unlike their professional counterparts, who have
been trained in coping with problematic countertransference, listeners may have nega-
tive emotions triggered and experience a worsening of their own condition as a result of
their relationship with the user. 7 Cups of Tea does suggest that listeners steer away from
subjects with which they themselves are struggling, but listeners cannot know in advance
if or when such a triggering issue may arise in a given session.
A further worrisome feature of the anonymous nature of technologies* such as 7 Cups
of Tea is that listeners have no way of ensuring that users are honest. Listeners may be
trolled, that is to say, a seemingly legitimate user may guide conversations into inappro-
priate or hurtful areas. This can be emotionally taxing for a listener who may be torn
between wanting to support the user and creating some self-​protection against abuse
by inappropriate questions or comments. We believe that this negotiation may be dif-
ficult and harmful particularly for younger listeners.10 7 Cups of Tea listener training
does instruct listeners-​in-​training to terminate a chat when one suspects that a user is a
troll, but there is a risk of cutting off a discussion with a person in actual need of help.11
7 Cups of Tea also releases itself of any legal responsibility for listeners’ actions by stating
that a listener is “solely and fully liable for all conduct, services, advice” and “solely [ …
] responsible and liable for any damages to any member to whom listener provides serv-
ices and where that member suffers damages arising from or connected to such services”
issued within the framework of the service (7 Cups of Tea 2016b). All this suggests that
listeners, who are generally no more than concerned, nonprofessional volunteers and,
with parental consent, can be as young as 15 years old (7 Cups 2016d) are expected to
operate in the context of professional duties and responsibilities for which they are likely
not equipped.
In conclusion, mobile and online mental health technology* has the potential to
make care more accessible. For young people for whom mobile technology is already
integrated into life, it may be particularly beneficial in enabling access to mental health-
care otherwise unavailable. The adoption of a nonprofessional technology* variants
of mental healthcare, however, represents a troubling erosion of professional norms.
Ethical duties and responsibilities are generated by technologies* such as 7 Cups of
Tea. Regulations and oversight in this new area of democratized mental healthcare are
urgently needed.
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98 The neuroethical future of wearable and mobile health technology

Authentic living
Wearable and mobile technology not only constitutes a new means for consumers and
healthcare providers to acquire unprecedented continuous and detailed information
about bodily and environmental goings-​on, it also affects the very way an individual
relates to herself. Thus, any neuroethical overview here would not be complete without
a consideration of the psychological and existential effects this technology* precipitates.
Use of this technology* is touted, particularly in the direct-​to-​consumer category, as
enabling individuals to take control of their quotidian habits and thus improve their over-
all health and well-​being. Increasingly, individuals use this technology* to continuously
track their heart rates, glucose levels, stress levels, activity patterns, food intake, sleep
activity, as well as numerous features of their environments (Boudway 2014). Adherents of
the so-​called quantified self movement, whose slogan may be taken to be “self-​knowledge
through numbers,” aim to employ this wealth of self-​centered data pertaining to their
bodies, minds, and environments to subtly alter everyday behaviors and decisions in pur-
suit of a more efficient, more productive, healthier, and happier life (Wolf 2009). In the
final section of this chapter, we explore a number of concerns that arise as a result of this
pursuit.
Approaching one’s being-​in-​the-​world, to use a Heideggerian notion, through quanti-
fication and self-​tracking presupposes a fundamentally reductionist model of the mind
and mental well-​being (Heidegger 1953).12 Here we do not mean to imply that the mind
is not identical to or supervenient on a physical entity. As do most philosophers these
days, we embrace physicalism about the mind. This does not entail, however, that psycho-
logical, behavioral, and social phenomena are reducible to quantities a wearable device
or smart phone app can track. The difficulty is threefold. Firstly, it is not at all clear that
aspects of daily living that matter to us correspond neatly to quantifiable dimensions.
A feeling of elation after a love interest’s text message may be accompanied by an increase
in heart rate, but it is not therefore given that an increase in heart rate is indicative of a
feeling of elation. Secondly, by quantifying aspects of mental or physiological processes,
we necessarily strip away the complexity and entanglement inherent in the experienced
present. In reality, the phenomenology of a particular instant is composed of a multitude
of mental, environmental, physiological, and antecedent phenomenological experiences
of the world. It is likely that by capturing a measurable data point, we are simply grasp-
ing a partial and conceivably accidental feature of that experience. This means we may
be missing the intended goal—​assuming this goal is something like greater well-​being or
happiness and not merely the attainment of certain quantitative values—​when we seek
to adjust our behavior to attain particular numerical results. Lastly, it may not be the
case that what amounts to a useful quantification of a facet of one individual’s experience
translates across individuals.
In general, the trend toward self-​tracking and the quantified self demonstrates our
changing relationship with health and sickness. As Schüll (2016, p.2) aptly notes, “once
understood as a baseline state temporarily interrupted by anomalous moments of illness,
health has been recast as a perpetually insecure state that depends on constant vigilance,
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Ethical considerations 99

assessment and intervention.” This twenty-​first century attitude toward our health and
well-​being brings with it the burden of constantly being in charge and aware of our bodily
functioning. Traditionally harmless behaviors, for example, sleeping too long, eating
irregularly, or skipping visits to the gym, become medicalized, and normal variation in
everyday life is pathologized. In light of all the technology at our fingertips, it is really a
shortcoming on the individual’s part, we might think, if she fails to keep her physiologi-
cal data points within levels that are hailed as desirable or at least condoned as normal.
Motivational features of these technologies range from gentle reminders to, say, take the
stairs instead of the elevator, to shaming-​inducing social media posts of a person’s unde-
sirable behavior, to physical pain upon the measurement of an unacceptable tracked value,
or the performance of an unsanctioned action (Leonard 2014). This trend may set up
unrealistic, overly onerous expectations of the user, and engender obsession and anxiety.
There is an analogy to be drawn here with calorie counting. Counting calories was long
thought to be a reliable way to reduce body weight. However, evidence is mounting that
by tracking and logging calories as a long-​term strategy, individuals become depressed,
lonely, preoccupied with food, lose their intuitive abilities to listen to their inner signals,
and are more prone to binge-​eating and over-​eating than if they were not counting calo-
ries (Smith et  al. 1999). Similar adverse and counterproductive effects are likely when
individuals attempt to control behavior by quantifying dimensions that previously resided
in the realm of intuitive functioning.
In fact, it has been shown that externally rewarding, inherently pleasurable activities
may negatively affect their enjoyableness. With respect to self-​tracking specifically, Etkin
(2016) provides preliminary experimental evidence that suggests that while measuring
output can increase the amount of activity an individual achieves, it can simultaneously
decrease how much the activity is enjoyed, to the point that it may reduce how happy and
satisfied the individual feels overall. In one study, participants who knew they were track-
ing their progress on walks through nature experienced less joy than those who did not.
It seems it is precisely the drawing of the attention toward output, rather than allowing
the individual to enjoy the pleasurable activity in itself, that undermines motivation and
overall happiness (Etkin 2016).
In a certain sense, we may think of this as an issue concerning the kind of epistemic
access we have to our inner states. While in the past a person may have relied primarily
on immediate access to inner states to know whether she was hungry or sated, tired or
energized, nervous or calm, with the increasing quantification of the self, we are turning
to external technology and thus, mediated access, to inform us of whether we are hungry
or tired, how warm we would like our apartment to be, or the kind of music to which
we would like to listen. This can be seen as an offloading of first-​person capacities to
third-​person means.
Similarly, some philosophers have argued that this technological external cognitive
scaffolding represents a development of the mind into something they call the extended
mind, which consists not only within the biological confines of the skull, but extends
into the world to the extent that information is readily available to the cognizer (Clark
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100 The neuroethical future of wearable and mobile health technology

& Chalmers 1998). As such, the mind, properly conceived, may encompass an indi-
vidual’s computing devices, smart phone, and arguably self-​tracker. Rather than being
merely a theoretical metaphysical stance, the extended mind hypothesis has moral and
existential implications. First, a reliance on non-​biological, external components of our
minds makes us dependent on this technology. Thus, should we temporarily or perma-
nently lose access to this technology, we may be rendered helpless in the face of cognitive
challenges that were hitherto within our capacities. Second, it may erode evolutionarily
established methods of determining bodily needs. Relying on GPS technologies for such
tasks as navigation has been shown to have adverse effects on memory and hippocampal
health (Edwards 2010). It is plausible that relying on technologies for other cognitive
tasks may also have detrimental effects for our brain health. Finally, offloading the moni-
toring of our mental and physiological processes, and relying on third person means
of acquiring self-​knowledge, we risk becoming removed from our bodily selves, rather
than experiencing the world in a present, in-​the-​moment fashion, characteristic of such
phenomena as flow.
We may even think of the integration of self-​tracking into everyday life as altering the
very way individuals relate to and conceive of themselves. Swan (2013, p.95) calls this a
“fourth-​person perspective” on the self. An individual’s being-​in-​the-​world is no longer
immediate, but is mediated by data, to constitute what Schüll (2016, p.8) calls the “self as
database.” This is a self not accessible via ordinary senses and thus is not phenomenologi-
cally parameterized. Rather the self is reconstituted as information, beyond the sensory
domain. The body, rather than functioning as a sensing entity through which the world
is experienced and “gains self-​knowledge [is instead] [ … ] a data-​generating device that
must be coupled to sensor technology and analytic algorithms in order to be known”
(Schüll 2016, p.10). Swan (2013, p.96) believes that the quantified self will be transformed
in to an “extended exoself ” as quantification and self-​tracking make the body “a more
knowable, calculable, and administrable object [ … ]. and individuals have an increas-
ingly intimate relationship with data as it mediates the experience of reality.” While this
future vision constitutes an exciting scenario for some, the mediation of one’s experience
of reality through data risks alienating the individual from her biological, instinctual self.
Much of the intelligence that drives our behavior is evolutionarily entrenched and below
the threshold of conscious decision-​making (Wilson 2004; Gigerenzer 2007). It is not
clear that by inserting a quantified layer between behavior and processing, we will truly
achieve greater mental and physical well-​being.

Conclusion
Neurological and mental health applications of wearable and mobile health technol-
ogy show great promise to benefit humans in their pursuit of health and knowledge.
In particular, in the hands of healthcare providers and medical researchers, this tech-
nology* can aid in the diagnosis, treatment, and research of illness. However, for this
 10

Conclusion 101

technology to be most beneficial to individuals and healthcare in general, it is impor-

tant to address the concerns raised in this chapter. These are (1) accuracy and reliabil-
ity, the absence of which could have harmful consequences for users and researchers;
(2) privacy and confidentiality, which are threatened due to the lack of regulation and
the ease of data sharing; (3)  consent, for which this kind of technology presents a
particular challenge since there is a risk of a mismatch of expectations concerning the
perceived and actual seriousness of the medical intervention; (4) duties and responsi-
bilities that are generated by the democratization of healthcare, for which we particu-
larly looked at the troubling case of direct-​to-​consumer mental health technology; and
(5) authentic living, which may be under threat from the alienating potential of self-​
tracking. We believe that with the appropriate consideration of these issues, new tech-
nologies* can function as empowering tools for neurological and mental health. Not
addressing these important issues as technologies* are developing would be a missed
opportunity to bring about such beneficial effects.

Notes
1. Smart thermostats are available from Ecobee (2016), sweat sensing technology from UC Berkeley
(Geddes 2016), and smart fridges from Samsung (Bohn 2016). Smart Plate makes smart plates (Pugh
2015). Smart toothbrushes are available from Kolibree (Kolibree 2016). The sleep system is the
Withings Aura™ (iClarified 2014).
2. In general, the purpose of a technology* is determined by the developer. However, the developer-​
intended purpose may be subverted by the user and a new or extended purpose may be generated.
The notion of “purpose” is meant to encompass all these meanings.
3. Examples here include activity and sleep tracking, in addition to mood-​logging and games to test
mental acuity, in an attempt to diagnose conditions such as bipolar disorder and schizophrenia.
4. This also raises privacy and consent issues, which we will look at in “Privacy and confidentiality” and
“Consent.”
5. We explore this issue further in “A case study: Mental health apps.”
6. This also seems to be a violation of consent, even though individuals are usually informed that their
conversations are being recorded for quality purposes.
7. We will take an in-​depth look at these kinds of technologies in “A case study: Mental health apps.”
8. A list of conditions addressed by this service is only accessible after signing on as a member, but
anyone can join at https://​www.7cups.com/​member/​.
9. It is possible that Europe, with its stronger privacy laws (European Union 1995), may actually pro-
hibit the sharing of identifiable information of users. This illustrates the complexity of privacy con-
siderations with a technology* that is not in any way geographically contained.
10. One of the authors experienced several presumed trolling experiences while acting as a listener.
11. Instructions on how to deal with trolling events are only accessible after one has signed into one’s
listener account. We therefore cannot provide a URL citation here. However, anyone can sign up as a
listener (7 Cups of Tea 2016d).
12. Heidegger himself was concerned that technology may convert people into things that are measur-
able and can be manipulated, thus ultimately reducing beings to not-​beings.
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102 The neuroethical future of wearable and mobile health technology

References
7 Cups of Teas (2016a). FAQ. Available from: http://​www.7cups.com/​about/​faq.php [accessed April
4, 2016].
7 Cups of Tea (2016b). Listener Agreement. Available from: https://​www.7cups.com/​inc/​listenerTOS.
html [accessed April 12, 2016].
7 Cups of Tea (2016c). Listener Reputation. Available from: https://​www.7cups.com/​about/​
faqBadgesCheers.php [accessed April 5, 2016].
7 Cups of Tea (2016d). Listener Signup. Available from: https://​www.7cups.com/​listener/​CreateAccount.
php [accessed April 13, 2016].
7 Cups of Tea (2016e). Privacy Policy. Available from: http://​www.7cups.com/​memberAgreement.php
[accessed April 5, 2016].
7 Cups of Tea (2016f). Start Feeling Better Today! Enroll in the 7 Cups Self-​Harm: Safer Solutions Path.
Available from: https://​www.7cups.com/​backus/​upgrade7cups_​19.php [accessed April 14, 2016].
7 Cups of Tea (2016g). Support Desk. Available from: http://​www.7cups.com/​supportDesk.php [accessed
April 4, 2016].
9Solutions (n. d.). Products. Available from: http://​www.9solutions.com/​home [accessed February
24, 2016].
Akkad, A., Jackson, C., Kenyon, S., Dixon-​Woods, M., Taub, N., and Habiba, M. (2006). Patients’
perceptions of written consent: questionnaire study. BMJ, 333(7567), 528.
Alba, D. (2015a, November 20). How smartphone apps can treat bipolar disorder and schizophrenia.
Wired Magazine. Available from: http://​www.wired.com/​2014/​11/​mental-​health-​apps/​ [accessed
April 3, 2015].
Alba, D. (2015b, January 15). This wearable helps you quit smoking by dosing you with nicotine. Wired
Magazine. Available from: http://​www.wired.com/​2015/​01/​chrono-​therapeutics/​ [accessed April
14, 2016].
American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (5th
ed.). Arlington, VA: American Psychiatric Publishing.
Apple Inc. (2015). Apple Introduces ResearchKit, Giving Medical Researchers the Tools to Revolutionize
Medical Studies. Available from: https://​www.apple.com/​pr/​library/​2015/​03/​09Apple-​Introduces-​
ResearchKit-​Giving-​Medical-​Researchers-​the-​Tools-​to-​Revolutionize-​Medical-​Studies.html
[accessed January 22, 2016].
Apple Inc. (2016). Health; An innovative way to use your health and fitness information. Available
from: http://​www.apple.com/​ios/​health/​ [accessed January 22, 2016].
Banerjee, T., Anantharam, P., Romine, W.L., and Lawhorne, L.W. (2015). Evaluating a Potential
Commercial Tool for Healthcare Application for People with Dementia. Available from: https://​drive.
google.com/​file/​d/​0By39GGXx-​P9NR29MeUx3b19abDQ/​view?pref=2&pli=1 [accessed April 13, 2016].
Baumel, A. (2015). Online emotional support delivered by trained volunteers: users’ satisfaction and
their perception of the service compared to psychotherapy. Journal of Mental Health, 24(5), 313–​320.
Belknap, R., Weis, S., Brookens, A., et al. (2013). Feasibility of an ingestible sensor-​based system for
monitoring adherence to tuberculosis therapy” PloS One, 8(1), e53373.
Bohn, D. (2016, January 5). Samsung’s new fridge can order Fresh Direct groceries from its humongous
touchscreen. The Verge. Available from: http://​www.theverge.com/​2016/​1/​5/​10708380/​samsung-​
family-​hub-​fridge-​mastercard-​app-​groceries-​ces-​2016 [accessed April 12, 2016].
Bonnington, C. (2014, January 28). Turn your smartphone into the ultimate fitness tracker. Wired.
Available from: http://​www.wired.com/​2014/​01/​smartphone-​fitness-​tracker/​ [accessed April 12, 2016].
 103

References 103

Boudway, I. (2014, June 6). Is Chris Dancy the most quantified self in America? Bloomberg News.
Available from: http://​www.bloomberg.com/​bw/​articles/​2014-​06-​05/​is-​chris-​dancy-​the-​most-​
quantified-​self-​in-​america [accessed April 11, 2016].
Breakthrough (2016). We Cover Most Insurance Plans. Available from: https://​www.breakthrough.com/​
how-​it-​works/​insurance [accessed April 22, 2016].
Cavazos, J., Girouard, M., and Whitmire, L. (2015). Novel ambulatory EMG-​based GTC seizure
detection device for home & hospital use (I6-​4B). Neurology, 84, 14 Supplement.
Cho, M.K., Magnus, D., Constantine, M., et al. (2015). Attitudes toward risk and informed consent
for research on medical practices: a cross-​sectional survey. Annals of Internal Medicine, 162(10),
690–​696.
Church, G.M. (2005). The personal genome project. Molecular Systems Biology, 1(1).
Cipriani, J. (2016, January 6). Lawsuit says Fitbit fitness trackers are inaccurate. Fortune. Available
from: http://​fortune.com/​2016/​01/​06/​fitbit-​heart-​rate-​accuracy-​lawsuit/​ [accessed March
15, 2016].
Clark, A. and Chalmers, D. (1998). The extended mind. Analysis, 58(1), 7–​19.
Ecobee (2016). The Smarter Wifi Thermostat with Remote Sensors. Available from: www.ecobee.com
[accessed March 10. 2016].
Edwards, L. (2010). Study Suggests Reliance on GPS May Reduce Hippocampus Function as We Age.
Available from: http://​phys.org/​news/​2010-​11-​reliance-​gps-​hippocampus-​function-​age.html
[accessed April 11, 2016].
Etkin, J. (2016). The hidden cost of personal quantification. Journal of Consumer Research, 42(6),
967–​984. Available from: https://​jcr.oxfordjournals.org/​content/​early/​2016/​03/​04/​jcr.ucv095.full
[accessed April 11, 2016].
European Commission (2014). Factsheet EU-​US Negotiations on Data Protection. Available from: http://​
ec.europa.eu/​justice/​data-​protection/​files/​factsheets/​umbrella_​factsheet_​en.pdf [accessed April
11, 2016].
European Union (1995). Directive 95/​46/​EC of the European Parliament and of the Council on the
Protection of Individuals with Regard to the Processing of Personal Data and on the Free Movement of
Such Data, 24 October. Available from: http://​www.refworld.org/​docid/​3ddcc1c74.html [accessed
April 18, 2016].
FDA (2013). Guidance for Industry Oversight of Clinical Investigations—​A Risk-​Based Approach to
Monitoring. Available from: http://​www.fda.gov/​downloads/​Drugs/​.../​Guidances/​UCM269919.pdf
[accessed January 12, 2016].
FDA (2014). Is the Product a Medical Device? Available from: http://​www.fda.gov/​MedicalDevices/​
DeviceRegulationandGuidance/​Overview/​ClassifyYourDevice/​ucm051512.htm [accessed March
22, 2016].
Felt, A.P., Ha, E., Egelman, S., Haney, A., Chin, E., and Wagner, D. (2012). Android permissions: user
attention, comprehension, and behavior. In: Proceedings of the Eighth Symposium on Usable Privacy
and Security, p.3, ACM. Washington, DC, July 11–​13.
Folkins, C.H. and Sime, W.E. (1981). Physical fitness training and mental health. American Psychologist,
36(4), 373–​389.
Garbarino, J. and Mason, C.E. (2016). The power of engaging citizen scientists for scientific progress.
Journal of Microbiology & Biology Education, 17(1), 7–​12.
Geddes, J. (2015, January 18). Fitness trackers up to 40% inaccurate: Fitbit, Jawbone, Nike, others
tested in new study, which performed best? Tech Times. Available from: http://​www.techtimes.com/​
articles/​27248/​20150118/​fitness-​trackers-​up-​to-​40-​inaccurate-​fitbit-​jawbone-​nike-​others-​tested-​in-​
new-​study-​which-​performed-​best.htm [accessed February 12, 2016].
104  1

104 The neuroethical future of wearable and mobile health technology

Geddes, L. (2016, January 27). Wearable sweat sensor paves way for real-​time analysis of body
chemistry. Nature News. Available from: http://​www.nature.com/​news/​wearable-​sweat-​sensor-​
paves-​way-​for-​real-​time-​analysis-​of-​body-​chemistry-​1.19254 [accessed April 13, 2016].
Gigerenzer, G. (2007). Gut Feelings: The Intelligence of the Unconscious. New York: Penguin.
Google Play (2016). 7 Cups of Tea. Available from: https://​play.google.com/​store/​apps/​details?id=com.
sevencupsoftea.app&hl=en [accessed April 12, 2016].
Greene, J.A. (2016). Do-​it-​yourself medical devices—​technology and empowerment in american health
care. New England Journal of Medicine, 374(4), 305–​308.
Haslam, C. (2015). Counting Sheep: The Best Sleep Trackers and Monitors. Available from: http://​www.
wareable.com/​withings/​best-​sleep-​trackers-​and-​monitors [accessed April 14, 2016].
Heidegger, M. (1953). An Introduction to Metaphysics. [Manheim, R., trans, in 1959.] New Haven,
CT: Yale University Press.
Hodson, H. (2014, May 7). Speech analyser monitors emotion for call centres. New Scientist. Available
from: https://​www.newscientist.com/​article/​mg22229683-​800-​speech-​analyser-​monitors-​emotion-​
for-​call-​centres/​ [accessed March 31, 2016].
iClarified (2014, January 6). Withing Unveils the First Active Sleep System “Aura. Available from: http://​
www.iclarified.com/​37345/​withings-​unveils-​the-​first-​active-​smart-​sleep-​system-​aura [accessed
February 22, 2016].
Illes, J., Kirschen, M.P., Edwards, E., et al. (2008). Practical approaches to incidental findings in brain
imaging research. Neurology, 70(5), 384–​390.
iTunes App Store (2016a). 7Cups of Tea. Available from: https://​itunes.apple.com/​us/​app/​7-​cups-​
anxiety-​stress-​depression/​id921814681?mt=8 [accessed April 11, 2016].
iTunes App Store (2016b). ReachOut Breathe. Available from: https://​itunes.apple.com/​us/​app/​reachout-​
breathe/​id985891649?mt=8 [accessed April 14, 2016].
iTunes App Store (2016c). What’s My M3. Available from: https://​itunes.apple.com/​us/​app/​whatsmym3/​
id515945611?mt=8 [accessed April 13, 2016].
Jacobson, R. (2014, November 1). 10 mobile apps that deliver advice and therapy. Scientific American.
Available from: http://​www.scientificamerican.com/​article/​10-​mobile-​apps-​that-​deliver-​advice-​and-​
therapy/​[accessed December 10, 2015].
Jeffrey, C. (2014, July 18). Vive aims to help avoid alcohol fueled social dangers” gizmag. Available
from: http://​www.gizmag.com/​vive-​bracelet-​concept/​32993 [accessed April 13, 2106].
Kaye, K. (2014). FTC: Fitness Apps Can Help You Shred Calories—​and Privacy. Available from: http://​
adage.com/​article/​privacy-​and-​regulation/​ftc-​signals-​focus-​health-​fitness-​data-​privacy/​293080/​
[accessed April 3, 2016].
Kelty, C. and Panofsky, A. (2014). Disentangling public participation in science and biomedicine.
Genome Medicine, 6(1), 8.
Kolibree (2016). Meet Kolibree: The Fun, Intelligent & Beautiful Tootbrush. Available from: https://​www.
kolibree.com/​en/​ [accessed April 2, 2016].
Lamas, D. (2014, August 4). Virtual therapy expanding mental health care. Boston Globe, Available
from: http://​www.bostonglobe.com/​lifestyle/​health-​wellness/​2014/​08/​03/​virtual-​therapy-​sessions-​
make-​mental-​health-​care-​more-​widely-​available/​t5kWYFmQP609BohewW3HuK/​story.html
[accessed April 13, 2016].
Lamkin, P. (2015). Fitness Tracker Market to Top $5bn by 2019. Available from: http://​www.wareable.
com/​fitness-​trackers/​fitness-​tracker-​market-​to-​top-​dollar-​5-​billion-​by-​2019-​995 [accessed January
12, 2016].
Leavitt, N. (2011). Mobile security: finally a serious problem? Computer, 44(6), 11–​14.
 105

References 105

Lehmkuhle, M., Elwood, M., Wheeler, J., Fisher, J., and Dudek, F.E. (2015). Development of Discrete,
Wearable EEG Device for Counting Seizures. Available from: https://​www.aesnet.org/​meetings_​
events/​annual_​meeting_​abstracts/​view/​2327785 [accessed April 3, 2016].
Leonard, A. (2014). Wearable technology that hurts you on purpose. Available from: http://​www.salon.
com/​2014/​07/​23/​wearable_​technology_​that_​hurts_​you_​on_​purpose/​ [accessed April 11, 2016].
Loria, K. (2016, March 2). Therapists have created a virtual reality ‘heroin cave’ in an attempt to help
addicts. Tech Insider. Available from: http://​www.techinsider.io/​university-​of-​houston-​heroin-​cave-​
virtual-​reality-​2016-​3 [accessed April 20, 2016].
Lufkin, B. (2014). A psychologist in Y combinator, and his controversial mission to revolutionize
therapy. Fast Company. Available from: http://​www.fastcompany.com/​3026967/​a-​psychologist-​in-​y-​
combinator-​and-​his-​controversial-​mission-​to-​revolutionize-​therapy [accessed February 6, 2016].
Lupton, D. (2013). Quantifying the body: monitoring and measuring health in the age of mHealth
technologies. Critical Public Health, 23(4), 393–​403.
Luxton, D.D., McCann, R.A., Bush, N.E., Mishkind, M.C., and Reger, G.M. (2011). mHealth
for mental health: Integrating smartphone technology in behavioral healthcare. Professional
Psychology: Research and Practice, 42(6), 505–​512.
McNeal, G.S. (2015, February 4). Health insurer Anthem struck by massive data breach. Forbes Online.
Available from: http://​www.forbes.com/​sites/​gregorymcneal/​2015/​02/​04/​massive-​data-​breach-​at-​
health-​insurer-​anthem-​reveals-​social-​security-​numbers-​and-​more/​ [accessed April 3, 2016].
Melnyk, B.M. (2007, April/​May). The child & adolescent mental health crisis: closing the service gap.
Imprint. Available from: http://​www.nsna.org/​Portals/​0/​Skins/​NSNA/​pdf/​Imprint_​AprMay07_​Feat_​
Child.pdf [accessed April 2, 2016].
Minassian, A., Henry, B.L., Geyer, M.A., Paulus, M.P., Young, J.W., and Perry, W. (2010). The
quantitative assessment of motor activity in mania and schizophrenia. Journal of Affective Disorders,
120(1–​3), 200–​206.
PatientsLikeMe (n.d.). Help Center. Available from: https://​support.patientslikeme.com/​hc/​en-​us/​
articles/​201245750-​How-​does-​PatientsLikeMe-​make-​money [accessed March 5, 2016].
Pugh, C. (2015, June 16). A plate that can count your calories and more. Huffington Post Blog [Blog
post]. Available from: http://​www.huffingtonpost.com/​caroline-​pugh/​a-​plate-​that-​can-​count-​yo_​b_​
7548948.html [accessed April 18, 2016].
Roepke, A.M., Jaffee, S.R., Riffle, O.M., McGonigal, J., Broome, R., and Maxwell, B. (2015).
Randomized controlled trial of SuperBetter, a smartphone-​based/​Internet-​based self-​help tool to
reduce depressive symptoms. Games for Health Journal, 4(3), 235–​246.
Rosner, G. (2014). Who owns your data? In: Proceedings of the 2014 ACM International Joint Conference
on Pervasive and Ubiquitous Computing: Adjunct Publication, pp. 623–​628. ACM. New York, USA.
Rothstein, M.A. (2010). Is deidentification sufficient to protect health privacy in research? American
Journal of Bioethics, 10(9), 3–​11.
Samson, K. (2015). Wearing the detectives: wristbands, smartwatches, and other wearable devices allow
for more real-​time monitoring of seizures and other neurologic symptoms—​and, possibly, more
precise treatment. Neurology Now, 11(4), 34–​36.
Sanicola, L. (2015). The Fitbit for the Mind. Available from: https://​www.linkedin.com/​pulse/​fitbit-​
mind-​lenny-​sanicola?trk=prof-​post&trkSplashRedir=true&forceNoSplash=true [accessed April
4, 2016].
Sarasohn-​Kahn, J. (2008). The Wisdom of Patients: Health are Meets Online Social Media. Available
from: http://​www.chcf.org/​publications/​2008/​04/​the-​wisdom-​of-​patients-​health-​care-​meets-​online-​
social-​media [accessed January 5, 2016].
106  1

106 The neuroethical future of wearable and mobile health technology

Schüll, N.D. (2016). Data for life: wearable technology and the design of self-​care. BioSocieties. Available
from: http://​www.palgrave-​journals.com/​biosoc/​journal/​vaop/​ncurrent/​abs/​biosoc201547a.html
[accessed March 30, 2016].
Siu, A.L., Bibbins-​Domingo, K., Grossman, D.C., et al. (2016). Screening for depression in adults: US
Preventive Services Task Force recommendation statement. JAMA, 315(4), 380–​387.
Siu, A.L. and US Preventive Services Task Force (2016). Screening for depression in children
and adolescents: US Preventive Services Task Force recommendation statement. Pediatrics,
137(3), 1–​8.
Smith, C.F., Williamson, D.A., Bray, G.A., and Ryan, D.H. (1999). Flexible vs. rigid dieting
strategies: relationship with adverse behavioral outcomes. Appetite, 32(3), 295–​305.
Stables, J. (2016). Best Fitness Trackers 2016: Jawbone, Misfit, Fitbit, Garmin and More. Available
from: http://​www.wareable.com/​fitness-​trackers/​the-​best-​fitness-​tracker [accessed April 12, 2016].
Stanford Medicine (2016). My Heart Counts iPhone Application. Available from: https://​med.stanford.
edu/​myheartcounts.html [accessed December 19, 2015].
Sutner, S. (2016). Physicians, Patients Benefit From Wearable Activity Trackers. Available from: http://​
searchhealthit.techtarget.com/​feature/​Physicians-​patients-​benefit-​from-​wearable-​activity-​trackers
[accessed April 2, 2016].
Swan, M. (2013). The quantified self: fundamental disruption in big data science and biological
discovery. Big Data, 1(2), 85–​99.
US Department of Health and Human Services (2003). Protecting Personal Health Information in
Research: Understanding the HIPAA Privacy Rule. Available from: http://​privacyruleandresearch.nih.
gov/​pdf/​HIPAA_​Booklet_​4-​14-​2003.pdf [accessed December 6, 2015].
US Department of Health and Human Services (2009). Mandatory Reporters of Child Abuse and
Neglect. Available from: http://​www.childwelfare.gov/​systemwide/​laws_​policies/​statutes/​manda.cfm
[accessed April 7, 2016].
Voida, S., Matthews, M., Abdullah, S., et al. (2013, September). MoodRhythm: tracking and supporting
daily rhythms. In: Proceedings of the 2013 ACM Conference on Pervasive and Ubiquitous Computing
Adjunct Publication, pp.67–​70. ACM, Zurich, Switzerland.
Wagner, B., Horn, A.B., and Maercker, A. (2014). Internet-​based versus face-​to-​face cognitive-​
behavioral intervention for depression: a randomized controlled non-​inferiority trial. Journal of
affective disorders, 152, 113–​121.
Walker, J. (2015, January 5). Can a smartphone tell if you’re depressed? The Wall Street Journal.
Available from: http://​www.wsj.com/​articles/​can-​a-​smartphone-​tell-​if-​youre-​depressed-​
1420499238?cb=logged0.14367316628029903 [accessed February 23, 2016].
Wearable Technologies (2016). Innovation World Cup Series. Available from: http://​www.
innovationworldcup.com/​2016/​01/​the-​wt-​wearable-​technologies-​innovation-​world-​cup-​crowned-​
the-​six-​most-​innovative-​wearable-​companies/​ [accessed March 24, 2016].
Wilson, T.D. (2004). Strangers to Ourselves. Cambridge, MA: Harvard University Press.
Winter, C. (2014, February 26). Personal sleep monitors: do they work? Huffington Post Blog [Blog
post]. Available from: http://​www.huffingtonpost.com/​dr-​christopher-​winter/​sleep-​tips_​b_​4792760.
html [accessed April 18, 2016].
Wolf, G. (2009, June 22). Know thyself: tracking every facet of life, from sleep to mood to pain, 24/​7/​
365. Wired Magazine. Available from: http://​www.wired.com/​2009/​06/​lbnp-​knowthyself/​ [accessed
December 1, 2015].
World Health Organization (1992). The ICD-​10 Classification of Mental and Behavioural
Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: World Health Organization.
 107

References 107

Zheng, Y.L., Ding, X.R., Poon, C.C.Y., et al. (2014). Unobtrusive sensing and wearable devices for
health informatics. IEEE Transactions on Biomedical Engineering, 61(5), 1538–​1554.
Zinko, C. (2015, July 3). Seen: partygoers in Thync to alter moods. SFGate. Available from: http://​www.
sfgate.com/​entertainment/​article/​Seen-​Partygoers-​in-​Thync-​to-​alter-​moods-​6363869.php#photo-​
8248816 [accessed April 5, 2016].
108  1

Chapter 6

Technologies of the extended mind:

Defining the issues
Peter B. Reiner and Saskia K. Nagel

Introduction
One of the primary concerns of the field of neuroethics has been the sanctity of the mind.
Whether the worry is over others gaining access to a person’s most private thoughts or
manipulating memories, increasing cognitive abilities beyond species-​typical functioning
or the authenticity of modern life, the recurring ethical issues center around the question
of whether people are masters of their own destinies. The progress that has been made in
exploring this fascinating terrain has been substantial, as evidenced by the growing matu-
rity of the field. Yet even while making great strides in defending the boundaries of what is
neuroethically acceptable, many people seem to be yielding the sanctity of their minds to
the convenience of modern devices. People do not rely only upon their 3-​pound brains to
navigate the world that surrounds them. Increasingly, a substantial portion of the popula-
tion is blending their cognitive space with the algorithmic devices that are nearly always
at hand. It is time that we recognize these devices as technologies of the extended mind
(TEMs) (Fitz & Reiner 2016; Nagel et al. 2016).

The extended mind hypothesis

The intellectual forerunner to the concept of TEMs is the extended mind hypothesis
(EMH) (Clark & Chalmers 1998), which suggests that cognition extends beyond the
brain into the world at large. Importantly, the EMH specifies that for external cognitive
processes to qualify as part of the mind, they must be active parts of the mind. Thus, the
EMH goes beyond merely suggesting that human cognition relies on external structures
for scaffolding and support. Rather, the EMH maintains that at least some of the physical
vehicles that realize our cognitive processes lie outside of the bounds of the skull.
The classic example from the original paper by Andy Clark and David Chalmers—​the
case of Otto and Inga—​illustrates the issue nicely (Clark & Chalmers 1998). Otto and
Inga live in New York City. One day, Inga hears about an exhibition at a museum that
she recalls is on 53rd Street and heads out the door, intent on seeing the artwork. Her
neighbor Otto has been having trouble remembering things. In order to overcome this
deficit, he has made a practice of storing important information in a small notebook that
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Technologies of the extended mind 109

he carries with him in his breast pocket. When he hears about the exhibition, he consults
his notebook, finds that the museum is on 53rd Street, and, just like Inga, sets off for the
same destination. The similarity between the two situations should now be obvious: the
cognitive function of storing information is mediated by neurons in one case and pen and
paper in the other.
From this example, Clark and Chalmers develop the parity principle, asserting that if a
process that unfolds in the external world would readily be classified as part of the cogni-
tive toolkit when it goes on in the head, then it is, at least for that point in time, part of
the cognitive process. Using the parity principle as a guide, Clark and Chalmers assert the
equivalence of neuronal memory and paper memory as information storage strategies in
the case of Otto and Inga.
The claims of the EMH are radical, and it remains a highly contentious theory in philos-
ophy of mind (Adams & Aizawa 2001, 2010; Rupert 2004, 2013; Menary 2010). However,
one need not fully accept the philosophical premise to appreciate that the concept reso-
nates with a key feature of modern life:  the growing sense that computers and smart-
phones (and soon “the Internet of Things”) function as sophisticated extensions of the
modern cognitive toolkit, even more so than Otto’s dog-​eared notebook. Moreover, rather
than relying upon the parity principle to guide thinking in this regard, we will provide
further specification on the features and uses of these algorithmic devices that serve to
qualify them as TEMs.

Technologies of the extended mind

Before we consider the circumstances under which a device qualifies as a TEM, it is useful
to explore what we mean when we use the word mind. A nuanced description of the term
is beyond the scope of this chapter, and there exists an entire subdiscipline of philosophy
that addresses the issue, but a few words of clarification are in order, in particular to place
the notion of TEMs in context.
The Oxford English Dictionary defines mind as the element of a person that enables
them to be aware of the world and their experiences, to think, and to feel:  the faculty
of consciousness and thought. Yet this definition is not satisfying, specifically because it
dodges the elephant in the room: the mind–​body problem. While we will use the term
mind liberally in this chapter, it is not our intent to slip into some version of substance
dualism in which there is brain-​stuff and mind-​stuff. But one specific distinction between
brain and mind is in order: as we view it, brain is a thing while mind is a concept. Mixing
those ontological levels is what often leads to confusion as to the relation between brain
and mind.
One way of thinking about the issue is to say that the mind represents the full set of
cognitive resources that we deploy in the service of thinking. Here we construe thinking
to include what Keith Stanovich calls reflective, algorithmic, and autonomous think-
ing (Stanovich 2009). One can quickly see how this definition is friendly to the EMH,
for once one uses the term full set of cognitive resources, one opens the door to things
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110 Technologies of the extended mind

other than the brain contributing to mind. Such formulations represent direct chal-
lenges to the hard neuroessentialist perspective which, one of us has argued, suggests
that there is no need to include anything other than the brain (Reiner 2011). Yet, as
we shall see below, once one begins to give due consideration to things outside of the
brain—​in particular TEMs—​it becomes difficult to conclude that they are not being
deployed in the service of thinking. In this view, mental processes and mind cannot
be fully reduced to cognitive processes, as they also refer to the plethora of affective,
motivational, and social resources that can influence thinking and go beyond it in vari-
ous ways. While many current TEMs aim at the extension of cognitive processes, this is
by no means a principal constraint; to the contrary, design might explicitly focus on an
extension of affective processes as well.
Having provided some conceptual clarity over what constitutes mind, we now address
the question of what sorts of devices are TEMs. It is not the case that every algorithmic
function carried out by devices external to the brain qualifies them as a TEM, but rather
that there is a relatively seamless interaction between brain and algorithm such that a per-
son perceives of the algorithm as being a bona fide extension of a person’s mind. This raises
the bar for inclusion into the category of algorithms that might be considered TEMs. It is
also the case that algorithmic functions that do not qualify as TEMs today may do so at
some future point in time and vice versa.
By way of illustration, consider the use of GPS in a smartphone, an example we have
previously described in Nagel et  al. (2016). Imagine a 35-​year-​old man John who has
lived in Manhattan for the past decade. John has rarely driven a car since he moved to
New York, as he now relies heavily on the subway or taxis to get about town. But John
recently had a baby and needs a bit of extra income, so he asks his brother whether he
thinks he could become a driver for Uber, a company that enables non-​professionals to
act as taxi drivers using their own vehicles. His brother, who has been making a fair bit
of money doing just that over the past year, is quite encouraging and even offers John the
use of his car in the evenings when it is idle. John signs up and within a week finds himself
behind the wheel of his brother’s car, answering calls for Uber drivers to come and ferry
people all over New York City.
In the normal course of events, Uber drivers are highly reliant on GPS. On his very first
day, John, an avid user of computer technology, is fascinated by how easy it is to enter
addresses into his smartphone and have it show him the best route to his passengers’
destinations. It is particularly helpful because otherwise John would often find himself
lost, as many of his fares lead him to visit neighborhoods with which he is unfamiliar. Of
course, John has heard stories that sometimes GPS can lead you to the wrong place, so he
remains alert to his environment in order to be certain that he delivers his passengers to
their destination without a hitch.
Is John’s GPS functioning as a TEM? It is certainly carrying out computational work
that is external to John’s brain. But it is probably most appropriate to consider the GPS
in John’s smartphone as cognitive support, for neither the algorithmic calculations nor
John’s reliance upon them are seamlessly integrated with John’s mind.
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The neuroethical issues 111

Now imagine that a week or two has passed. John has taken dozens of passengers to
their destinations. Even though he now knows the city a bit better than before, he always
uses the GPS in his smartphone, and it has not let him down even once. At this point,
when he enters an address and the route flashes up on the screen, he doesn’t give it a
moment’s notice before following it to the destination suggested by his smartphone. The
GPS now functions very much as a TEM, for John has integrated its algorithmic output
into the working of his mind.
Much as neuroessentialism challenges traditional views of how people view themselves
(Reiner 2011), conceiving of the mind as a blend between brain and algorithm poses a
challenge to a range of existing worldviews. At one end of the spectrum, if one is troubled
attempting to reconcile concepts of ensoulment with mechanistic explanations of how the
brain works (Bering 2006; Farah & Murphy 2009; Preston et al. 2013), the realization that
an algorithm is now an extension of one’s mind makes the issue even more problematic.
At the other end of the spectrum, the very same mechanistic explanations of brain func-
tion that lead to the position that “we are our brains” (Greene & Cohen 2004; Roskies
2007; Reiner 2011) are somewhat destabilized by the emerging reality of TEMs. For these
reasons, people may very well resist the disruptive concept of TEMs. However, the intru-
sion of algorithms upon daily life seems relentless, and in much the same way as John’s
GPS transitioned from external computational algorithm to bona fide TEM, we envision
this concept becoming an emergent meme, with an ever-​growing share of the population
perceiving of their devices as TEMs, even if they do not explicitly conceptualize them
as such.

The neuroethical issues
The neuroethical issues engendered by the EMH were first brought to light by Neil Levy
in a prescient paper published in 2007 (Levy 2007). At the time, he allowed that the EMH
was an obscure debate, but nonetheless suggested that it had substantial implications for
the field. He points out that part of what makes neuroethics a discipline is the claim,
sometimes explicit but nearly always implicit, that there is something different about
intervening in the brain, that such interventions are different than traditional means of
altering mental states. Levy suggests that if one accepts the EMH, the exceptionalism that
is normally offered to worries about intrusions, manipulations, and surveillance of mental
states in the brain naturally flow to the extended mind as well. He sums the situation up
nicely in his concluding paragraph:
These reflections on the prima facie parity between environmental manipulations and new tech-
nologies may seem to reduce the importance of neuroethics. On the contrary, I think that it dra-
matically increases it. It might seem that the extended mind thesis entails that neuroethics is less
important inasmuch as, in its light, it becomes apparent that neurological interventions into the
mind—​that is, interventions that target neurons, neurotransmitters or brain structures—​are not
after all so special: they represent merely the latest means of doing something that is quite ubiq-
uitous in human cultures. Although it is true that the extended mind thesis may dampen some of
the hype surrounding these technologies, it should be seen as dramatically expanding the scope of
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112 Technologies of the extended mind

neuroethics, not detracting from its importance. Neuroethics focuses ethical thought on the physi-
cal substrate subserving cognition, but if we accept that this substrate includes not only brains, but
also material culture, and even social structures, we see that neuroethical concern should extend
far more widely than has previously been recognized. In light of the extended mind thesis, a great
many questions that are not usually seen as falling within its purview—​questions about social pol-
icy, about technology, about food and even about entertainment—​can be seen to be neuroethical
issues. (Levy 2007)

We agree with Levy that the EMH has profound implications for our thinking about neu-
roethics. Three issues are particularly worthy of further elaboration: the threat to auton-
omy posed by manipulation of our TEMs, the threat to privacy of thought by peering
into TEMs, and the relevance of TEMs to questions regarding cognitive enhancement.
Each has changed substantially in the decade since Levy’s paper, a decade in which adop-
tion of smartphones as ubiquitous computing has moved from concept to reality. This
development is worth highlighting, as it seems to be more than just another technology,
but rather has been a major influence that shapes our technological surroundings. Other
influences are and will be relevant, but the prevalence of smartphones—​nearly half the
adult population on the planet has one (Pew Research Center 2016)—​and our readiness
to rely on them is certainly remarkable. These features make it a useful example with
which to explore some of the neuroethical issues associated with TEMs.

Autonomy
The concept of autonomy is foundational to modern thinking about who we are as sen-
tient beings. Particularly since the Enlightenment, Western societies have largely accepted
the position that we—​and only we—​have the right to determine the course of our lives.
Autonomy underpins many of the most celebrated political and social movements of
modernity. In human rights, it is autonomy that beckons us to consider the needs and
desires of the individual as having primacy. In politics, autonomy is the firmament upon
which democratic governance rests. Autonomy shows no signs of losing its appeal, con-
tinually forcing us to modify our practices. This is best exemplified in the medical realm
in which modern bioethical principles have invoked the concept of autonomy to pro-
duce a sea change in the way that physicians and their patients interact (Beauchamp &
Childress 2012).
A fundamental feature of the concept of autonomy is that the autonomous individ-
ual should not be unduly influenced when making decisions (Frankfurt 1971; Dworkin
1981). One need look no further than the ideal of the rugged individualist who navigates
their environment relying on nothing more than his or her wits to see how this works.
In this common trope, the autonomy of decision-​making by the individual is held as sac-
rosanct, and any infringement is considered a violation. It turns out that this picture of
humans as self-​sufficient rational actors who live their lives independently of others is
at substantial variance with how people actually live in the real world. Rather, decisions
are regularly influenced by the input of others, whether it is in the form of the books and
newspapers that we read, the opinions of people that we listen to, or other features of the
 13

The neuroethical issues 113

social and physical environment around us. Recognizing this, feminist and communitar-
ian scholars have updated the concept, developing variants on what is commonly known
as relational autonomy (Nedelsky 1989; Friedman 2003; Christman 2004; Meyers 2005;
Mackenzie 2010). The relational account of autonomy suggests that when people make
decisions, they often admit input from friends, family, colleagues, or professionals. That
this occurs without demurral complicates the calculus for evaluating when an external
influence might be considered due and undue. Indeed, “representing these two sorts of
effects with roughly accurate proportionality is, however, a formidable project [since]
matters of degree are notoriously difficult to specify philosophically” (Friedman 2003).
If it is a struggle to determine what influences are due and undue in the context of input
from other people, the task is even more complicated when we consider the influence of
TEMs upon these very same decisions. Before we do so, it is worth considering the general
features of algorithms that might modify the degree to which an influence is perceived as
violating autonomy. We have suggested that three factors are key: (1) the persuasiveness
of the algorithm in the decision-​making process, (2) the seriousness of the decision, and
(3) the ability for the algorithm to learn about user preferences (Nagel et al. 2016).
Persuasiveness seems to be a central feature of technological autonomy violations.
Decision-​making can be influenced across a spectrum ranging from minimally to highly
persuasive, and can even turn into being coercive (Fogg 2002; Verbeek 2006, 2009). If the
ability to thoughtfully engage in the decision-​making process and to reflect on the situ-
ation is ensured, the influence of the technology will not be perceived as a particularly
problematic autonomy violation, as self-​control does not seem to be harmed.
The seriousness of the decision also varies across a spectrum that differs depending
upon the level of potential harm or benefit an individual may experience as a result of a
particular choice. The lower the assumed potential harms or benefits, the lower the per-
ceived seriousness of the decision. Imagine for a moment the grave real-​world situation of
an individual grappling with the decision of whether to undergo a course of chemother-
apy that will briefly extend his or her life by some weeks but will compromise the quality
of those weeks substantially. Many such patients consult—​and trust—​online resources to
help them evaluate the relative risks and benefits. Under such circumstances, even a small
misstep in influence can result in a substantial autonomy violation.
The ability to learn about user preferences is important, as it makes a great difference
as to whether a system only follows a set of preprogrammed instructions or is able to
monitor individual behaviors and preferences and learns from them. If we return to the
situation of the individual confronting the decision of whether to embark upon a course
of chemotherapy, we can easily imagine two versions of the online resource. In the static
version where the information that is found online is offered by an unknown designer,
the opportunity for the designers’ preferences to be unwittingly smuggled into the algo-
rithmic calculation is high, and the possibility that an autonomy infraction may occur
not insubstantial. A more dynamic version would have the underlying algorithm learn
something about the preferences of the user and then provide advice accordingly. Since
the algorithm has learned at least something about the user’s worldview, the advice that
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114 Technologies of the extended mind

it offers might better be tailored to their second-​order desires, and the likelihood of an
autonomy violation diminished.
Having laid the groundwork for our thinking about the issue, we turn our attention to
an example in which the external technology is a TEM. We will use a simple and rela-
tively trivial example to illustrate the relevant issues, but the reader can readily imagine
how modifying persuasiveness, seriousness, and learning user preferences can affect the
degree of perceived autonomy violation.
To begin, consider an algorithm that is not a TEM, for example, the GPS app on John’s
smartphone in the example described in the previous section. Imagine that on the first
evening that John used the GPS function (i.e., before it has transitioned into being a TEM),
John passes a billboard advertising a bakery. Pushing the bounds of current practice (but
only slightly), let’s also imagine the smartphone calls attention to the billboard and alerts
John to the fact that the bakery is just up ahead; sealing the deal, the smartphone “asks” if
John wishes to drop in to get something sweet. John is tempted, and although he likes to
manage his intake of sugar, he decides that there would be little harm. A moment later he
stops at the bakery, purchases a donut, and soon is smiling as he tastes the sugary treat. In
this scenario, the GPS program has clearly influenced John, sufficiently so that he altered
his second-​order desires about his food intake. Many people would call such an influ-
ence undue and, despite the relative triviality of the infraction, the situation represents an
autonomy violation of sorts.
Now let us imagine that 2 weeks have passed, and the relationship between John and
the GPS app has grown more intimate—​John now integrates its algorithmic output into
the working of his mind while driving his Uber cab. For all intents and purposes, the GPS
algorithm is now functioning as a TEM. Of course, because John carries his smartphone
everywhere, the device gathers a fair bit of information about his daily activities, and the
abilities that this confers on the smartphone only serve to reinforce the feeling that the
suite of apps on the phone are functioning as a more-​or-​less unified TEM. It requires little
in the way of stretching credulity to imagine that the GPS might not only call attention
to a billboard alongside the road, but having “consulted” a database that indicates that
John frequently shops at an organic grocery store, instead of suggesting that John get
something sweet, the smartphone now suggests that he may wish to get a piece of organic
blueberry pie. Adding to the persuasiveness of the suggestion, the GPS program on his
smartphone—​which also monitors his activity levels during the day—​reminds John that
he went for a 5K run this morning and can probably afford the calories. A few minutes
later, John is smiling as he enjoys a forkful of delicious pie. Once again, the GPS program
has influenced John, sufficiently that he altered his second-​order desires about his food
intake. But given that the suggestions are aligned with John’s overall desire to eat organic
food, and that they include at least a rough calculation on calories burned earlier in the
day, does the persuasive influence of the GPS app represent an autonomy violation?
The difference between the two scenarios described above depends to a substantial
degree on how John perceives the algorithmic device that accompanies him everywhere.
As his relationship to the smartphone becomes closer, as both he and device provide
 15

The neuroethical issues 115

information that the other uses to help them navigate the world around them and John
perceives more and more that he relies on the program’s advice, the device increasingly
becomes an integral part of his extended mind. Given the considerations from relational
autonomy, the influence of the smartphone on John’s behavior in the second scenario
appears to be less “undue” than it was in the first instance. In this view, the more that
devices become TEMs, the likelihood that their advice results in perceived autonomy
violations diminishes.
However, there is something missing from this description, and that is that the very
same algorithm that is an extension of John’s mind is also an extension of the mind of an
other—​in this case the corporate entity that has designed the GPS app. It is not at all out
of the bounds of modern economic activity that the corporate entity would be paid for
directing John to the bakery. Thus, while one objective of that app is to align John’s behav-
ior with his second-​order desires, a second objective of another entity is also smuggled
into the relationship. In view of such potential conflicts of interest, it becomes harder to
accept the premise that as our devices become TEMs, autonomy violations become less
likely; if anything, they become more insidious. Serving two masters is certainly part of
the issue, but it is also the case that the privacy implications are impossible to ignore.

Privacy of thought
One of the most controversial topics in neuroethics is the worry over mind reading (Wolpe
et al. 2005; Illes 2006, 2007; Greely & Illes 2007; Parens & Johnston 2014). Frances Shen
has summarized the sentiments of many by suggesting that using advances in neurosci-
ence to access the most private of spaces—​our minds—​would have tremendous privacy
implications (Shen 2013). Yet despite intriguing insights obtained with functional mag-
netic resonance imaging (Haynes & Rees 2006; Mitchell et al. 2008; Naselaris et al. 2009;
Rissman et  al. 2010), it remains difficult to obtain more than a rudimentary profile of
the thoughts of individuals by measuring brain activity (Farah et al. 2009). In contrast, it
seems that a great deal of what might be termed the inner life of the mind may be acces-
sible via the technologies on our desktops, and even more so, in our pockets. Cognizant
that this is a discourse that has encountered more than its fair share of hype, it seems
prudent to consider whether access to our TEMs may represent intrusions upon privacy
of thought.
Such considerations come in the context of the well-​known fact that online privacy
is generally under threat. Illegal breaches and over-​sharing of digital information have
grown from the occasional to everyday events. While any intrusion on privacy may be
unwelcome, some transgressions are more problematic than others. When others gain
access to information that reflects one’s innermost thoughts, the incursion may go beyond
privacy to intrude upon privacy of thought. Such intrusions have particular normative
significance in neuroethics, and thus our analysis focuses upon this subset of privacy
concerns.
The manifesto establishing the right to privacy was drafted in 1890 by Samuel Warren
and Louis Brandeis (Warren & Brandeis 1890). As influential as it has been in legal circles,
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116 Technologies of the extended mind

it is the historical sweep of the article that draws one’s awe. As Warren and Brandeis inci-
sively explain, at one time liberty meant freedom from physical restraint, but as society
increasingly recognized the inner life of individuals, the right to life came to mean the
right to enjoy life, and protection of corporeal property expanded to include protection of
the products of the mind such as literature and art, trademarks, and copyrights. Warren
and Brandeis noted that “recent inventions and business methods call attention to the
next step which must be taken for the protection of the person.” In 1890, their worry was
the intrusiveness of photographers, but more generally their article suggested that as tech-
nology changes, societal norms might require updating. In the modern world, in which
information all-​too-​readily moves online, we appear to be overdue for just such a review.
Legal arguments support such a view. Pointing out that under the third-​party doctrine
“an individual does not have a reasonable expectation of privacy with respect to informa-
tion he voluntarily discloses to a third party, like a bank or a telecommunications carrier,”
Wittes and Chong suggest that the third-​party doctrine is ill-​suited to the modern situa-
tion in which devices generate data about their users (Wittes & Chong 2014). In a chilling
demonstration of how much information is contained within metadata—​the data about
the numbers we call, or where our phone is at a particular moment, who we e-​mail and
the subject lines of those messages, our search queries and the websites we visit—​Ton
Siedsma, a researcher at the Dutch digital rights foundation Bits of Freedom, allowed an
app on his cellphone to collect such metadata for 1 week (Tokmetzis 2014). The limited
analysis of this information revealed not only Ton’s circles of friends and the like, but also
the types of information included in his search queries. That Ton might have an interest
in bicycles is fairly innocuous, but what if he was searching for information about antide-
pressants or gender reassignment surgery, and these were topics that were in his head, but
he had not—​and more importantly did not wish to discuss with others?
Just such a situation is described by Wittes and Lui when alerting us to the fact that “the
privacy that consumers value in practice is not always the privacy that activists devoted
to privacy value on their behalf.” To illustrate the matter, they point out that many people
acquire medical information, salacious images, and more online because “they would
rather be tracked online by commercial vendors than have to face parents, teachers, doc-
tors, or the stern-​faced old lady at a news stand” (Wittes & Liu 2015). In a similar vein,
Frances Shen reminds us that what he terms the “privacy panic script” unfolds first with
fear mongering regarding the power of technology, followed by the suggestion that insti-
tutions will use the technology in devious ways, and that current laws are insufficient to
protect the average citizen (Shen 2013). These observations suggest that when advocating
in favor of privacy, humility may be in order.
Given these varied interests, we suggest that explicitly recognizing some of our devices
as TEMs may help us in arriving at a more reasonable state of affairs, especially if we arrive
upon a clearer understanding of what we mean by privacy of thought. The philosopher
Michael Lynch, writing as Amicus Curiae in support of the plaintiffs in American Civil
Liberties Union v. James Clapper, the lawsuit that challenged the legality of the National
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The neuroethical issues 117

Security Agency’s bulk phone metadata collection program traces the notion of privacy of
thought back to Descartes and Locke, who both held that:
what identifies your thoughts as your thoughts is that you have “privileged access” to them. This
means at least two things. First, you access them in a way I cannot. Even if I could walk a mile in
your shoes, I cannot know what you feel in the same way you can: you see it from the inside, so
to speak. Second, you can, at least sometimes, control what I know about your thoughts. You can
refrain from telling me the extent of your views and your feelings. (Lynch 2013)

In the context of TEMs, these criteria seem appropriate: if you have a private means of
accessing information on your device that is not available to others, and you have the
means of controlling that access, it seems as if you have demonstrated that, in your view,
it is private. The problem arises, of course, when those very same devices are connected to
others by virtue of the ever-​present Internet.
To see how this may play out, it is worth recalling the infamous case of the discount
retailer Target and the pregnant teen. By combining metadata that was packaged, bought,
and sold (online, of course) with analysis of something as innocent as the shopping
behavior of young women, Target was able to predict with high accuracy when women
were in their second trimester of pregnancy (Hill 2012). The commercial objective was to
target these potential customers with ads for diapers, baby clothes, and the like, but when
Target did so, customers felt so invaded that they complained (in this case, it was a father
who only discovered his daughter’s pregnancy through this route). So Target modified
their strategy; instead of sending ads just for diapers, etc., they mixed those ads in with
ads for everyday items unrelated to pregnancy just to prevent the perception that they had
invaded their customer’s privacy.
Similar brinkmanship can be seen in the relationship between Facebook and its users.
In a longitudinal study of 5076 Facebook users between 2005 and 2011, Facebook users
increasingly exhibited privacy-​seeking behavior, decreasing the amount of personal data
that they shared publicly. At the same time, the amount of personal information they
revealed privately to so-​called connected profiles increased. The unintended result was
that disclosures to “silent listeners” on the network—​Facebook itself, third-​party apps,
and ultimately advertisers—​grew. The authors conclude that these findings “highlight the
tension between privacy choices as expressions of individual subjective preferences, and
the role of the environment in shaping those choices” (Stutzman et al. 2012).
From these examples we can see that the networked nature of our TEMs makes them
particularly vulnerable to intrusions upon privacy of thought. While people may take
steps toward increasing the privacy of their online behavior, the corporate entities at the
other end of the phone, as it were, are continually mining these very same actions in an
effort to enhance their competitive position in the world of commerce. What is lost in
the conversation is that along the way, people may perceive of their devices as extensions
of their minds. We suggest that this implicit tagging of Internet-​connected algorithmic
devices as TEMs raises the bar for privacy, qualifying the information within the amalgam
of our brains and our devices as private thoughts.
18  1

118 Technologies of the extended mind

Cognitive enhancement
Discussion of the propriety of using advanced neurotechnologies to enhance cognitive
abilities has been among the most protracted of debates in neuroethics (Parens 1998;
Farah et al. 2004; Greely et al. 2008). Ethical arguments from different biopolitical posi-
tions (Reiner 2013) have been waged over a number of issues, but the cardinal concerns
of safety, pressure, distributive justice, and authenticity have dominated (Fitz et al. 2014).
In many ways, the debate is more pragmatic than philosophical, and so we will restrict our
comments regarding the implications of TEMs to the cognitive enhancement debate to a
short outline of the relevant issues.
The debate over cognitive enhancement is somewhat compromised by the observation
that the agents that are available today—​drugs and electrical stimulation devices—​do not
yield the sorts of enhancements that people seek: effect sizes tend to vary from minimal to
none (Farah 2015; Ilieva et al. 2015). As we have recently suggested, this may be because
attempts to bolster cognitive function from within run up against the hard limits of neu-
robiological reality (Fitz & Reiner 2016). Indeed, we suggest that a better strategy is to
rely upon our TEMs to enhance cognitive function, not only because it is more effective
but because we are already well down the road toward “commingling our cognitive space
with technology.”
The question that remains open, and one that merits further normative and empirical
work in the field, is the degree to which considering TEMs as cognitive enhancers settles
debates that have gone on for over a decade now. The answer is likely to be a mixed bag—​
the ubiquity of TEMs might help to dispel the distributive justice concern, but concerns
over safety, pressure, and authenticity now morph into new territory. We predict that
exploring these issues with a new technological lens may assist the field in clarifying how
we should move forward, even if it involves playing catch-​up to how we live today.

TEMs necessitate a new framework for neuroethics

The many important issues that have made neuroethics such a vibrant and fascinating
field—​ranging from questions on handling of incidental findings, brain reading to detect
deception, brain intervention of offenders, to enhancement of healthy people by means of
pharmacological agents or electrical brain stimulation—​have largely been focused on the
brain. Recognizing that TEMs qualify as extensions of the mind provides the impetus for
“dramatically expanding the scope of neuroethics,” as Neil Levy has argued (Levy 2007).
This expansion is even more interesting the more one recognizes that the role of technolo-
gies is not just one of cognitive support but is fundamental to the modern way of being in
our technological culture.
In philosophy, it has long been well accepted that humans cannot be understood
and often do not conceive of themselves as isolated beings. Rather, people are socially
embedded, existing as part of a collection of other beings who shape us and our image of
ourselves. This idea of our deeply social nature can be found already in the writings of
Hegel and Marx, and has been extensively developed by the critical psychologist Klaus
 19

The neuroethical issues 119

Holzkamp (Holzkamp 1985). Importantly, in this view social embeddedness goes beyond
the direct private relations between and among individuals, reaching out to the various
social institutions that surround and influence us.
Analogously, the modern world with its increasingly technological surroundings defines
us as technologically embedded beings. Consider that today the trajectory of a life begins
surrounded by reproductive technologies and often ends with a different array of medical
technologies easing us into death. Just try to imagine for a moment the technologies that
are around you right now—​from the lightbulb above you, to the heat in the corner, to
the smartphone in your pocket. Perhaps you took a drug this morning to help normalize
some bodily function, or maybe you will use a car or bus or train to move from place to
place, or even have a video-​chat with a colleague on a different continent. Indeed, humans
rely on a vast array of technologies, and one might argue that they depend upon them—​
some of us more, some less. Such is the modern predicament (Scialabba 2011) that it is
hard to hear silence, that many live in fear of the content of their food, that it has become
a common experience to feel estranged from the natural world. No matter how one evalu-
ates being surrounded by and dependent upon technologies, it is fair to say that we are
increasingly embedded by technologies.
It is no surprise then that some of those technologies engage with our cognitive pro-
cesses. Even more: that they serve as TEMs by functioning as part of the mind that resides
outside of the brain. And as the mind is perceived as perhaps the most intimate part of
us, conceptualizing technologies as extensions of the mind deeply challenges the sense of
who we are as humans. The questions Who am I? Am I my brain? Am I my mind? Am
I my relationships? (Haslam 2004; Rose 2005; Feinberg 2006; Glannon 2009; Burwood
2009; Noë 2009; Brand 2010; Brenninkmeijer 2010; Pardo & Patterson 2010; Reiner
2011) are viewed from a different angle when a person recognizes that technologies serve
as a functional part of the self. Ultimately, with this perspective, humans must find a new
mode of being, and consequently a new mode of understanding ourselves and others. For
if our cognitive processes are not restricted to our biological brains, we need to give seri-
ous consideration to their role in our being.
An important result is that the relationship that people have with those devices merits
much closer attention than they have received to date. We might go as far as arguing that
we need to consider TEMs as new actors on the neuroethical stage. Thus, we call for a
new framework for neuroethics that is informed by philosophy of mind which needs to
reconsider how humans conceive of who they are today: What is at stake when studying
neuroethical questions? What is the “substrate” we are dealing with? If we take the nature
of the intertwinement of modern humans with their surroundings seriously—​and we
argue that we should—​we cannot any longer focus on the human brain as isolated or, at
most, integrated into a body. The body and the brain are not only in constant interaction
with the environment (Varela et al. 1991; Gallagher 2005; Fuchs 2011; Nagel 2015), they
also constantly make use of their surroundings, of significant and non-​significant others,
and of technologies. Thus, in this new framework, neuroethics is not so much concerned
with an organ but ultimately with what makes us human beings, and recognizing the
120  1

120 Technologies of the extended mind

impact of technology upon what makes us “us” today matters for the relevant questions
in the field.

References
Adams, F. and Aizawa, K. (2001). The bounds of cognition. Philosophical Psychology, 14(1), 43–​64.
Adams, F. and Aizawa, K. (2010). Defending the bounds of cognition. In: Menary, R. (Ed.) The Extended
Mind, pp.67–​80. Cambridge, MA: MIT Press.
Beauchamp, T.L. and Childress, J.F. (2012). Principles of Biomedical Ethics (7th edn.). New York: Oxford
University Press.
Bering, J. (2006). The folk psychology of souls. Behavioral and Brain Sciences, 29(5), 453–​462.
Brand, C. (2010). Am I still me? Personal identity in neuroethical debates. Medicine Studies, 1(4), 393–​406.
Brenninkmeijer, J. (2010). Taking care of one’s brain: how manipulating the brain changes people’s
selves. History of the Human Sciences, 23(1), 107–​126.
Burwood, S. (2009). Are we our brains? Philosophical Investigations, 32, 113–​133.
Christman, J. (2004). Relational autonomy, liberal individualism, and the social constitution of selves.
Philosophical Studies, 117(1), 143–​164.
Clark, A. and Chalmers, D. (1998). The extended mind. Analysis, 58(1), 7–​19.
Dworkin, G. (1981). The concept of autonomy. Grazer Philosophische Studien, 12, 203–​213.
Farah, M.J. (2015). The unknowns of cognitive enhancement. Science (New York, NY), 350, 379–​380.
Farah, M.J. and Murphy, N. (2009). Neuroscience and the soul. Science (New York, NY),
323(5918), 1168.
Farah, M.J., Illes, J., Cook-​Deegan, R., et al. (2004). Neurocognitive enhancement: what can we do and
what should we do? Nature Reviews Neuroscience, 5(5), 421–​425.
Farah, M.J., Smith, M.E., Gawuga, C., Lindsell, D., and Foster, D. (2009). Brain imaging and brain
privacy: a realistic concern? Journal of Cognitive Neuroscience, 21(1), 119–​127.
Feinberg, T.E. (2006). Our brains, our selves. Dædalus, 135(4), 72–​80.
Fitz, N.S. and Reiner, P.B. (2016). Time to expand the mind. Nature, 531, S9.
Fitz, N.S., Nadler, R., Manogaran, P., Cong, E.W.J., and Reiner, P.B. (2014). Public attitudes toward
cognitive enhancement. Neuroethics, 7(2), 173–​188.
Fogg, B.J. (2002). Persuasive Technology: Using Computers to Change What We Think and Do. San
Francisco, CA: Morgan Kaufmann.
Frankfurt, H.G. (1971). Freedom of the will and the concept of a person. Journal of Philosophy,
68(1), 5–​20.
Friedman, M. (2003). Autonomy and social relationships: rethinking the feminist critique.
In: Autonomy, Gender, Politics, pp.81–​97. Oxford: Oxford University Press.
Fuchs, T. (2011). The brain—​a mediating organ. Journal of Consciousness Studies, 18, 196–​221.
Gallagher, S. (2005). How the Body Shapes the Mind. New York: Oxford University Press.
Glannon, W. (2009). Our brains are not us. Bioethics, 23(6), 321–​329.
Greely, H.T. and Illes, J. (2007). Neuroscience-​based lie detection: the urgent need for regulation.
American Journal of Law & Medicine, 33(2–​3), 377–​431.
Greely, H.T., Sahakian, B., Harris, J., et al. (2008). Towards responsible use of cognitive-​enhancing
drugs by the healthy. Nature, 456(7223), 702–​705.
Greene, J. and Cohen, J. (2004). For the law, neuroscience changes nothing and everything.
Philosophical Transactions of the Royal Society B: Biological Sciences, 359(1451), 1775–​1785.
 12

References 121

Haslam, N. (2004). Essentialist beliefs about personality and their implications. Personality and Social
Psychology Bulletin, 30(12), 1661–​1673.
Haynes, J.-​D. and Rees, G. (2006). Decoding mental states from brain activity in humans. Nature
Reviews Neuroscience, 7(7), 523–​534.
Hill, K. (2012). How Target Figured Out A Teen Girl Was Pregnant Before Her Father Did. Available
from: http://​www.forbes.com/​sites/​kashmirhill/​2012/​02/​16/​how-​target-​figured-​out-​a-​teen-​girl-​was-​
pregnant-​before-​her-​father-​did/​4/​#583f593d34c6 [accessed March 27, 2016].
Holzkamp, K. (1985). Grundlegung der Psychologie. Frankfurt: Campus-​Verlag.
Ilieva, I.P., Hook, C.J., and Farah, M.J. (2015). Prescription stimulants’ effects on healthy inhibitory
control, working memory, and episodic memory: a meta-​analysis. Journal of Cognitive Neuroscience,
27(6), 1069–​1089.
Illes, J. (Ed.) (2006). Neuroethics: Defining the Issues in Theory, Practice, and Policy. Oxford: Oxford
University Press.
Illes, J. (2007). Empirical neuroethics. Can brain imaging visualize human thought? Why is neuroethics
interested in such a possibility? EMBO Reports, 8, S57–​S60.
Levy, N. (2007). Rethinking neuroethics in the light of the extended mind thesis. American Journal of
Bioethics, 7(9), 3–​11.
Lynch, M. (2013). Brief of Michael P. Lynch as Amicus Curiae in Support of the Plaintiffs,
American Civil Liberties Union v. James R. Clapper. Available from: https://www.academia.
edu/4579430/_The_Privacy_Brief_Amicus_Curiae_Brief_in_Support_of_the_ACLU_vs._NSA.
Mackenzie, C. (2010). Imagining oneself otherwise. In: Mackenzie, C. and Stoljar, N. (Eds.)
Relational Autonomy: Feminist Perspectives on Autonomy, Agency, and the Social Self, pp.124–​150.
New York: Oxford University Press.
Menary, R. (2010). The Extended Mind. Cambridge, MA: MIT Press.
Meyers, D. (2005). Decentralizing autonomy: five faces of selfhood. In: Christman, J. and Anderson,
J. (Eds.) Autonomy and the Challenges to Liberalism: New Essays, pp.27–​55. New York: Cambridge
University Press.
Mitchell, T.M., Shinkareva, S.V., Carlson, A., et al. (2008). Predicting human brain activity associated
with the meanings of nouns. Science (New York, NY), 320(5880), 1191–​1195.
Nagel, S.K. (2015). Thickening descriptions with views from pragmatism and anthropology. In: Metzinger,
T. and Windt, J.M. (Eds.) Open MIND (Vol. 1), pp.829–​839. Cambridge, MA: MIT Press.
Nagel, S.K., Hrincu, V., and Reiner, P.B. (2016, May 13–​14). Algorithm Anxiety—​Do Decision-​Making
Algorithms Pose a Threat to Autonomy? Presented at 2016 IEEE International Symposium on Ethics
in Engineering, Science and Technology, Vancouver, BC.
Naselaris, T., Prenger, R.J., Kay, K.N., Oliver, M., and Gallant, J.L. (2009). Bayesian reconstruction of
natural images from human brain activity. Neuron, 63(6), 902–​915.
Nedelsky, J. (1989). Reconceiving autonomy: sources, thoughts and possibilities. Yale Journal of Law &
Feminism, 1(1), 5.
Noë, A. (2009). Out of Our Heads: Why You Are Not Your Brain, and Other Lessons from the Biology of
Consciousness. New York: Hill and Wang.
Pardo, M.S. and Patterson, D. (2010). Philosophical foundations of law and neuroscience. University of
Illinois Law Review, 5, 1211–​1250.
Parens, E. (1998). Enhancing Human Traits: Ethical and Social Implications. Washington,
DC: Georgetown University Press.
Parens, E. and Johnston, J. (2014). Neuroimaging: beginning to appreciate its complexities. Hastings
Center Report, 44(s2), S2–​S7.
12

122 Technologies of the extended mind

Pew Research Center (2016). Smartphone Ownership and Internet Usage Continues to Climb in Emerging
Economies. Available from: http://​www.pewglobal.org/​2016/​02/​22/​smartphone-​ownership-​and-​
internet-​usage-​continues-​to-​climb-​in-​emerging-​economies/​ [accessed January 31, 2017].
Preston, J.L., Ritter, R.S., and Hepler, J. (2013). Neuroscience and the soul: competing explanations for
the human experience. Cognition, 127(1), 31–​37.
Reiner, P.B. (2011). The rise of neuroessentialism. In Illes, J. and Sahakian, B.J. (Eds.) Oxford Handbook
of Neuroethics, pp.161–​175. Oxford: Oxford University Press.
Reiner, P.B. (2013). The biopolitics of cognitive enhancement. In: Hildt, E. and Franke, A. (Eds.)
Cognitive Enhancement: An Interdisciplinary Perspective, pp.189–​200. New York: Springer
Science+Business Media.
Rissman, J., Greely, H.T., and Wagner, A.D. (2010). Detecting individual memories through the neural
decoding of memory states and past experience. Proceedings of the National Academy of Sciences of
the United States of America, 107(21), 9849–​9854.
Rose, S.P.R. (2005). Human agency in the neurocentric age. EMBO Reports, 6(11), 1001–​1005.
Roskies, A.L. (2007). The illusion of personhood. American Journal of Bioethics, 7(1), 55–​57.
Rupert, R.D. (2004). Challenges to the hypothesis of extended cognition. Journal of Philosophy, 101(8),
389–​428.
Rupert, R.D. (2013). Distributed cognition and extended mind theory. In: Kaldis, B. (Ed.)
Encyclopedia of Philosophy and the Social Sciences, pp.209–​213. Thousand Oaks, CA: Sage
Publications Inc.
Scialabba, G. (2011). The Modern Predicament. Boston, MA: Pressed Wafer.
Shen, F.X. (2013). Mind, body, and the criminal law. Minnesota Law Review, 97, 2036–​2175.
Stanovich, K.E. (2009). Distinguishing the reflective, algorithmic, and autonomous minds: is it time for
a tri-​process theory. In Evans, J. and Frankish, K. (Eds.) In Two Minds: Dual Processes and Beyond,
pp.55–​88. Oxford: Oxford University Press.
Stutzman, F., Gross, R., and Acquisti, A. (2012). Silent listeners: the evolution of privacy and disclosure
on Facebook. Journal of Privacy and Confidentiality, 2, 7–​41.
Tokmetzis, D. (2014). How Your Innocent Smartphone Passes on Almost Your Entire Life to the Secret
Service. Available from: https://​www.bof.nl/​2014/​07/​30/​how-​your-​innocent-​smartphone-​passes-​on-​
almost-​your-​entire-​life-​to-​the-​secret-​service/​ [accessed March 27, 2016].
Varela, F.J., Thompson, E., and Rosch, E. (1991). The Embodied Mind: Cognitive Science and Human
Experience. Cambridge, MA: MIT Press.
Verbeek, P.-​P. (2006). Persuasive technology and moral responsibility toward an ethical framework for
persuasive technologies. Persuasive, 6, 1–​15.
Verbeek, P.-​P. (2009). Ambient intelligence and persuasive technology: the blurring boundaries between
human and technology. NanoEthics, 3(3), 231–​242.
Warren, S.D. and Brandeis, L.D. (1890). The right to privacy. Harvard Law Review, 4(5), 193–​220.
Wittes, B. and Chong, J. (2014). Our Cyborg Future: Law and Policy Implications. Center for Technology
Innovation at Brookings. Available from: https://​www.brookings.edu/​research/​our-​cyborg-​future-​
law-​and-​policy-​implications/​ [accessed January 31, 2017].
Wittes, B. and Liu, J.C. (2015). The Privacy Paradox: The Privacy Benefits of Privacy Threats. Center
for Technology Innovation at Brookings. Available from: https://​www.brookings.edu/​wp-​content/​
uploads/​2016/​06/​Wittes-​and-​Liu_​Privacy-​paradox_​v10.pdf [accessed January 31, 2017].
Wolpe, P., Foster, K., and Langleben, D. (2005). Emerging neurotechnologies for lie-​detection: promises
and perils. American Journal of Bioethics, 5(2), 39–​49.
 123

Chapter 7

Neuromodulation ethics: Preparing

for brain–​computer interface medicine
Eran Klein

Introduction
An expressed aim of brain–​computer interface (BCI) or brain–​machine interface (BMI)
research is to develop devices that improve lives of people with disabilities (Hochberg and
Anderson 2012; Shih et al. 2012; Murphy et al. 2016).1 BCIs are integrated input–​output
devices that acquire and translate brain signals in order to change physiologic function
or the environment through control of an output device. BCI research has experienced
explosive growth in recent years (Mak & Wolpaw 2009) due to a confluence of advances,
including computational power for modeling brain function, electrode design, neuro-
imaging and electroencephalography (EEG) capabilities, and clinical experience with
implanted neural devices such as deep brain stimulation (DBS). BCI technology is being
envisioned as a way to address unmet or suboptimally met medical needs. BCIs can be
wearable, such as EEG-​based devices that detect brain waves through the skull, or implant-
able, such as electrodes inserted into the brain to electrically stimulate or record neuronal
activity. Though there are few current clinical applications of BCI and significant techni-
cal challenges to wider translation remain, implantable and nonimplantable BCI-​based
devices promise to be used for a wide range of disorders of movement, affect, sensation,
and cognition (Mak & Wolpaw 2009; Wolpaw & Wolpaw 2012; Soekedar et al. 2014).
Human BCI devices raise interesting ethical questions, some of which have been
explored at the research and policy level:
◆ Privacy of thought (Clausen 2011)
◆ Security of brain data (Denning et al. 2009)
◆ Changes to identity (Goering 2014)
◆ Responsibility for action (Haselager 2013)
◆ Access to expensive technology and post-​study obligations to subjects (Schneider
et al. 2012)
◆ Informed consent for research participation (Klein 2016).
Though ethical issues raised by BCI research overlap with those of other neural interven-
tions, such as DBS, neural cell transplantation, and neuropharmacology, the coupling of
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124 Neuromodulation ethics

recorded brain data to output interventions (e.g., electrical, mechanical, molecular, and
sensory-​mediated) opens new possibilities for precise and timely modulation of brain
function. A goal for BCI-​based applications is to use algorithms to automatically adjust
device function in a closed-​loop fashion, substituting machine learning for manual inter-
rogation and adjustment of devices (Hebb et al. 2014). The prospect of closed-​loop medi-
cal devices with embedded artificial intelligence raises particularly challenging ethical
questions for BCI research and policy such as determining agency and responsibility for
behavior related to device function (Glannon 2016).
The transition of BCI devices from research into clinical practice raises clinical ethics
challenges as well. A few of these challenges are already beginning to come into view. For
instance, seizure detection and stimulation devices—​an early kind of BCI—​raise ques-
tions related to predictive, advisory, and automated functionalities (Gilbert 2015). How
will new capabilities affect a patient’s sense of autonomy? What would it mean to over-​
rely on such a device? How central to an individual’s autonomy is feeling in control over
a device (Goering 2015)? Such concerns provide a hint of the kinds of ethical questions
that clinicians and patients are likely to face. The development of BCI technology and the
prospect of its wider incorporation into the practice of medicine raise clinical ethics chal-
lenges that are worth trying to anticipate and preemptively address.
The purpose of this chapter is to sketch out some of the clinical ethics challenges of
BCI medicine and to facilitate a discussion about how best to approach these. In the first
section, I give an overview of the kinds of BCI devices that are likely to become a part of
medicine in the near term—​devices that target motor, communication, sensation, cogni-
tion, consciousness and affective impairments. This is not meant to be a comprehensive
survey of BCI technology, but to give a glimpse of the current state and ambitions of the
field and the prospect for clinically meaningful devices. In the second section, I explore
some of the ethical issues around consent to BCI-​based medical devices. In the third sec-
tion, I discuss some of the ethical challenges of neuromodulation. In the final section,
I  argue that looking to an engineering model of medicine for ethical guidance in BCI
medicine is problematic but that a rehabilitation model of medicine holds promise.

Near-​term horizon of brain–​computer interface medicine

BCI devices can be wearable or surgically implanted with different potential clinical uses
and capabilities. Different kinds of brain signals can be obtained through implanted sen-
sors versus nonimplantable technology, such as EEG, functional magnetic resonance
imaging (fMRI), or near-​infrared spectroscopy (NIRS), as well as different intended out-
puts of the BCI, for instance, implanted versus skull surface neurostimulation (Soekadar
et al. 2014). For some BCI-​based devices, brain signal information obtainable through
nonimplanted means may be sufficient whereas for others the fine-​grained, high signal-​
to-​noise ratio neural data available from implanted electrodes may be necessary. Similarly
for the output side of BCI, implanted electrodes or other implanted devices may be needed
to appropriately target a specific brain region for some clinical indications, whereas this
 125

Near-term horizon of brain–computer interface medicine 125

may be unnecessary in other kinds of BCIs, for instance, to apply skull surface stimulation
or to control a robotic prosthetic limb or communication speller. The technological and
functional tradeoffs of wearable versus implantable BCI take place against a backdrop of
risks associated with surgical implantation and ongoing care of implanted devices.
The neurophysiologic brain signals used in BCI can be metabolic or magnetic, but cur-
rently the principal type is electrophysiologic (Mak & Wolpaw 2009). Four types of elec-
trophysiologic brain signals are currently being investigated as a basis of wearable BCI
technology (Soekadar & Birbaumer 2015):  (1)  slow cortical potentials, (2)  sensorimo-
tor or motor-​related beta rhythms, (3)  event-​related potentials, and (4)  steady-​state or
auditory-​evoked potentials. Surgically implanted electrodes, on the other hand, whether
strips, grids, or other arrays, can provide brain signal information at a different level, such
as local field potentials, (2) single unit activity, or (3) multiunit activity. The brain signals
can be generated actively, reactively, or passively, depending on whether the user needs
to attend to or respond to a task or whether background cognitive monitoring is involved
(Soekadar et al. 2014). Once the desired brain signal is acquired, the features of the signal
encoding the intent of the user must be extracted, transformed by algorithm into a device
command, and transmitted to a device for execution (Wolpaw et al. 2002).
Potential clinical applications of BCI span a wide range. BCI is currently being explored
for use in controlling computer cursors, wheelchairs, robotic arms, or reanimated limbs
(Mak & Wolpaw 2009). Depending on how widely BCI is defined and how the future of
technological development and acceptance proceeds, BCI devices one day could be per-
vasive in medicine. Near-​term clinical uses of BCI can be schematically grouped by func-
tional impairment domains: motor, communication, sensation, cognition, consciousness,
and affect.2 Technology for BCI devices—​wearable, implantable, or both—​is being devel-
oped currently within each of these domains. In this section, I will briefly give examples of
potential BCI devices being explored in each of these impairment domains.3 It should be
noted that many of these devices exist at an early stage of development, some merely at a
proof-​of-​principle stage, and whether any of these particular devices will prove clinically
beneficial or commercially viable is an open question.

Motor impairment
Examples of BCI for improving or substituting for impaired motor function include BCI-​
controlled exoskeletons, prosthetics, or robotics. Functional electrical stimulation repre-
sents an example of a BCI system for motor control in which EEG signals can be used to
control electrical stimulation of impaired muscle systems, for instance, to facilitate the
grasping motion of a paralyzed hand (Pfurtscheller et al. 2003) or assist in walking (King
et al. 2014). The Braingate system is a well-​known example of robotic control using brain-​
implanted electrodes. Hochberg and colleagues implanted dense electrode arrays in two
individuals with quadriplegia that allowed them to use local field potentials to control
computer cursors (Hochberg et al. 2006). Other subjects have been able to use devices
with implanted electrodes to control prosthetic limbs (Collinger et al. 2013b).
126  1

126 Neuromodulation ethics

A hope for BCI technology is that it may improve on neurostimulation devices

already in clinical use, such as DBS for Parkinson’s disease, essential tremor, dystonia,
and Tourette’s syndrome. An example of this is a BCI-​based closed-​loop DBS system
for essential tremor. Essential tremor is a condition characterized by episodic tremor
of the head or extremities made worse by initiation of movement, such as holding a
pen or coffee cup. When medications are ineffective or not tolerated, open-​loop DBS
can be an effective treatment for essential tremor. Standard open-​loop DBS systems for
essential tremor involve always-​on neurostimulation through electrodes placed into
the ventral intermediate nucleus of the thalamus. Though effective, open-​loop DBS
systems provide a fixed pattern of electrical stimulation, even though essential tremor
is only episodically symptomatic. BCI-​based systems are being explored that could
combine DBS with additional implanted electrodes capable of detecting the onset of
tremor (Herron et  al. 2015). BCI-​based DBS applies stimulation only when needed,
when characteristic neural patterns of tremor are detected. Potential advantages of
a BCI-​based system over current open-​loop DBS include battery conservation and
reduction in short-​and long-​terms side effects experienced by individuals with fixed
neurostimulation settings.

Communication
BCI offers a way to restore or enhance communication in individuals with communica-
tive impairment (Akcakaya et al. 2014). BCI-​based devices use (1) slow cortical potentials,
(2) sensorimotor rhythms, (3) event-​related potentials, or (4) steady-​state visual-​evoked
potentials to control communication devices that allow individuals to answer yes/​no ques-
tions or select semantic elements, such as letters, words, or phrases (Soekadar & Birbaumer
2015). The first clinically useful BCI allowed two individuals with severe paralysis due
to amyotrophic lateral sclerosis to communicate using slow cortical potentials to move a
computer cursor to select letters (Birbaumer et al. 1999). Individuals who are incompletely
locked-​in due to conditions like amyotrophic lateral sclerosis or stroke can communicate
through muscle twitches or eye movements. Such communication can be laborious and
inefficient and individuals can lose these means of communication if their conditions dete-
riorate and they become completely locked-​in and unable to communicate through voli-
tional movement at all. BCI communication promises a way to maintain and potentially
restore communication for this and other conditions affecting communication.
An example of BCI for communication is an EEG-​based speller for individuals with
locked-​in state due to conditions like amyotrophic lateral sclerosis or brainstem stroke
(Chaudhary & Birbaumer 2015). Event-​related potentials, such as steady-​state evoked
potentials or P300, can allow individuals to communicate by selecting language elements.
As this BCI paradigm is based on an individual focusing on and hence selecting from
language elements from those presented on a screen, such as letters or words, measured
by a P300 or other response, training and cognitive demands involved may be signifi-
cantly less than other BCI communication approaches. Development of spellers that can
be individualized to user neurophysiologic and language patterns and can incorporate
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Near-term horizon of brain–computer interface medicine 127

lessons from natural language models may substantially improve accuracy and speed of
BCI-​based communication (Mainsah et al. 2015).

Sensation
BCI may be a way to bypass, modify, or substitute for impaired or aberrant sensory pro-
cesses (Konrad & Shanks 2010). Sensory neural implants with the widest clinical use
are cochlear implants for sensorineural hearing loss, where direct electrical stimulation
is applied outside the central nervous system to the basilar membrane of the cochlea.
Auditory brainstem implants are a form of BCI that have shown success at restoring
some level of speech recognition in individuals with acoustic nerve damage (Colletti et al.
2009). Visual prosthetics have been developed with electrodes capable of stimulating the
retina, visual cortex, or lateral geniculate body of the thalamus (Cohen 2007).
Stroke is the leading cause of disability worldwide and BCI is emerging as a promising
area of research for stroke-​related needs (Soekadar et al. 2015). BCI research after stroke
has focused on (1) bypassing corticospinal pathways damaged by stroke to activate distal
muscles or nerves directly or to control neuroprostheses or (2) facilitating neuroplasti-
city and motor learning for functional motor recovery (Mak & Wolpaw 2009). There is
increasing recognition that sensory feedback is a critical element of stroke recovery and
in control of stroke-​related motor prostheses (Patil & Turner 2008).

Cognition and consciousness

BCI may be used to improve cognition or states of consciousness that support cogni-
tive processes. Neurodegenerative disease, such as Alzheimer’s disease, dementia with
Lewy bodies, frontotemporal dementia, and nondegenerative conditions, like stroke or
traumatic brain injury, are potential targets of both nonimplantable and implantable
BCI devices. Implantable neurostimulation is an active area of research in disorders of
consciousness (Giacino et al. 2014). Up to 30–​40% of individuals diagnosed as being in
a vegetative state retain conscious awareness (Seel et  al. 2010). DBS has been used in
one subject diagnosed as minimally conscious due to traumatic brain injury to improve
arousal and restore some functional movements of upper extremities and the ability to
self-​feed (Schiff et al. 2007). Nonimplantable neurostimulation, such as transcranial mag-
netic stimulation (TMS), has been explored in disorders of consciousness as well (Giacino
et al. 2014).
Treatment of dementia is a potential application of BCI (Freund et al. 2009; Mirzadeh
et al. 2015). Individuals with Alzheimer’s disease exhibit changes in neurophysiological
measures, including delta, theta, and beta band frequencies (Soekedar et al. 2014). These
differences relative to controls may be useful in diagnosis but could also be used in a BCI
device to target brain regions for neurostimulation therapy. For instance, nonimplant-
able neurostimulation using TMS and transcranial direct current stimulation (Elder &
Taylor 2014) and implantable neurostimulation using a vagus nerve stimulator (Sjögren
et al. 2002) and DBS (Kuhn et al. 2015) have demonstrated modest cognitive benefits in
subjects with dementia. Neurostimulation may activate neurotransmitter systems (e.g.,
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128 Neuromodulation ethics

acetylcholine) and stem loss of hippocampal volumes, as has been shown in some subjects
with DBS (Sankar 2015; Sankar et al. 2015). Although the clinical significance of cognitive
benefits in this population is far from clear (Nardone et al. 2015), the results suggest that
neurostimulation could be useful. For instance, a BCI device might be used to promote
neuroplasticity for cognitive rehabilitation in combination with future interventions that
slow or stop neurodegenerative processes. Although admittedly speculative, BCI devices
could provide a way to measure substrates of impaired cognition and provide targeted
therapeutic neurostimulation.

Affect
Depression is the most common psychiatric illness, with a lifetime prevalence of nearly
20% (Bromet et al. 2011). Standard pharmacologic therapy and psychotherapy fail to alle-
viate symptoms in a substantial fraction of patients (Warden et al. 2007). Neurostimulation
is an active area of research for treatment-​resistant psychiatric disease, including depres-
sion. Electroconvulsive therapy is a well-​ recognized therapy for treatment-​ resistant
depression. Newer methods of nonimplantable neurostimulation, such as TMS and tran-
scranial direct current stimulation, have shown modest benefits (George & Aston-​Jones
2010). Repetitive TMS received approval from the US Food and Drug Administration
for mild treatment-​resistant depression in 2008. DBS has been studied in major depres-
sive disorder, with mixed results. Open-​label studies of DBS showed success (Mayberg
et al. 2005; Malone et al. 2009) while two formal clinical trials did not meet primary out-
comes (Dougherty et al. 2015). Differences in psychiatric symptoms across individuals
and within individuals over time have been postulated to explain this discrepancy (Widge
et al. 2017).
BCI-​based (closed-​loop) DBS offers a way to address the heterogeneity of depression
(Widge 2016). With embedded algorithms designed to automatically adjust stimulation
to need, BCI-​based DBS may be a significant improvement on open-​loop DBS used in
the failed clinical trials. Rather than employing a one-​size-​fits-​all approach, which may
be responsible for common side effects, such systems could detect real-​time fluctuations
in depressive symptoms and individualize stimulation to meet clinical need. The type,
and even the location, of stimulation could be fine-​tuned to meet clinical need or neuro-
physiological markers of happiness or quality of life. The potential to further incorporate
machine learning into BCI systems offers a way to not only treat depression in increas-
ingly effective ways but detect patterns of brain activity correlated with depression trig-
gers and intervene before symptoms can take hold.

Clinical ethics and consent to brain–​computer interface devices

The incorporation of BCI technology into medical devices, as with any new medical tech-
nology, raises ethical issues, not just at the level of research and policy, but at the level of
patient and clinician interaction. Individual patients and their clinicians make decisions
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Clinical ethics and consent to brain–computer interface devices 129

about whether or when to opt for medical devices. Consent to a medical device is not
an isolated event, but a decisional process situated against a backdrop of relationships
with family, friends, clinicians, and others—​and is ethically freighted. What responsibili-
ties and expectations come with accepting a device? Will adoption require a change to
daily routine? Will the device come with direct or ancillary financial or other costs? How
will adopting (or declining) the device change burdens on or relationships with caregiv-
ers? Will having the device engender unwanted expectations of family, clinicians, or even
self? For implanted devices, what are the risks of surgery? What are the alternatives to
or opportunity costs of adopting (or declining) a device? These kinds of ethical consid-
erations are important to the consent process and fall under the provenance of what is
commonly called clinical ethics.
Clinical ethics is a subdiscipline of bioethics concerned with ethical issues arising
within the practice of medicine, such as decisions about diagnosis and therapy (Miller
et al. 1996). Clinical ethics, insofar as it takes the clinical relationship as a focal point,
provides a lens through which to view clinician responsibilities within the consent pro-
cess. A principal responsibility of clinicians is to help patients understand risks associated
with potential interventions. In the case of consent to BCI research, six risk domains
have been identified (Klein 2016). Several of these risk domains—​safety, cognitive and
communicative impairment, inappropriate expectations, and privacy and security—​are
particularly relevant to clinical adoption of BCI devices as well. It is worth exploring these
risk domains as they pertain to BCI medicine and what responsibilities clinicians have or
will have in helping patients navigate the choice to adopt or decline a BCI.
The first challenge pertains to safety. Even after meeting regulatory standards for
approval, important short-​and long-​term safety uncertainties will remain with respect to
BCI devices. Just as certain side effects or adverse events are not known or fully appreciated
until after a medication reaches wide clinical use (Klein & Bourdette 2013), so too with
devices. For instance, biocompatibility and durability of implantable electrodes is an ongo-
ing concern as electrodes can fail or lose fidelity over time due to breakdown of electrode
components or to brain tissue reactive processes, such as gliotic encapsulation of elec-
trodes (McGie 2013). Such longevity and long-​term reliability uncertainties of BCI systems
are important considerations in the consent process. This is particularly true when weigh-
ing potential benefits against risks of surgical implantation. Some individuals may be will-
ing to undergo neurosurgery and tolerate uncertainties about how long a device will last,
whereas others may have a lower risk tolerance and be willing to pass up potential benefits.
There are safety risks of nonimplantable devices as well. For instance, transcranial direct
current stimulation may cause electrical burns of the scalp. Clinicians have a responsibility
to not only stay abreast of and effectively communicate the current state of known safety
risks, but to explore how safety risks fit with patient values and future plans (Klein 2016).
A second challenge is that of progressive cognitive impairment. BCI may one day
prove useful in stopping, slowing, or reversing pathological processes leading to cog-
nitive impairment, such as Alzheimer’s disease, or in treating noncognitive symptoms
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130 Neuromodulation ethics

in patients with cognitive disorders, such as tremor in patients with Parkinson’s disease
dementia. Consent to BCI therapy in individuals with mild to moderate levels of cog-
nitive impairment will require special attention to decision-​making capacity. Do indi-
viduals demonstrate adequate understanding of the risks and benefits of a BCI device?
Do they appreciate what impact adopting a BCI device will or will not likely have on
their symptoms, level of functioning, and quality of life? Can they reason through BCI
as a potential therapeutic option versus other available options? Can individuals make
and express a choice about whether to go forward with or decline a BCI device? Though
assessment of decisional capacity can be less formal and woven into ongoing discussions
between patients, families, and clinicians, more formalized tools are available to assist
with capacity assessments in individuals with known cognitive impairment, such as the
MacArthur Competence Assessment Tool for Treatment (Grisso & Appelbaum 1998).
In addition, multidisciplinary teams that incorporate individuals with relevant expertise,
such as neuropsychologists, nurses, and social workers, can provide more comprehensive
assessment of capacity to consent to BCI therapy. Models of multidisciplinary involve-
ment in the consent process have been developed for DBS (Ford & Kubu 2006).
When decision-​making capacity is absent or sufficiently diminished due to cognitive
impairment, clinicians identify and work with appropriate surrogate decision-​makers.
While severe cognitive impairment may limit the range of applicable BCI devices, some
BCI devices may still be of benefit. For instance, individuals with dementia can experi-
ence somatic pain that is undertreated in part due to difficulty communicating the expe-
rience of pain to caregivers (Malloy & Hadjistavropoulos 2004). A BCI that senses brain
patterns characteristic of pain and in turn controls a neurostimulation device to treat the
pain could address this problem. In this case, clinicians and surrogates will need to work
together to determine whether BCI is in the overall best interest of patients. The matter
will be more complicated when BCI is proposed as a way to restore cognitive capabilities
in individuals who have lost them. This may require designing consent processes that
make room for a revisiting of the decision to pursue a BCI or how it operates as elements
of decision-​capacity progressively improve. Something similar has been suggested with
respect to DBS research in minimally conscious states (Giacino et al. 2012).
BCI may also have adverse effects on cognition. Some individuals with DBS for
Parkinson’s disease, for instance, experience more cognitive decline than would be
expected as a result of the natural course of the disease (Combs et al. 2015). Concerns
about potential cognitive side effects of BCI need to be approached with caution. Not
enough is currently known about long-​term cognitive effects of neurostimulation and the
terms “cognition” and “BCI” are exceeding broad and often imprecisely used. It would not
be surprising, however, if BCI devices led simultaneously to beneficial and detrimental
effects on different areas of cognition depending on the type and target location of BCI
and how cognition is measured.
Clinicians will have a responsibility to counsel patients on the range of cognitive effects
of BCI-​based therapies. Individuals with impaired communication but normal cogni-
tive capabilities face barriers to meaningful informed consent (Fenton & Alpert 2008).
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Clinical ethics and consent to brain–computer interface devices 131

In individuals with partially locked-​in syndrome, standard informed consent processes

that involve demonstrating—​through words or gestures—​an understanding of disclosed
information and a reasoning process about potential options, do not meet clinical reality.
Extremely limited and intermittent communication is often incompatible with exigent
demands of clinical decision-​making. Even if such individuals are able to communicate
by using a BCI, it is unclear whether yes/​no or other linguistically constrained communi-
cation methods are sufficient for the nuanced and emotionally complex decisions about
treatment in locked-​in syndrome, such as declining life-​sustaining treatment (Glannon
2016). Clinicians may lack the experience in how to engage in these discussions using a
BCI device or how to assess the reliability and authenticity of patient responses. Consent to
a BCI communication device by individuals with completely locked-​in syndrome—​where
no speech or gestural communication is possible at all—​presents a different issue. The
ability to communicate is so central to the exercise of individual autonomy and to quality
of life (Birbaumer et al. 1999) that it may be reasonable for surrogates to consent for inter-
ventions that aim to restore communicative ability, even if they involve significant risks.
A third challenge is that of managing expectations. Unrealistic expectations are a prob-
lem in BCI research (Haselager et al. 2009) and, if the transition to clinical use of DBS is
a guide (Bell et al. 2010), this will be true of BCI as well. Most BCI devices are not imple-
mented as off-​the-​shelf technology, but require significant training that involves physical
and emotional investment on the part of the user (Mak & Wolpaw 2009; McGie et al.
2013). Clinicians have a responsibility to prepare patients and families for the work that
is required of them and for the unfortunate possibility that a BCI device may not work as
well as a patient or family hopes. Helping patients titrate expectations is a general respon-
sibility of clinicians, but is particularly important and difficult with BCI devices when
overly optimistic portrayals of BCIs in the media create headwinds for reasonable patient
expectations. Conversely, inappropriately low expectations are a problem in BCI medicine
as well. For instance, individuals with locked-​in syndrome who require chronic artificial
respiration and feeding demonstrate a higher quality of life than is typically presumed by
significant others (Kübler et al. 2005). A poor understanding of quality of life and disabil-
ity among clinicians and families could influence decisions about life sustaining therapy,
advance directives, and BCI-​based therapies, such as BCI-​assisted communication.
A fourth challenge is privacy and security. BCI devices have the potential to record and
store vast amounts of data on individual brain function. This raises data security concerns
(Denning et al. 2009). Brain data can be collected, stored, and transmitted in more or less
secure ways and hence have the potential to be stolen and put to nefarious uses. The hack-
ing of implantable devices is a noted risk. For instance, former US Vice President Richard
Cheney reportedly had the wireless capability of his implanted cardiac defibrillator dis-
abled out of concern that it might be susceptible to hacking (Kolata 2013). Technological
solutions to prevent hacking are worth pursuing but the presence of recordable brain data
creates an ineliminable risk.
Privacy concerns exist beyond the security challenges. A BCI device may collect data
over which an individual wants to exert control. For instance, an individual with a BCI
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132 Neuromodulation ethics

device for communication may not want every conversation recorded or may want to
dump brain data associated with conversations, perhaps to protect a family member’s feel-
ings or because of embarrassment. The desire to provide individuals with such a sphere
of cognitive privacy may run up against competing interests, such as the need to establish
competency for financial or healthcare decisions. Did the patient ever indicate a desire to
change their last will and testament and give everything to charity? Were the preferences
in their living will consistent (before falling into their current incapacitated state), or does
a BCI record indicate ambivalent feelings? BCI data may become a trove of information
to which parties seek access. The clinician has a role in preparing patients for privacy risks
associated with BCI brain data, even if the scope and available protections of this privacy
are not currently clear.
While it is clear that clinicians have ethical responsibilities to assist patients as they
engage in the consent process for BCI devices, clinicians also have responsibilities after
adoption of a BCI device. A  critical feature of BCI technology is the need to moni-
tor and adjust device function over time. This feature of BCI medicine—​the need for
neuromodulation—​raises its own set of ethical issues (Ford & Henderson 2006; Fukushi
2012). How should the settings of a device be determined? Who determines whether a
device is working well or needs to be adjusted? Who should have a say—​patients, families,
clinicians, others—​in decisions about neuromodulation? In BCI systems that incorporate
machine learning, when should clinicians or others be able to intervene, say, if patients are
unaware or disagree that a device is malfunctioning?

Clinical ethics and neuromodulation

Neuromodulation can be understood as an iterative, goal-​directed intervention in the
nervous system. This description spans a wide range. Individuals can neuromodulate
through various neural interventions, or what the Presidential Commission for the Study
of Bioethics Issues calls neural modifiers (Presidential Commission 2015). This can range
from reaching for a caffeinated beverage to counter a lag in concentration to implantation
of DBS electrodes to treat Parkinson’s disease. The term neuromodulation, however, is
typically reserved for pharmacologic or mechanical interventions into the nervous sys-
tem. Neuromodulation is “a technology that impacts upon neural interfaces and is the
science of how electrical, chemical, and mechanical interventions can modulate or change
central and peripheral nervous system functioning” (Krames et al. 2009, p.5). With the
exception of one-​off interventions, for example, a one-​time dose of tissue plasminogen
activator for acute stroke treatment, most neural modifiers are neuromodulatory inso-
far as they satisfy three criteria: (1) they are dynamic and ongoing (either continuous or
intermittent), (2) their effects are mediated through neural networks, and (3) their clini-
cal effect is continuously controllable by modifying device or intervention parameters
(Holsheimer 2003).
Clinicians already play a central role in neuromodulation using implantable devices.
Neural stimulators, microinfusion pumps, and other devices are currently used or being
developed for diverse disorders, including disorders of cardiac pacing, gastric motility,
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Clinical ethics and consent to brain–computer interface devices 133

urinary dysfunction, eyesight, hearing, epilepsy, movement, chronic pain, spasticity,

and mental health (Kames et  al. 2009). As a result, clinicians from across the medical
spectrum—​ anesthesiologists, cardiologists, gastroenterologists, neurologists, neuro-
surgeons, ophthalmologists, otolaryngologists, pain physicians, psychiatrists, physical
medicine and rehabilitation specialists, and urologists—​have developed skills at setting,
monitoring, and adjusting parameters of implanted devices. A ready example of this is
programming visits after implantation of DBS for movement disorders like Parkinson’s
disease. After surgical implantation, patients or research subjects with these devices are
evaluated at set intervals and device settings—​frequency, pulse width, and voltage—​are
adjusted to treat symptoms, such as a reduction in tremor, or otherwise improve quality
of life. The need to develop such neuromodulatory skills was recognized soon after the
introduction of DBS: “Movement disorders specialists becoming involved with this ther-
apy need to acquire new skills to optimally adapt stimulation parameters and medication
after implantation of a DBS system” (Volkmann et al. 2002, S181).
Decisions about how best to modulate brain function can be a source of ethical conflict
between clinician and patient. Peter Kramer’s Listening to Prozac describes the experi-
ences of patients treated with antidepressants and the difficulties that arise in defining
appropriate and successful treatment. Kramer notes that clinicians and patients can dis-
agree on proper use of or indications for these medications. He describes the case of Sally,
a shy, anxious, and socially isolated 41-​year-​old woman transformed by Prozac®, becom-
ing “brighter, calmer, self-​assured, in firm control of herself ” (Kramer 1993, p.147). The
extent of this transformation led to conflict between the psychiatrist, Kramer, and Sally:

I felt concern that Sally may have “overshot,” that this new personality was too different from her
old one. She demurred. She said Prozac had let her personality emerge at last—​she had not been
alive before taking an antidepressant. Sally insisted I not stop the medication, but I tapered the dose
slightly. (Kramer 1993, pp.147–​148, italics added)

Similar concerns about nonpharmacologic neuromodulation have been discussed in

the context of DBS. Schermer (2013) describes the case of a Dutch patient treated with
DBS for obsessive–​compulsive disorder who failed to achieve relief from symptoms of
obsessive–​compulsive disorder, but who felt “better and happier” with the DBS. Her psy-
chiatrist refused her request to continue DBS stimulation, and turned off the stimulator,
noting that physicians are not in the business of “trading happiness.” Similarly, Synofzik
and Fins (2012) describe the case of a German man with obsessive–​compulsive disorder
and anxiety implanted with a DBS who experienced symptoms of pathologic euphoria
at high voltage settings. Despite the patient’s request for settings that would allow him
to feel “a bit better,” his clinician refused: “After extensive yet difficult deliberation about
the benefits of an only intermediate stage of happiness and an intermediate voltage, the
parameter settings were left unchanged” (Synofzik & Fins 2012, p.32).
This raises a number of questions about the role of the clinician in neuromodulation.
Some of these questions relate to potential conflict between clinician and patient. What
justifies a clinician abiding by a patient’s neuromodulation request or refusing it? Should
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134 Neuromodulation ethics

clinicians invoke notions of clinical integrity or the goals of medicine in refusing patient
requests for neuromodulation (Woopen 2012; Schermer 2013)? Other questions relate
to tradeoffs involved in neuromodulation. What is the clinician’s role in advising about
scientific uncertainties of BCI, for instance, if electrodes begin to fail and applying higher
levels of current to overcome encapsulation resistance offers a potential remedy but at an
unknown risk of longer-​term tissue damage? Or what if uncertainty exists as to whether
a device is failing or an individual instead is experiencing progression of their disease?
Moreover, how should a clinician counsel about side effects of treatment if a patient and
family disagree about the value of these side effects, for example, increased disinhibition
due to BCI in a previously painfully shy individual like Kramer’s Sally? How might these
questions change if choice points for modulation are obviated by device algorithms that
automatically decide how to adjust device settings? Does this change the obligations of
clinicians to counsel and care for patients with BCI devices? These questions might be
reframed at a more general level: what constitutes responsible neuromodulation?

Neuromodulation and the engineering model of medicine

One way to approach this question is to look at the clinical skills involved in neuromod-
ulation. Just as clinicians have developed expertise in how to adjust antidepressants to
treat symptoms of depression or DBS stimulation parameters to more effectively treat
symptoms of tremor, clinicians will develop technical skills at modulating the function
of medical BCI devices. Neuromodulation viewed as a set of technical skills makes sense
from within a particular view of medicine. Robert Veatch coined this view of medicine
the “engineering model” (Veatch 1972).4 Veatch argues that clinicians within this view
are applied scientists who possess a repository of technical skills. These skills range from
manual dexterity of surgeons to deductive logic of medical diagnosticians, are developed
and refined through medical education, and both help define the boundaries of medical
practice and the identities of its practitioners.
Viewed from within an engineering model of medicine, the skills of neuromodula-
tion are inherently non-​normative. Such skills can be more or less developed or more or
less effectively employed. Whether these technical skills in turn are used responsibly is a
second-​order question. Responsible neuromodulation, on the engineering view, depends
on how technical skills are put to use. Do these skills advance the interest or well-​being
of a particular patient? Does the exercise of these skills in a particular instance serve the
interest of the broader community? Are these skills developed and exercised as part of
society’s social contract with the medical profession? Put simply, the clinician’s neuro-
modulatory skills are a “tool” that can be put to good or bad use.
Consider an analogy. The medical specialty that cares for people with multiple
sclerosis (MS) is called clinical neuroimmunology (or just neuroimmunology).5
Neuroimmunologists are clinicians specialized in understanding and modulating inter-
actions between the nervous system and the immune system. Immune modulation thera-
pies (or “disease-​modifying therapies”) for MS have expanded in recent years, starting
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Neuromodulation and the engineering model of medicine 135

with subcutaneous interferons in the early 1990s and expanding to a broad range of thera-
pies (Ransohoff et al. 2015). Immunomodulatory therapies involve a tradeoff—​in order to
counter the body’s autoimmune attack on the nervous system, a reduction in the ability
of the immune system to perform its normal functions, such as fighting infections (Rizvi
& Coyle 2011), can result. The introduction of one medication, natalizumab, typifies the
immunomodulatory trade-​off. When initially introduced, natalizumab demonstrated
significantly better effectiveness at treating MS, but this increased effectiveness came
with a cost: a 1:1000 risk of progressive multifocal leukoencephalopathy, a devastating,
untreatable, and potential fatal brain infection (Clifford et al. 2010). For some patients,
the potential benefits of natalizumab outweigh the rare chance of progressive multifocal
leukoencephalopathy, for others, this is not the case. Patients and clinicians face similar,
though perhaps less stark, tradeoffs with other immunomodulatory therapies.
Immune modulation decisions—​ whether to start, reduce, escalate, or abandon a
therapy—​in turn, raise ethical questions. What is a reasonable tradeoff? What level of
consent is needed? Can a clinician refuse to start therapy, say, if adherence to follow-​up
surveillance is likely to be poor? The engineering model of medicine provides one way
to approach these kinds of ethical questions. Clinicians bring technical expertise—​the
ability to assess symptoms, note physical signs, examine biomarkers of disease stability
or progression, and effectively communicate information—​and patients bring a moral
framework—​comprised of their preferences, belief systems, and modes of reasoning. Dan
Brock describes the division of labor at the heart of the engineering model as:
In this approach, both physicians and patients have essential roles in ideal treatment decision mak-
ing. Physicians are to use their knowledge, training, and expertise to provide their patients with a
diagnosis and a prognosis if no treatment is undertaken, together with information about alterna-
tive treatments that might improve the prognosis, including the risks and benefits and attendant
uncertainties of such treatments. Patients articulate their own aims, preferences, and values in
order to evaluate which alternative is best for them. (Brock 1991, p.31)

This division of labor has implications for assignment of moral responsibility. On the
engineering model, the primary obligation of the clinician is to develop technical exper-
tise and to translate this expertise into information for patients. This has led Emanuel and
Emanuel (1992) to describe the engineering model as primarily centered on delivery of
information. This information consists of assessment of the patient’s health, diagnostic
and therapeutic options, and relevant probabilities. The information might even include
the clinician’s assessment of what she takes the patient’s values to be (though without
taking a stand on them). One sees this in discussions of shared decision-​making in MS
(Heesen et al. 2011). On this view, whatever subsidiary obligations clinicians may have can
be viewed as deriving from a primary obligation: develop and exercise technical expertise.
On an engineering model, the role of the clinician in neuromodulation is to apply tech-
nical skills to “fix” some dysfunctional aspect of the nervous system. Technical expertise
is problem-​oriented. Skills are put to use to solve or fix a particular problem or set of
problems. This orientation centered on fixing is important because it helps structure how
ethical issues are approached and how clinician responsibilities are understood. As an
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136 Neuromodulation ethics

example, consider the individual shown to kick a soccer ball by using a BCI-​based exo-
skeleton at the 2016 World Cup in Brazil (Smith 2014). A team of researchers identified a
problem—​the inability of an individual with lower extremity paralysis to stand indepen-
dently and kick an object—​and developed a plan to solve it. By framing this research in
terms of a single fixable problem (or series of problems) ethical questions that might be
raised about this research inherit this frame. What was the consent process like? Is this
a just use of societal resources? How should the media be utilized to educate the public
about an emerging technology? Questions about consent, justice, responsible conduct of
research, and other matters have their meaning in reference to solving a particular tech-
nical problem: fixing the neural dysfunction that is preventing kicking a soccer ball. As
such, an engineering model provides a simplifying framework for reflecting on the ethical
responsibilities of a “neuromodulationist.”

Limitations of the engineering model

The engineering model of medicine has been criticized within bioethics (Clouser 1983;
Emanuel & Emanuel 1992; Brody 1997). An argument against the engineering model’s
commitment to fixing can be found outside bioethics in recent work in disability the-
ory. Disability has long been understood along a medical model (Silvers 2009). Within a
medical model, disability is a property of individual bodies. This contrasts with a social
model of disability that locates disability outside individual biological bodies and locates
it, at least in large part, in the relationship between the individual and the social and built
environment. An individual in a wheelchair may have a disability if trying to board a bus
that lacks a chair lift, but not have a disability if a lift is present or, more to the point, have
something quite unlike a disability if the wheelchair allows one to speed down a long
hill and catch a bus before departing. Disability is a way of understanding the mismatch
between individual preferences and needs and environmental or social obstacles to their
fulfilment. An outgrowth of the medical model of disability is to view loss of a function—​
or the body out of which it arises—​as something to fix with medicine or science. Here the
engineering model of medicine and the medical model of disability overlap. Both models
share a subject matter: broken bodies or functions that are in need of a fix.
Applying the disability critique to BCI medicine helps shed light on several distorting
features of the engineering model: a tendency to overlook the perspectives of end users,
obscure the normative features of BCI problems, and misunderstand that desired out-
comes of BCI device can be underdetermined.
The first way in which the fixing frame distorts is that it presumes that problems to be
fixed are self-​evident and easily identifiable from any standpoint, leading to such overly
simplistic questions as: Who wouldn’t want to restore walking ability with the use of a
BCI exoskeleton? Who wouldn’t want to restore the ability to write with the use of a BCI
prosthetic device? Who wouldn’t want to be fixed? Yet research in populations targeted
by BCI devices challenge received assumptions about what individuals do and do not
value. Anderson (2004) surveyed 681 individuals with spinal cord injury and found that
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Brain–computer interfaces as enabling technology 137

regaining walking function was not a high priority among individuals with quadriplegia
and paraplegia, whereas restoration of upper extremity and sexual function were. The
value of end-​user perspectives in BCI research is beginning to be recognized (Huggins
et al. 2011; Collinger et al. 2013a; Kübler et al. 2015).
The second way in which the fixing frame can distort is in obscuring how problems
addressed by BCI are normatively defined. Take the example of designing a BCI neuro-
prosthetic arm that allows an individual to shake hands (Klein et al. 2015). The character-
istics of handshakes are known to vary across cultures (Dibiase & Gunnoe 2004). What
constitutes a handshake depends on norms and context. A grip that is strong and lingers
may indicate confidence and competence in certain contexts, like a business meeting, but
may be awkward or threatening in others, such as meeting a prospective son-in-law or
daughter-in-law for the first time. That problems might not be definable without reference
to social norms undermines the fixing frame. The promise of a purely technical fix only
makes sense for problems that can be technically defined without remainder, and many of
the functions that BCI devices target will be, at least in part, normatively defined.
The final limitation of the engineering model applied to BCI medicine derives from the
iterative nature of neuromodulation. As discussed earlier, consent to obtain a BCI device
is an important decision, and one that involves the patient and clinician in a discussion
of goals, values, and expected outcomes. A process of shared decision-​making is under-
taken. One of the challenges of the engineering model is that while it may be of adequate
fit for the initial decision to get a BCI device, it fits poorly decisions (or iterative consents)
related to ongoing neuromodulation. The clinical benefit of a BCI device will turn to a
great extent on a multitude of decisions about how to modulate the device function over
time. The endpoint around which this modulation occurs is not fixed. An individual may
start out wanting no tremor or no depression but over time develop a more nuanced set
of preferences for BCI function, such as no tremor in church, or no depressive symptoms
related to self-​worth. What is important is that the goals of BCI therapy will be under-
determined at initiation of therapy. Patients, clinicians, and family will have to engage
in an iterative practice of values exploration in order to modulate the device function
effectively.

Brain–​computer interfaces as enabling technology

An alternative framework for neuromodulation may be found in rehabilitation medicine.
A  central feature of rehabilitation is the use of enabling technology. Enabling technol-
ogy includes traditional tools such as canes, walkers, and prosthetics, but increasingly
includes tools with technological sophistication, such as BCI devices. What makes tools
enabling technology (as opposed to enhancing or fixing technology) is that they alleviate
the impact of disease or disability; such tools can be therapeutic, compensatory, assistive,
or universal technology (Hansson 2007). The clinician’s role in rehabilitation is not to fix
patients with enabling technology but help them use technology to pursue goals rela-
tive to a given reference point. As a patient’s abilities and possibilities change during the
138  1

138 Neuromodulation ethics

course of rehabilitation therapy, clinicians help patients reevaluate and reformulate goals
over time in light of these changes. Most BCI devices under development are a form of
assistive technology.
Consider a hypothetical case of Judith, a woman who receives a BCI-​based DBS device
for treatment-​resistant depression. Judith’s device has electrodes that record neural sig-
nals relevant to depression and uses these to adjust stimulation settings of DBS elec-
trodes. At the outset of therapy, Judith and her clinician decide on the initial setting for
her device. Whenever a certain pattern of activity is detected that correlates with her
depressive symptoms, the DBS electrodes will apply stimulation to return her brain to a
normal state. Over time, Judith and her clinician will reevaluate and adjust her device set-
tings, that is, neuromodulate. What happens if Judith and her clinician disagree on new
settings? Perhaps Judith comes to miss the fluctuations of her pre-​device self or feels that
a little dysthymia is helpful for her work as an artist. And maybe her clinician becomes
wary, based on his prior relationship with her that a closed-​loop system permissive of
fluctuations may allow her to “spiral down” toward suicide. How should decisions about
neuromodulation be made? What does consent mean in this context?
An advantage of looking to rehabilitation medicine is that it provides an alternative
model of consent for neuromodulation. Purtilo (1988) argues that rehabilitation medi-
cine provides a good example of why the event model of consent is inadequate. Decisions
made in rehabilitation are most often iterative and incremental: as a patient’s condition or
functional capabilities change, therapies are adjusted, often in small ways. For example,
the consent to a rehabilitation program to retrain one’s upper extremity for self-​feeding
after a stroke is more accurately understood as a series of decisions that are made over
time and represent small steps. “Today I will agree to work with the physical therapist.”
“Today I will try to move my fingers.” “Today I will ignore spastic pain.” “Today I will try
to grasp an object.” “Today I will try to lift an object.” And so on. These decisions may not
be linear or wholly predictable. They are a process. A process view of consent is a better fit
for the iterative decisions that characterize BCI medicine.
The introduction of clinical BCI devices raises important ethical questions. Some of
these questions will be faced by patients and clinicians as they decide on whether to pur-
sue a BCI device. Other questions will arise in the practice of neuromodulation. How
much control should individuals be given over their cognitive, affective, or motoric life?
When should clinicians abide by or refuse patient requests for device settings? Though
there are unlikely to be easy answers to these questions, it is worth anticipating now the
kinds of ethical issues that patients and clinicians will face as BCI devices come into
greater clinical use and exploring possible resources, such as those found in rehabilitation
medicine, for addressing them.

Acknowledgments
This work was supported by a grant from the National Science Foundation (NSF Award
#EEC-​1028725). The views expressed are solely those of the author and do not represent
the views of the NSF.
 139

References 139

Notes
1. Although efforts have been made to establish different referents for BCI and BMI, the terms are used
interchangeably in the literature. For instance, some prefer to reserve BMI for neural interfaces con-
trolling robotic or prosthetic devices (Wolpaw & Wolpaw 2012). For the sake of simplicity, BCI will be
used synonymously here.
2. This impairment-​based schema has its limitations. For instance, if not put in context it may seem to
reinforce certain questionable dichotomies in our thinking, such as between normal and abnormal
function and able and disabled bodies. In addition, the domains are imperfect in that they are not
comprehensive and in some cases overlap. For instance, does a seizure detection and stimulation BCI
system belong in the motor, sensory, or cognition/​consciousness domain? Nonetheless, this rough
grouping maps onto both traditional medical and scientific categories and so is a useful preliminary
framework.
3. The devices and technologies highlighted, both wearable and implantable, give a representative feel for
work in each domain. This is helpful for exploring the ethical issues discussed in this section, even if
the chosen examples are not the most representative technology or are not the closest to translation in
a given domain. No position is taken on the warrant of pursuing wearable versus implantable devices
in any given domain.
4. Veatch juxtaposes the engineering model (unfavorably) to the priestly, collegial, and contractual
models.
5. Medical conditions falling within the scope of neuroimmunology typically include Guillain–​Barré
syndrome, myasthenia gravis, central nervous system vasculitis, dermatomyositis, and others, but
multiple sclerosis, an inflammatory demyelinating and neurodegenerative disorder of the nervous sys-
tem, is the paradigmatic example of a neuroimmunological disease.

References
Akcakaya, M., Peters, B., Moghadamfalahi, M., et al. (2014). Noninvasive brain–​computer interfaces
for augmentative and alternative communication. Biomedical Engineering, IEEE Reviews, 7, 31–​49.
Anderson, K.D. (2004). Targeting recovery: priorities of the spinal cord-​injured population. Journal of
Neurotrauma, 21(10), 1371–​1383.
Bell, E., Maxwell, B., McAndrews, M.P., Sadikot, A., and Racine, E. (2010). Hope and patients’
expectations in deep brain stimulation: healthcare providers’ perspectives and approaches. Journal of
Clinical Ethics, 21, 112–​124.
Birbaumer, N., Ghanayim, N., Hinterberger, T., et al. (1999). A spelling device for the paralysed.
Nature, 398(6725), 297–​298.
Brock, D.W. (1991). The ideal of shared decision making between physicians and patients. Kennedy
Institute of Ethics Journal, 1(1), 28–​47.
Brody, H. (1997). The physician-​patient relationship. Medical Ethics, 2, 75–​101.
Bromet, E., Andrade, L.H., Hwang, I., et al. (2011). Cross-​national epidemiology of DSM-​IV major
depressive episode. BMC Medicine, 9(1), 1.
Chaudhary, U. and Birbaumer, N. (2015). Communication in locked-​in state after brainstem stroke: a
brain-​computer-​interface approach. Annals of Translational Medicine, 3(Suppl. 1), S29.
Clausen, J. (2011). Conceptual and ethical issues with brain–​hardware interfaces. Current Opinion in
Psychiatry, 24(6), 495–​501.
Clifford, D.B., De Luca, A., Simpson, D.M., Arendt, G., Giovannoni, G., and Nath, A. (2010).
Natalizumab-​associated progressive multifocal leukoencephalopathy in patients with multiple
sclerosis: lessons from 28 cases. Lancet Neurology, 9(4), 438–​46.
140  1

140 Neuromodulation ethics

Clouser, K.D. (1983). Veatch, May, and models: a critical review and a new view. In: Shelp, E.E. (Ed.)
The Clinical Encounter, pp.89–​103. Netherlands: Springer.
Cohen, E.D. (2007). Prosthetic interfaces with the visual system: biological issues. Journal of Neural
Engineering, 4(2), R14.
Colletti, V., Shannon, R.V., Carner, M., Veronese, S., and Colletti, L. (2009). Progress in restoration of
hearing with the auditory brainstem implant. Progress in Brain Research, 175, 333–​345.
Collinger, J.L., Boninger, M.L., Bruns, T.M., Curley, K., Wang, W., and Weber, D.J. (2013a). Functional
priorities, assistive technology, and brain-​computer interfaces after spinal cord injury. Journal of
Rehabilitation Research and Development, 50(2), 145–​160.
Collinger, J.L., Wodlinger, B., Downey, J.E., et al. (2013b). High-​performance neuroprosthetic control
by an individual with tetraplegia. The Lancet, 381(9866, pp.557–​564.
Combs, H.L., Folley, B.S., Berry, D.T., et al. (2015). Cognition and depression following deep brain
stimulation of the subthalamic nucleus and globus pallidus pars internus in Parkinson’s disease: a
meta-​analysis. Neuropsychology Review, 25(4), 439–​454.
Denning, T., Matsuoka, Y., and Kohno, T. (2009). Neurosecurity: security and privacy for neural
devices. Neurosurgical Focus, 27(1), E7.
Dibiase, R. and Gunnoe, J. (2004). Gender and culture differences in touching behavior. Journal of
Social Psychology, 144(1), 49–​62.
Dougherty, D.D., Rezai, A.R., Carpenter, L.L., et al. (2015). A randomized sham-​controlled trial
of deep brain stimulation of the ventral capsule/​ventral striatum for chronic treatment-​resistant
depression. Biological Psychiatry, 78(4), 240–​248.
Elder, G.J. and Taylor, J.P. (2014). Transcranial magnetic stimulation and transcranial direct current
stimulation: treatments for cognitive and neuropsychiatric symptoms in the neurodegenerative
dementias? Alzheimer’s Research and Therapy, 6(9), 74,
Emanuel, E.J. and Emanuel, L.L. (1992). Four models of the physician-​patient relationship. Journal of
the American Medical Association, 267(16), 2221–​2226.
Fenton, A. and Alpert, S. (2008). Extending our view on using BCIs for locked-​in syndrome.
Neuroethics, 1(2), 119–​132.
Ford, P.J. and Henderson, J.M. (2006). The clinical and research ethics of neuromodulation.
Neuromodulation: Technology at the Neural Interface, 9(4), 250–​252.
Ford, P.J. and Kubu, C.S. (2006). Stimulating debate: ethics in a multidisciplinary functional
neurosurgery committee. Journal of Medical Ethics, 32(2), 106–​109.
Freund, H.J, Kuhn, J., Lenartz, D., et al. (2009). Cognitive functions in a patient with Parkinson-​
dementia syndrome undergoing deep brain stimulation. Archives of Neurology, 66(6), 781–​785.
Fukushi, T. (2012). Ethical practice in the era of advanced neuromodulation. Asian Bioethics Review,
4(4), 320–​329.
George, M.S. and Aston-​Jones, G. (2010). Noninvasive techniques for probing neurocircuitry and
treating illness: vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS) and
transcranial direct current stimulation (tDCS). Neuropsychopharmacology, 35(1), 301–​316.
Giacino, J.T., Fins, J.J., Machado, A., and Schiff, N.D. (2012). Central thalamic deep brain stimulation
to promote recovery from chronic posttraumatic minimally conscious state: challenges and
opportunities. Neuromodulation: Technology at the Neural Interface, 15(4), 339–​349.
Giacino, J.T., Fins, J.J., Laureys, S., and Schiff, N.D. (2014). Disorders of consciousness after acquired
brain injury: the state of the science. Nature Reviews Neurology, 10(2), 99–​114.
Gilbert, F. (2015). A threat to autonomy? The intrusion of predictive brain implants. American Journal
of Bioethics: Neuroscience, 6(4), 4–​11.
Glannon, W. (2016). Ethical issues in neuroprosthetics. Journal of Neural Engineering, 13(2), 021002.
 14

References 141

Goering, S. (2014). Is it still me? DBS, agency, and the extended, relational me. American Journal of
Bioethics: Neuroscience, 5(4), 50–​51.
Goering, S. (2015). Stimulating autonomy: DBS and the prospect of choosing to control ourselves
through stimulation. American Journal of Bioethics: Neuroscience, 6(4), 1–​3.
Grisso, T. and Appelbaum, P.S. (1998). MacArthur Competence Assessment Tool for Treatment
(MacCAT-​T). Sarasota, FL: Professional Resource Press.
Hansson, S.O. (2007). The ethics of enabling technology. Cambridge Quarterly of Healthcare Ethics,
16(3), 257–​267.
Haselager, P. (2013). Did I do that? Brain–​computer interfacing and the sense of agency. Minds and
Machines, 23(3), 405–​418.
Haselager, P., Vlek, R., Hill, J., and Nijboer, F. (2009). A note on ethical aspects of BCI. Neural
Networks, 22(9), 1352–​1357.
Hebb, A.O., Zhang, J.J., Mahoor, M.H., et al. (2014). Creating the feedback loop: closed-​loop
neurostimulation. Neurosurgery Clinics of North America, 25(1), 187–​204.
Heesen, C., Solari, A., Giordano, A., Kasper, J., and Köpke, S. (2011). Decisions on multiple sclerosis
immunotherapy: new treatment complexities urge patient engagement. Journal of the Neurological
Sciences, 306(1), 192–​197.
Herron, J., Denison, T., and Chizeck, H.J. (2015). Closed-​loop DBS with movement intention.
In: Proceedings of the 2015 7th International IEEE/​EMBS Conference on Neural Engineering (NER),
pp.844–​847. Montpellier, France, April 2015
Hochberg, L.R., Serruya, M.D., Friehs, G.M., et al. (2006). Neuronal ensemble control of prosthetic
devices by a human with tetraplegia. Nature, 442(7099), 164–​171.
Hochberg, L. and Anderson, K. (2012). BCI users and their needs. In: Wolpaw, J.R. and Wolpaw, E.W.
(Eds.) Brain-​Computer Interfaces, pp. 317–​323. New York: Oxford University Press.
Holsheimer, J. (2003). Letters to the editor. Neuromodulation, 6(4), 270–​2.
Huggins, J.E., Wren, P.A., and Gruis, K.L. (2011). What would brain-​computer interface users want?
Opinions and priorities of potential users with amyotrophic lateral sclerosis. Amyotrophic Lateral
Sclerosis, 12(5), 318–​324.
King, C., McCrimmon, C., Wang, P., Chou, C., Nenadic, Z., and Do, A.H. (2014). Brain-​computer
interface driven functional electrical stimulation system for overground walking: a case report.
Neurology, 82(Suppl. 10), P3–​055.
Krames, E.S., Peckham, P.H., Rezai, A.R., and Aboelsaad, F. (2009). What is neuromodulation?
In: Krames, E.S., Peckham, P.H., and Rezai, A.R. (Eds.) Neuromodulation, pp.3–​8. San Diego,
CA: Academic Press.
Klein, E. (2016). Informed consent in implantable BCI research: identifying risks and exploring
meaning. Science and Engineering Ethics, 22(5), 1299–​1317.
Klein, E. and Bourdette, D. (2013). Postmarketing adverse drug reactions: a duty to report?
Neurology: Clinical Practice, 3(4), 288–​294.
Klein, E., Brown, T., Sample, M., Truitt, A.R., and Goering, S. (2015). Engineering the brain: ethical
issues and the introduction of neural devices. Hastings Center Report, 45(6), 26–​35.
Kolata, G. (2013, October 27). Of fact, fiction and Cheney’s defibrillator. The New York Times. http://​
nytimes.com/​2013/​10/​29/​science/​of-​fact-​fiction-​and-​defibrillators.html [accessed June 25, 2016].
Konrad, P. and Shanks, T. (2010). Implantable brain computer interface: challenges to neurotechnology
translation. Neurobiology of Disease, 38(3), 369–​375.
Kübler, A., Winter, S., Ludolph, A.C., Hautzinger, M., and Birbaumer, N. (2005). Severity of depressive
symptoms and quality of life in patients with amyotrophic lateral sclerosis. Neurorehabilitation and
Neural Repair, 19(3), 182–​193.
142  1

142 Neuromodulation ethics

Kübler, A., Holz, E., Kaufmann, T., and Zickler, C. (2013). A user centred approach for bringing BCI
controlled applications to end-​users. In: Fazel-​Rezai, R. (Ed.) Brain-​Computer Interface Systems-​
Recent Progress and Future Prospects. InTech, DOI: 10.5772/​55802. Available from: http://​www.
intechopen.com/​books/​brain-​computer-​interface-​systems-​recent-​progress-​and-​future-​prospects/​
a-​user-​centred-​approach-​for-​bringing-​bci-​controlled-​applications-​to-​end-​users
Kuhn, J., Hardenacke, K., Lenartz, D., et al. (2015). Deep brain stimulation of the nucleus basalis of
Meynert in Alzheimer’s dementia. Molecular Psychiatry, 20(3), 353–​360.
Mainsah, B.O., Collins, L.M., Colwell, K.A., et al. (2015). Increasing BCI communication rates with
dynamic stopping towards more practical use: an ALS study. Journal of Neural Engineering, 12(1),
016013.
Mak, J.N. and Wolpaw, J.R. (2009). Clinical applications of brain-​computer interfaces: current state and
future prospects. IEEE Reviews in Biomedical Engineering, 2, 187–​199.
Malloy, D.C. and Hadjistavropoulos, T. (2004). The problem of pain management among persons
with dementia, personhood, and the ontology of relationships. Nursing Philosophy, 5(2), 147–​159.
Malone, D.A., Dougherty, D.D., Rezai, A.R., et al. (2009). Deep brain stimulation of the ventral
capsule/​ventral striatum for treatment-​resistant depression. Biological Psychiatry, 65(4), 267–​275.
Mayberg, H.S., Lozano, A.M., Voon, V., et al. (2005). Deep brain stimulation for treatment-​resistant
depression. Neuron, 45(5), 651–​660.
McGie, S.C., Nagai, M.K., and Artinian-​Shaheen, T. (2013). Clinical ethical concerns in the
implantation of brain-​machine interfaces: Part II: specific clinical and technical issues affecting
ethical soundness. Pulse, IEEE, 4(2), 32–​37.
Miller, F.G., Fins, J.J., and Bacchetta, M.D. (1996). Clinical pragmatism: John Dewey and clinical ethics.
Journal of Contemporary Health Law & Policy, 13(27), 27–​51.
Mirzadeh, Z., Bari, A., and Lozano, A.M. (2015). The rationale for deep brain stimulation in
Alzheimer’s disease. Journal of Neural Transmission, 123(7), 775–​783.
Murphy, M.D., Guggenmos, D.J., Bundy, D.T., and Nudo, R.J. (2016). Current challenges facing the
translation of brain computer interfaces from preclinical trials to use in human patients. Frontiers in
Cellular Neuroscience, 9, 497.
Nardone, R., Höller, Y., Tezzon, F., et al. (2015). Neurostimulation in Alzheimer’s disease: from basic
research to clinical applications. Neurological Sciences, 36(5), 689–​700.
Patil, P.G. and Turner, D.A. (2008). The development of brain-​machine interface neuroprosthetic
devices. Neurotherapeutics, 5(1), 137–​146.
Pfurtscheller, G., Müller, G.R., Pfurtscheller, J., Gerner, H.J., and Rupp, R. (2003). Thought–​control
of functional electrical stimulation to restore hand grasp in a patient with tetraplegia. Neuroscience
Letters, 35(1), 33–​36.
Presidential Commission for the Study of Bioethical Issues (2015). Gray Matters: Topics at the
Intersection of Neuroscience, Ethics, and Society, 2. Washington, DC: United States Government.
Purtilo, R.B. (1988). Ethical issues in teamwork: the context of rehabilitation. Archives of Physical
Medicine and Rehabilitation, 69(5), 318–​322.
Ransohoff, R.M., Hafler, D.A., and Lucchinetti, C.F. (2015). Multiple sclerosis—​a quiet revolution.
Nature Reviews Neurology, 11(3), 134–​142.
Rizvi, S.A. and Coyle, P.K. (2011). Clinical Neuroimmunology: Multiple Sclerosis and Related Disorders.
New York: Springer.
Sankar, T. (2015). Alzheimer’s disease: a novel application for deep-​brain stimulation? Future Neurology,
10(4), 297–​300.
Sankar, T., Chakravarty, M.M., Bescos, A., et al. (2015). Deep brain stimulation influences brain
structure in Alzheimer’s disease. Brain Stimulation, 8(3), 645–​654.
 143

References 143

Schermer, M. (2013). Health, happiness and human enhancement—​dealing with unexpected effects of
deep brain stimulation. Neuroethics, 6(3), 435–​445.
Schiff, N.D., Giacino, J.T., Kalmar, K., et al. (2007). Behavioural improvements with thalamic
stimulation after severe traumatic brain injury. Nature, 448(7153), 600–​603.
Schneider, M.J., Fins, J.J., and Wolpaw, J.R. (2012). Ethical issues in BCI research. In: Wolpaw,
J.R. and Wolpaw, E.W. (Eds.) Brain-​Computer Interfaces, pp. 373–​383. New York: Oxford
University Press.
Seel, R.T., Sherer, M., Whyte, J., et al. (2010). Assessment scales for disorders of
consciousness: evidence-​based recommendations for clinical practice and research. Archives of
Physical Medicine and Rehabilitation, 91(12), 1795–​1813.
Shih, J.J., Krusienski, D.J., and Wolpaw, J.R. (2012). Brain-​computer interfaces in medicine. Mayo
Clinic Proceedings, 87(3), 268–​279.
Silvers, A. (2009). An essay on modeling: the social model of disability. In: Ralston, D.C. and Ho, J.H.
(Eds.) Philosophical Reflections on Disability, pp. 19–​36. Netherlands: Springer.
Sjögren, M.J.C., Hellström, P.T.O., Jonsson, M.A.G., Runnerstam, M., Silander, H.C., and Ben-​
Menachem, E. (2002). Cognition-​enhancing effect of vagus nerve stimulation in patients with
Alzheimer’s disease: a pilot study. Journal of Clinical Psychiatry, 63(11), 972–​980.
Smith, S. (2014). Mind-​controlled exoskeleton kicks off World Cup. CNN. Available from: http://​www.
cnn.com/​2014/​06/​12/​health/​exoskeleton-​world-​cup-​kickoff/​ [accessed May 12, 2016].
Soekadar, S.R. and Birbaumer, N. (2015). Brain–​machine interfaces for communication in complete
paralysis: ethical implications and challenges. In: Illes, J. and Sahakian, B.J. (Eds.) Handbook of
Neuroethics, pp.705–​724. Netherlands: Springer.
Soekadar, S.R., Cohen, L.G., and Birbaumer, N. (2014). Clinical brain-​machine interfaces. In: Tracy,
J.I., Hampstead, B.M., and Sathian, K. (Eds.) Cognitive Plasticity in Neurologic Disorders, pp.347–​
362. New York: Oxford University Press.
Soekadar, S.R., Birbaumer, N., Slutzky, M.W., and Cohen, L.G. (2015). Brain–​machine interfaces in
neurorehabilitation of stroke. Neurobiology of Disease, 83, 172–​179.
Synofzik, M., Schlaepfer, T.E., and Fins, J.J. (2012). How happy is too happy? Euphoria, neuroethics,
and deep brain stimulation of the nucleus accumbens. American Journal of Bioethics: Neuroscience,
3(1), 30–​36.
Veatch, R.M. (1972). Models for ethical medicine in a revolutionary age. Hastings Center Report, 2(3), 5–​7.
Volkmann, J., Herzog, J., Kopper, F., and Deuschl, G. (2002). Introduction to the programming of deep
brain stimulators. Movement Disorders, 17(S3), S181–​S187.
Warden, D., Rush, A.J., Trivedi, M.H., Fava, M., and Wisniewski, S.R. (2007). The STAR* D Project
results: a comprehensive review of findings. Current Psychiatry Reports, 9(6), 449–​459.
Widge, A.S., Deckersbach, T., Eskandar, E.N., and Dougherty, D.D. (2016). Deep brain stimulation
for treatment-​resistant psychiatric illnesses: what has gone wrong and what should we do next?
Biological Psychiatry, 79(4), e9–​10.
Widge, A.S, Ellard, K.K, Paulk, A.C., et al. (2017). Treating refractory mental illness with closed-​loop
brain stimulation: progress towards a patient-​specific transdiagnostic approach. Experimental
Neurology, 287(Pt 4), 461–​472.
Wolpaw, J.R. and Wolpaw, E.W. (2012). Brain-​Computer interfaces: Principles and Practice.
New York: Oxford University Press.
Wolpaw, J.R., Birbaumer, N., McFarland, D.J., Pfurtscheller, G., and Vaughan, T.M. (2002). Brain-​
computer interfaces for communication and control. Clinical Neurophysiology, 113(6), 767–​791.
Woopen, C. (2012). Ethical aspects of neuromodulation. International Review of Neurobiology, 107,
315–​332.
14

Chapter 8

Integrating ethics into

neurotechnology research and
development: The US National
Institutes of Health BRAIN Initiative®
Khara M. Ramos and Walter J. Koroshetz

Introduction
The human brain contains approximately 84 billion neurons, collectively making trillions
of connections. Fascination with this staggeringly complex organ has long drawn scien-
tists to study the brain. Indeed, advances in neuroscience are emerging at an amazing
rate, supported by investments in science such as the Brain Research through Advancing
Innovative Neurotechnologies (BRAIN) Initiative® (http://​braininitiative.nih.gov) that
aims to accelerate the development and application of innovative neurotechnologies to
revolutionize the understanding of the human brain.
The public in developed countries is becoming ever more interested in how the brain
works and how scientists can bring meaningful solutions to those who suffer from dis-
orders of the nervous system, which can be categorized in terms of neurological, mental
health, and substance abuse (NMS) disorders. The disabling features of NMS disorders
stem from dysfunction in neural circuits, but our current tools are unable to identify the
abnormalities in signaling or normalize the circuit dysfunction. Around the world, dis-
ease burden continues to shift from communicable to noncommunicable diseases such as
those in the NMS classification, and from early death to years spent living with a disabil-
ity. Brain-​based diseases and disorders comprise a significant share of this toll. In 2010,
mental and behavioral disorders comprised 7.4% of the global burden of disease, stroke
comprised 4.1%, and neurological disorders another 3% (Bloom et al. 2011; Murray et al.
2012). This rising burden causes immense human suffering and poses unprecedented
challenges for healthcare. For example, Alzheimer’s disease not only progressively destroys
essential mental functions like memory but it is also an incredibly costly chronic disease.
In 2015, the cost to American society of caring for Alzheimer’s disease patients totaled
an estimated $226 billion, with half of the costs borne by Medicare. If current trends con-
tinue, by 2050, that cost is estimated to rise to over $1.1 trillion (Alzheimer’s Association
2015). These facts and figures underscore the need for action, and point to the impor-
tance and potential impact of neuroscience research for human health. The problems are
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difficult, and more powerful tools and greater fundamental knowledge of the nervous
system are needed to solve them. Modern neuroscience is undergoing a revolution, one
that is propelled by huge leaps in technological capabilities and focused on tool develop-
ment. As Freeman Dyson famously noted (1997), new directions in science are launched
by new tools much more often than by new concepts. That mindset, embodied in the
BRAIN initiative®, will deliver powerful new tools and technologies that fall into two main
classes: those that enable us to interrogate and monitor neural circuit activity, and those
that enable us to modulate it. The ethical and societal issues attached to the medical and
nonmedical use of these technologies are not subtle, nor are they entirely new.
The attempt to discern what a patient is feeling or experiencing is an inherent part of
medicine. There are also nonmedical examples of trying to understand what is unfolding
in someone’s mind. For instance, scientists have long been interested in ferreting out the
neurobiology of lying and deception. Early methods of lie detection rely on nonverbal
cues, such as facial microexpressions and increased perspiration, but these are indirect
reflections of the brain function that is at the core of processing and retelling information
about the world. Modern neuroscience methods have enabled researchers to come closer
to studying that brain function. Functional magnetic resonance imaging (fMRI) measures
brain activity by detecting changes associated with blood flow, and Mohamed and col-
leagues (2006) found that fMRI could be used to discriminate patterns of brain activity
associated with deception from those associated with telling the truth. They observed
that deception triggered activity in brain regions associated with memory encoding and
retrieval, response inhibition (i.e., suppressing the truth), and emotion. Though fMRI has
taken us one step closer to accessing these types of higher-​order cognitive functions, the
BRAIN Initiative® holds promise of delivering tools to push this to another level, deliver-
ing both precision and accessibility (i.e., tools that are miniaturized compared to contem-
porary brain scanners, and widely available).
What might this look like in medical practice? As one example, psychiatrists might one
day be equipped with lightweight brain-​scanning helmets, which could rapidly, precisely,
and noninvasively measure brain circuit function to aid diagnosis of autism, general-
ized anxiety disorder, post-​traumatic stress disorder, manic versus depressive episodes in
bipolar disorder, suicidality, or attention deficit hyperactivity disorder. New tools could
give physicians and researchers ways to objectively measure pain, or assess the circuit
abnormalities underlying epilepsy, cognitive impairment, dystonia, spasticity in cerebral
palsy, and so on. From an ethics perspective, issues around the privacy and use of such
data would be key, as the data will likely contain information linked to multiple core char-
acteristics of the individual. Innovative neural circuit monitoring technologies may pose
new challenges for ethicists and society, since they would far outstrip the current ability to
record brain activity underlying thoughts, mood, and sensations, which is fairly primitive
and not widely in use.
Of course, interrogating brain function is only half of the story. Dysregulated brain
circuits are the most proximal cause of NMS disorders, and from a medical perspec-
tive, modulating brain circuits for health benefit is the basis of all treatments for NMS
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146 Integrating ethics into neurotechnology research and development

disorders. Currently, the most common symptomatic treatments are drugs that alter neu-
ral circuit function, but direct electrical modulation of brain circuits is also part of the
therapeutic armamentarium. Following decades of study to identify the circuit abnormal-
ity underlying the motor symptoms of tremor and slowness of movement in Parkinson’s
disease, deep brain stimulation (DBS), in which a patient is implanted with a device to
deliver electrical current focused on specific deep regions of the brain, is now a com-
mon neurosurgical treatment for Parkinson’s disease (DeLong & Wichmann 2015). Major
depressive disorder (often simply referred to as “depression”), a leading cause of disabil-
ity around the world, has been treated to varying degrees of success with different types
of brain stimulation (Murray et  al. 2012; Deng et  al. 2015). Electroconvulsive therapy,
in which a generalized seizure is induced by delivering electricity directly to the brain,
was originally developed in the 1930s and is still used for patients with severe depres-
sion, as it relatively rapidly elicits high rates of remission (Lisanby 2007). Attempts to
understand the abnormalities in brain circuits that underlie depressed mood have already
given researchers and clinicians brain targets for DBS as an option for treatment-​resistant
depression (Mayberg 2009). Beyond electroconvulsive therapy and DBS, researchers are
also focused on noninvasive, subconvulsive methods of brain stimulation for depression,
including transcranial direct current stimulation and transcranial magnetic stimulation.
What all of these techniques have in common is that they are aimed at modulating
brain circuit function, and they vary in their precision in targeting brain circuitry. What
is needed are the tools to both pinpoint the circuit dysfunction that underlies brain disor-
ders and precisely modulate circuit activity to correct this dysfunction. Rendering these
tools noninvasive would decrease risk and increase the number of people who could be
treated, also expanding the pool of research subjects and thereby hastening the pace at
which neuroscience unravels the mysteries of NMS disorders. Noninvasive technologies
also open the door to nonmedical uses as illustrated by the current use of direct current
brain stimulation for a variety of effects. The new circuit modulating technologies raise
the same ethical and societal issues that surround drugs that have the potential to be
mind or brain altering, but the magnitude and precision of the effects may be signifi-
cantly greater. The questions that arise from medical use of the new technologies will be
complicated, but they likely pale in comparison to the questions surrounding nonmedical
uses of neurotechnologies that enable interrogating and modulating the neural circuits of
individuals.

A brief history of the BRAIN Initiative®

The examples in the previous section illustrate how technology development can inter-
sect with advances in scientific understanding of the brain. Indeed, over the past decade,
technological advances in diverse fields such as physics and chemistry have yielded
unprecedented opportunities for integration across scientific fields, and enabled power-
ful, entirely new ways of studying and modulating nervous system function. Recognizing
this inflection point in neuroscience research, US President Barack Obama launched the
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BRAIN Initiative® in April 2013. The BRAIN Initiative® aims to accelerate the develop-
ment and application of new neurotechnologies, empowering researchers to produce a
revolutionary, dynamic picture of the brain that, for the first time, shows how individual
cells and complex neural circuits interact in time and space. A richer understanding of
brain function will inform much-​needed progress in diagnosing, treating, and even cur-
ing NMS disorders.
Given this bold goal, the President called for the BRAIN Initiative® to be an “all hands
on deck” effort involving not only US government agencies (currently the National
Institutes of Health (NIH), National Science Foundation (NSF), Intelligence Advanced
Research Projects Activity (IARPA), Defense Advanced Research Projects Agency
(DARPA), and the Food and Drug Administration (FDA)), but also companies, private
research institutes, patient advocacy organizations, state governments, research universi-
ties, philanthropists, and more. Many groups signed on in an enthusiastic response to
this call, even extending internationally. Currently, the Brain Canada Foundation, the
Australian National Health and Medical Research Council, and the Lundbeck Foundation
are NIH BRAIN Initiative® partners. The NIH, NSF, FDA, IARPA, the Kavli Foundation,
Simons Foundation, and the Allen Institute for Brain Science coordinate communication
activities through the BRAIN Initiative® Alliance with affiliates DARPA and the Howard
Hughes Medical Institute at Janelia Research Campus.
To inform scientific planning for the BRAIN Initiative®, NIH established a high-​level
working group of the Advisory Committee to the NIH Director (ACD) (http://​acd.od.nih.
gov/​brain.htm). This working group sought broad input from the scientific community,
patient advocates, and the general public. Their report, released in June 2014 and enthu-
siastically endorsed by the ACD, articulated the scientific goals of the NIH component of
the BRAIN Initiative® and developed a multiyear scientific roadmap for achieving these
goals, including timetables, milestones, and cost estimates (Advisory Committee to the
National Institutes of Health Director (2014). BRAIN 2025: A Scientific Vision outlines
a plan for accelerating technology development for neuroscience, with the intention of
developing and using new tools to acquire fundamental new insights into how the ner-
vous system functions in health and disease. The working group identified the analy-
sis of neural circuits as being particularly suitable for potentially revolutionary scientific
advances. Table 8.1 outlines how the NIH currently organizes scientific programming for
the BRAIN Initiative®.

Neurotechnology research and development

In thinking about neurotechnology research and development under the BRAIN
Initiative®, one can envision advances falling under three major categories: direct record-
ing of neural circuit activity, direct stimulation of neurons and neural circuits, and ana-
tomical techniques to define the wiring diagram of the brain. Layered onto these, the
field will also need new conceptual foundations for understanding information flow and
processing in the circuits that generate specific behaviors or sensations. By expanding the
capability to record circuit activity on multiple scales, vast quantities of neural data will
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148 Integrating ethics into neurotechnology research and development

Table 8.1  The scientific landscape of the US NIH BRAIN Initiative®

Scientific focus Description

Cell census Identify and provide experimental access to the different
brain cell types to determine their roles in health and
disease. Integrate information on molecular identity and
gene expression with connectivity, morphology, location, and
physiology

Circuit technologies Develop tools and technologies for circuit mapping and func-
tional, specifically targeted manipulation of circuit activity
Neural recording and modulation Record and manipulate neural activity with cellular resolution,
at multiple depths and locations across the brain
Human imaging and noninvasive Develop next-​generation imaging technologies, and advance
neuromodulation understanding of the relationship between imaging signals and
the underlying brain circuits and cellular activity. Promote the
development, implementation, and integration of innovative
new technologies for human neuroscience research
Understanding circuit function Understand the circuits and patterns of neural activity that give
rise to mental experience and behavior
Training and dissemination Disseminate new neurotechnologies and tools to a wide scien-
tific user base, along with the knowledge required to use them
well
Neuroethics Support neuroethics efforts that can both guide BRAIN
Initiative® research and address ethical dilemmas raised
through advancements in neuroscience

be generated and will challenge current methods of data analysis and intuitive interpre-
tation of meaning. To date, 125 projects have been funded, exceeding an investment of
$130 million USD. These include a systematic inventory of the different cell types of the
brain; targeted genetic and nongenetic approaches for accessing specific cells and circuits;
new and improved capabilities for recording from, and modulating activity of, rapidly
firing collections of neurons; and development of new theories, models, and methods to
analyze complex neural data. Some new tools have already sparked a significant shift in
neuroscience research. For example, optogenetics and chemogenetics are two methods
for cell type-​specific modulation; the former uses light and the latter uses engineered
receptor/​ligand pairs to control the activity of cells, such as targeted neurons, in living tis-
sue. In contrast to current tools such as DBS or available pharmaceuticals, these tools have
unprecedented spatial and temporal control. They are currently used with much success
in animal models to probe brain circuitry and modulate behaviors such as fear condition-
ing and susceptibility to stress (Haubensak et al. 2010; Perova et al. 2015). The use of these
and other tools to interrogate and modulate circuits in animal studies may soon be used
to study human circuits in ex vivo human brain tissue from surgical biopsies, autopsy
tissue, or cerebral organoids derived from induced pluripotent stem cells. In the future,
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Neurotechnology research and development 149

harnessing these tools to modulate brain circuit function in patients may provide thera-
peutic relief for NMS disorders (for discussion, see Whittle et al. 2014).
Of particular note when considering the potential ethical implications of NIH BRAIN
Initiative® research are current efforts toward understanding human brain function and
treating human brain disorders. To date, the NIH BRAIN Initiative® has funded 14 proj-
ects involving human subjects. These include studies to understand the signals underly-
ing noninvasive imaging modalities, more sophisticated understanding of noninvasive
neuromodulation techniques, and development of novel methods of noninvasive neuro-
modulation. Examples of the latter already studied in humans include focused ultrasound
(Legon et  al. 2014), and transcranial magnetic stimulation and direct current stimula-
tion (Deng et al. 2015). In addition, BRAIN Initiative® projects are focused on developing
genetic means to confer electromagnetic sensitivity (Stanley et  al. 2016; Wheeler et  al.
2016) or chemical sensitivity (Roth 2016) to precise brain circuits.
The NIH is also expanding its portfolio of research with implantable neuromodula-
tion devices, including a new BRAIN Public–​Private Partnership Program, which will
connect academic researchers with manufacturers of next-​generation invasive devices for
recording and modulation in the human central nervous system. Further, to understand
the unique properties and functions of human neural circuits, the NIH is supporting
research opportunities for studies with neurosurgical patients. This pool of patients com-
prises three types: people who are receiving DBS, people implanted with brain–​computer
interfaces, and people with implanted devices that perform activity monitoring for epi-
lepsy control.
One specific project proposes to use DBS to improve the level of consciousness in peo-
ple suffering from severe traumatic brain injuries. Traumatic brain injury (TBI) afflicts
hundreds of thousands of Americans each year, producing chronic cognitive disabilities
that lack effective treatment. Preliminary studies with TBI patients and nonhuman pri-
mates suggest that these cognitive disabilities may be due to disrupted circuit function
in the brain, specifically involving impaired connections between the thalamus and the
frontal cortex (Kinomura et al. 1996; van der Werf et al. 2002; Schiff et al. 2007). Some
investigators are using the latest device technology to deliver DBS to the thalamus, in
hopes of developing a next-​generation device for treating cognitive impairment associ-
ated with TBI.
Another project in the area of human imaging aims to develop a completely new, non-
invasive method for measuring brain activity. This work is focused on the feasibility of
sonoelectric tomography, in which ultrasound to tag specific locations in the brain is
combined with conventional scalp electroencephalography to measure electrical activ-
ity. The information can then be used to construct a tomographic map of neuronal cur-
rents, leveraging the millisecond temporal resolution of electroencephalography and the
millimeter spatial resolution of ultrasound. If successful, this would be a powerful next-​
generation imaging method, with the capacity not only to map the functions of brain
circuits in healthy individuals, but also for understanding and potentially diagnosing
complex neuropsychiatric disorders.
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150 Integrating ethics into neurotechnology research and development

Neuroethical issues
The previously discussed example projects give us some insight into the potential ethi-
cal issues associated with neurotechnology research and development. Importantly,
although we recognize that tools to understand and modulate brain function are and
will continue to be used for a range of purposes, the NIH’s perspective is focused solely
on applications to improve health and reduce illness and disability—​that is, medical
applications. Many experts have given much thought to the various relevant ethical
issues, and important scholarship is also stimulated by leadership of the International
Neuroethics Society (a small sampling:  Fins 2011; Illes & Bird 2006; Farah 2015;
Sahakian et al. 2015). The NIH has hosted two meetings in Bethesda, MD, bringing
together scientists and ethicists to discuss key issues in neuroethics (proceedings from
these meetings, held in November 2014 and February 2016, can be found on the NIH
BRAIN Initiative® website http://​braininitiative.nih.gov/​about/​newg.htm). Some of
these neuroethical issues are not new—​that is, they can be thought of as classic bioeth-
ical issues that are not fundamentally different from those that ethicists and scientists
grapple with in other areas of biomedical research.
For example, new methods for direct stimulation of neurons and neural circuits raise
questions of safety and the acceptable degree of risk for human patients:
◆ What benchmarks should be adopted for testing new methods before they are put to
use with humans, and who should make such decisions?
◆ What level of antecedent evidence is necessary to justify translating preclinical research
into work with human subjects?
◆ When contemplating testing new methods in people who have brain disorders and
diseases, what is the best way to balance decision-​making between the patient and
legal surrogate in deciding on an acceptable level of risk?
These important questions are not substantively different from those that would be posed
when considering new methodologies for use in other areas of biomedical research,
except that brain disorders can affect the circuits actually employed in decision-​making
and brain circuits uniquely define personhood.
A second classic bioethical issue to consider is the question of incidental findings. Current
brain imaging techniques such as MRI are sufficiently sophisticated that, in the course of
imaging undertaken for the purpose of research, an investigator might unintentionally find
abnormalities or early indicators of disease. Indeed, incidental findings on brain scans with
modern MRI technology are common, and prevalence increases with age (Morris et  al.
2009). As neurotechnology research progresses and new methods for deciphering brain
function develop, the domains of such incidental findings will undoubtedly expand. The
question, of course, is what to do with this information, especially if the indicator reveals
an uncertain degree of risk, or the disease or disorder is one for which there is no effective
treatment. One field that has also spurred much thought on this question is genetics. Genes
can be predictive, though often in complex patterns of association that modern science
does not yet fully understand, making prognostication based on genetic testing nuanced
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Neuroethical issues 151

(Pasic et al. 2013). A further complicating factor, and one that may give a hint of what is to
come for the field of neuroscience, is the growing usage of commercial direct-​to-​consumer
genetic testing. In December 2013, the Presidential Commission for the Study of Bioethical
Issues (Bioethics Commission) released its report Anticipate and Communicate:  Ethical
Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-​to-​
Consumer Contexts. The Commission argued that researchers, clinicians, and companies
should expect incidental findings, plan ahead for how to address them, and communicate
with patients or subjects about handling such findings in advance of conducting any tests.
These recommendations echo those made by Illes and colleagues regarding incidental find-
ings in neuroimaging (Illes et al. 2006). The authors argued that disclosure of suspicious
neuroimaging-​associated incidental findings to subjects is ethically desirable, though wide
variability exists in such disclosure for the estimated tens of thousands of human subjects
involved in neuroimaging research annually. Even with acknowledgment that disclosure is
desirable, additional questions abound such as whether all neuroimaging studies should
include a physician trained to interpret brain scans, and how to assist vulnerable popula-
tions (e.g., uninsured subjects) in navigating incidental findings.
Beyond such classic bioethical issues exist various ethical questions uniquely associated
with neuroscience research that require careful thought. These questions arise because
the brain is the organ of the mind, and our new neuroscience tools and technologies
provide powerful, unprecedented ways of understanding and modulating brain func-
tion. Such scientific progress must be carefully considered, since it has the potential to
fundamentally alter the understanding of our innate and autonomous sense of self, and
could conflict with our deeply held beliefs about personal volition and responsibility. In
recognition of these concerns, when launching the BRAIN Initiative® in 2013, President
Obama charged his Bioethics Commission to identify proactively a set of core ethical
standards to both guide neuroscience research and address ethical dilemmas raised by
the application of neuroscience research findings. The Commission held public stake-
holder meetings in 2013 and 2014, and issued a two-​part report to respond to the rap-
idly emerging and evolving field of neuroscience (Presidential Commission for the Study
of Bioethical Issues 2014, 2015). In the first volume of Gray Matters, the Commission
focused on the importance of integrating ethics into neuroscience research across the
life of a research endeavor. Preemptive integration of ethics into the scientific process
can help guard against ethical setbacks that might undermine research and erode public
support and trust. Thus their recommendation can be succinctly stated as: integration,
not intervention. The European Union’s Human Brain Project (HBP) offers one model
of this approach in action: the HBP has a robust Ethics and Society Programme, which
recognizes the social, ethical, and philosophical implications of HBP-​related work, and
aims to recognize concerns early and address them in an open and transparent manner.
Additional recommendations from Gray Matters relate to the importance of integrating
ethics into science education at all levels, the value of including ethicists on scientific
advisory groups, and, from the second volume, specific analysis on the topics of cognitive
enhancement, consent capacity, and neuroscience and the legal system.
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152 Integrating ethics into neurotechnology research and development

Integrating ethics into research

At the NIH, we are engaged in efforts to integrate a rigorous program of ethics into the
BRAIN Initiative®. The BRAIN Multi-​Council Working Group (MCWG) provides ongo-
ing oversight of the long-​term scientific vision of the BRAIN Initiative® at NIH, in the con-
text of the evolving neuroscience landscape (http://​braininitiative.nih.gov/​about/​mcwg.
htm). The BRAIN MCWG comprises distinguished neuroscientists, and additional at-​
large members appointed to supplement the group’s expertise as appropriate, with ethics
being a key area for inclusion. As of fall 2015, the MCWG now includes a Neuroethics
Division. In broad terms, the group’s purpose is to recommend overall approaches for how
the NIH BRAIN Initiative® might handle issues and problems involving ethics. What this
will look like in practice remains a work in progress. This work is informed not only by
Gray Matters, but also by BRAIN 2025, which includes several recommendations regard-
ing core ethical principles that will maximize the value of the BRAIN Initiative®. The
authors of the latter publication noted that while there are well‐established and agreed
upon standards for human research, studies that involve recording from or stimulating
the human brain require ongoing oversight. This need, they argue, is best served by a con-
tinual dialogue between researchers and ethical advisory groups that include members
who are well informed in neuroscience research and aware of the historical context of
brain manipulations and recordings.
In early 2016, as the Neuroethics Division has begun ramping up its efforts, our per-
spective has been for their deliberations and activity to be grounded in the science itself—​
that is, the existing portfolio of BRAIN research supported by the NIH, and the trajectory
of the BRAIN Initiative® as described in BRAIN 2025. With that body of scientific work
in mind, the group has discussed areas of BRAIN research that raise ethical concerns or
questions of ethical risk, as well as different approaches to address these concerns. That
fruitful conversation serves as the basis to shape our efforts in this space going forward,
and is summarized here.
The group agreed on the complexity of these issues and the need to address them
thoughtfully, with involvement of appropriate content experts as necessary. There
are many relevant ethical questions, but four topics in particular emerged as hav-
ing the highest priority. One area of focus is the ethics of research with invasive
neurotechnologies:
◆ How might a clinician best determine a patient’s competence for understanding the
risks and benefits before deciding to participate in research?
◆ How can a patient consent to participate in research if the disease affects the very organ
that grants consent?
◆ Once a patient is involved in a research study, what are best practices for managing
unexpected physical or perceived nonphysical harm?
◆ Who should control devices that affect mood and the brain’s reward systems? The
patient? The doctor?
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Integrating ethics into research 153

◆ If a device is placed in the brain as part of a research study, what is a researcher’s

responsibility for continued care of the patient and upkeep of the device?
◆ Who owns the data collected by such devices?
With widespread use of technologies such as fMRI, questions about the privacy of an
individual’s neural data and the need to protect those data are not new. As technology to
record brain function and analyses to interpret those data become more sophisticated,
the ethical, legal, and social challenges will undoubtedly intensify. Contemporary neuro-
science may reveal information about individual traits that has social, medical, or even
legal relevance. For example, a recent study suggested that patterns of resting state brain
connectivity correlate with specific patterns of covariance between various behavioral
and demographic indicators (Smith et  al. 2015). The study received much press, since
the behavioral and demographic indicators included data such as history of substance
use, performance on tests of fluid intelligence, and level of education. The public may be
uneasy with advances in neurotechnology if, beyond applications for reducing the bur-
den of NMS disorders, these new techniques are perceived to be capable of parceling
individuals into personality types or cognitive abilities. This is an area where the field of
genetics may again provide a useful model. With rapid advances in genomic science at the
turn of the millennium came widespread enthusiasm for the potential of genetic research
to offer new insights into disease treatment and prevention. However, as researchers
came to understand that each of us has some degree of genetic predisposition toward
disease, many began to express concern about the potential for discrimination based on
genetic testing. After years of discussion in the United States Congress, in 2008, President
Bush signed the Genetic Information Nondiscrimination Act (GINA), which protects
Americans against employment and health insurance discrimination based on genetic
information. Many see GINA as a way to help citizens feel secure in taking part in modern
genetic research, and taking advantage of the promise of genetic testing to inform person-
alized medicine (Slaughter 2008).1 Some have called for a neuroscience analog of GINA,
which could serve as a tool for grappling with the ethical, legal, and social implications
of contemporary neuroscientific methods. A  simple example underscores the current
uneven landscape regarding discrimination associated with neurological disease predic-
tion. Currently, if a person were found to be at high risk for Alzheimer’s disease based on
genetic testing, he or she would be protected against health insurance discrimination by
GINA. If, however, high risk for developing Alzheimer’s were revealed by a scan of brain
metabolism, there is no legal protection against subsequent discrimination.
Additional questions are important points of focus. Novel neurotechnologies may pres-
ent unprecedented ways of altering, enhancing, or manipulating the self and personal
agency. How will society respond? There is a sense of fairness ingrained in the notion of
working hard to ensure success; it remains to be seen how neural devices used to enhance
memory, attention, or reasoning will fit with this mindset. From a clinical perspective,
there could be great value in altering specific memories of traumatic experiences, for
instance, to ease the suffering associated with post-​traumatic stress disorder. In mice,
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154 Integrating ethics into neurotechnology research and development

scientists used optogenetics to prompt immediate recall of memory by activating a small

population of neurons underlying a memory engram (Liu et al. 2012). Knowing this is
possible, it seems only a matter of time before researchers adapt technologies for manipu-
lating memories in humans, which raises concerns: Is it a violation of one’s autonomous
and continuous sense of self to alter specific memories? Does it impinge on the authentic-
ity of personal identity?
In the longer term, one can readily imagine efforts to move neurotechnologies devel-
oped for the clinic or research contexts into the nonmedical commercial space. What are
the necessary standards for validity and safety, or ensuring privacy? How should society
collectively manage potential conflicts of interest as novel neurotechnologies are com-
mercialized for nonmedical, public use? These are big questions for society to process.
Philosophers, ethicists, legal scholars, journalists, and educators will be needed to navi-
gate these issues, and to promote discussion and engagement with the general public,
regulatory agencies, and policymakers.

Conclusion
We have described just some of the issues associated with neurotechnology research
and development that a program of neuroethics can help navigate. The broad and var-
ied neuroethical landscape will require different types of approaches. Some of the issues
are particularly amenable to empirical or normative research. For example, it would be
essential to analyze how participants, participants’ families, and researchers differ in their
perceptions of risk in clinical research with novel neurotechnologies, particularly in stud-
ies with children and cognitively impaired adults. These concrete data could then inform
best practices for the consent process in these studies. Other areas, such as sharing human
clinical research data or managing incidental findings, might benefit from the develop-
ment of guidance documents. In some cases, additional scholarship may be needed, which
could take the form of workshops with extensive discussion and published proceedings.
Going forward, the NIH BRAIN Initiative® will lean heavily on its Neuroethics Division
to consider neuroethics issues and suggest ways to address them. Experts in philoso-
phy, bioethics, psychology, and neuroscience will be consulted to inform future steps.
Additional services may be important, such as providing ethics consultations to funded
researchers working in this space. More broadly, we hope to foster dialogue between
BRAIN-​funded researchers and ethicists and their colleagues worldwide, empower sci-
entists’ and clinicians’ consideration of the ethical issues, and urge them to be stewards of
their own work. These efforts will help ensure that neurotechnology research and devel-
opment rests on a solid ethical foundation.
Brain activity forms the physical basis of our humanity and neuroethics provides a
framework for discussing the ethical use of technologies that monitor or modulate the
fundamental features that make us unique as individuals. Society has engaged in a con-
tinuous dialogue over the centuries about accepting, rejecting, or regulating the tools that
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References 155

spring from science; that focus needs to sharpen on neuroscience as new tools open new
windows into the brain.

Note
1. Editor’s note: an act similar to GINA, the Genetic Non-Discrimination Act, was passed by the
Parliament of Canada in March 2017.

References
Alzheimer’s Association (2015). Alzheimer’s disease facts and figures. Alzheimer’s & Dementia, 11(3),
332–​384.
Advisory Committee to the National Institutes of Health Director (2014). BRAIN 2025: A Scientific
Vision. United States Government. Available from: http://​braininitiative.nih.gov [accessed March
2, 2016].
Bloom, D.E., Cafiero, E.T., Jané-​Llopis, E., et al. (2011). The Global Economic Burden of
Noncommunicable Diseases. World Economic Forum. Available from: http://​www.weforum.org/​
EconomicsOfNCD [accessed March 2, 2016].
DeLong, M.R. and Wichmann, T. (2015). Basal ganglia circuits as targets for neuromodulation in
Parkinson disease. JAMA Neurology, 72(11), 1354–​1360.
Deng, Z.D., McClintock, S.M., Oey, N.E., Luber, B., and Lisanby, S.H. (2015). Neuromodulation
for mood and memory: from the engineering bench to the patient bedside. Current Opinion in
Neurobiology, 30, 38–​43.
Dyson, F. (1997). Imagined Worlds. Cambridge, MA: Harvard University Press.
Farah, M.J. (2015). An ethics toolbox for neurotechnology. Neuron, 86(1), 34–​37.
Fins, J.J. (2011). Neuroethics, neuroimaging, and disorders of consciousness: promise or peril?
Transactions of the American Clinical and Climatological Association, 122, 336–​346.
Haubensak, W., Kunwar, P.S., Cai, H., et al. (2010). Genetic dissection of an amygdala microcircuit that
gates conditioned fear. Nature, 468(7321), 270–​276.
Illes, J. and Bird, S.J. (2006). Neuroethics: a modern context for ethics in neuroscience. Trends in
Neuroscience, 29(9), 511–​517.
Illes, J., Kirschen, M.P., Edwards, E., et al. (2006). Working Group on Incidental Findings in Brain
Imaging Research. Ethics. Incidental findings in brain imaging research. Science, 311(5762), 783–​784.
Lisanby, S.H. (2007). Electroconvulsive therapy for depression. New England Journal of Medicine,
357(19), 1939–​1945.
Liu, X., Ramirez, S., Pang, P.T., et al. (2012). Optogenetic stimulation of a hippocampal engram
activates fear memory recall. Nature, 484(7394), 381–​385.
Kinomura, S., Larssen, J., Gulyas, B., and Roland, P.E. (1996). Activation by attention of the human
reticular formation and thalamic intralaminar nuclei. Science, 271, 512–​515.
Legon, W., Sato, T.F., Opitz, A., et al. (2014). Transcranial focused ultrasound modulates the activity of
primary somatosensory cortex in humans. Nature Neuroscience, 17(2), 322–​329.
Mayberg, H.S. (2009). Targeted electrode-​based modulation of neural circuits for depression. Journal of
Clinical Investigation, 119(4), 717–​725.
Mohamed, F.B., Faro, S.H., Gordon, N.J., Platek, S.M., Ahmad, H., and Williams, J.M. (2006). Brain
mapping of deception and truth telling about an ecologically valid situation: functional MR imaging
and polygraph investigation—​initial experience. Radiology, 238(2), 679–​688.
156

156 Integrating ethics into neurotechnology research and development

Morris, Z., Whiteley, W.N., Longstreth, W.T., Jr., et al. (2009). Incidental findings on brain magnetic
resonance imaging: systematic review and meta-​analysis. BMJ, 339.
Murray, C.J., Vos, T., Lozano, R., et al. (2012). Disability-​adjusted life years (DALYs) for 291 diseases
and injuries in 21 regions, 1990–​2010: a systematic analysis for the Global Burden of Disease Study
2010. The Lancet, 380(9859), 2197–​2223.
Pasic, M.D., Samaan, S., and Yousef, G.M. (2013). Genomic medicine: new frontiers and new
challenges. Clinical Chemistry, 59(1), 158–​167.
Perova, Z., Delevich, K., and Li, B. (2015). Depression of excitatory synapses onto parvalbumin
interneurons in the medial prefrontal cortex in susceptibility to stress. Journal of Neuroscience,
35(7), 3201–​3206.
Presidential Commission for the Study of Bioethical Issues (2013). Anticipate and
Communicate: Ethical Management of Incidental and Secondary Findings in the Clinical,
Research, and Direct-​to-​Consumer Contexts. United States Government. Available from: https://​
bioethicsarchive.georgetown.edu/​pcsbi/​node/​3183.html [accessed February 12, 2017].
Presidential Commission for the Study of Bioethical Issues (2014). Gray Matters: Integrative
Approaches for Neuroscience, Ethics, and Society. United States Government. Available from: https://​
bioethicsarchive.georgetown.edu/​pcsbi/​node/​3543.html [accessed February 12, 2017].
Presidential Commission for the Study of Bioethical Issues (2015). Gray Matters: Topics at the
Intersection of Neuroscience, Ethics, and Society. United States Government. Available from: https://​
bioethicsarchive.georgetown.edu/​pcsbi/​node/​4704.html [accessed February 12, 2017].
Roth, B.L. (2016). DREADDs for neuroscientists. Neuron, 89(4), 683–​694.
Sahakian, B.J., Bruhl, A.B., Cook, J., et al. (2015). The impact of neuroscience on society: cognitive
enhancement in neuropsychiatric disorders and in healthy people. Philosophical Transactions of the
Royal Society B: Biological Sciences, 370(1677), 20140214.
Schiff N.D., Giacino, J.T., Kalmar, K., et al. (2007). Behavioural improvements with thalamic
stimulation after severe traumatic brain injury. Nature, 448(7153), 600–​603. [Erratum in: Nature,
2008, 452(7183), 120.]
Slaughter, L.M. (2008). The Genetic Information Nondiscrimination Act: why your personal genetics
are still vulnerable to discrimination. Surgical Clinics of North America, 88(4), 723–​738.
Smith, S.M., Nichols, T.E., Vidaurre, D., et al. (2015). A positive-​negative mode of population
covariation links brain connectivity, demographics and behavior. Nature Neuroscience, 18(11),
1565–​1567.
Stanley, S.A., Kelly, L., Latcha, K.N., et al. (2016). Bidirectional electromagnetic control of the
hypothalamus regulates feeding and metabolism. Nature, 531(7596), 647–​650.
van der Werf, Y.D., Witter, M.P., and Groenewegen, H.J. (2002). The intralaminar and midline nuclei
of the thalamus. Anatomical and functional evidence for participation in processes of arousal and
awareness. Brain Research Reviews, 39, 107–​140.
Wheeler, M.A., Smith, C.J., Ottolini, M., et al. (2016). Genetically targeted magnetic control of the
nervous system. Nature Neuroscience, 19(5), 756–​761.
Whittle, A.J., Walsh, J., and de Lecea, L. (2014). Light and chemical control of neuronal
circuits: possible applications in neurotherapy. Expert Review of Neurotherapeutics, 14(9),
1007–​1017.
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Part II

Neuroethics at the frontline

of healthcare
158
 159

Chapter 9

What do new neuroscience

discoveries in children mean
for their open future?
Cheryl D. Lew

Introduction
At the time of publication of the first edition of Neuroethics: Defining the Issues in Theory,
Practice and Policy (Illes 2006), there was focus on the implications of the new neuro-
sciences on questions of self-​determination, personal identity, and moral responsibility.
There was also acknowledgment that both genetic and environmental factors were signifi-
cant determinants in the neurocognitive capacity of children to achieve across domains of
academic performance, social adaptations, and socioeconomic ends (Farah et al. 2006).
Early concerns emerged about how this information should be and could be used, and
what implications such information would have on how children should be viewed as
individuals or as members of particular populations vulnerable to prejudicial labeling.
Observational studies in childhood of intellectual quotient, personality, and behav-
ioral inventories date back to early in the twentieth century. Piaget’s work began in the
1920s (Piaget 1926). In addition to characterizing patterns of infancy through child-
hood behavioral development, he also described preliminary findings of normal moral
development (Piaget 1997)  based on observations of games play. He was an impor-
tant influence on subsequent generations of developmental investigators including
Lawrence Kohlberg (Kohlberg 1981) who elaborated a highly controversial theory of
moral development in children stratified according to gender. The expected stages of
early infancy and childhood development learned by every pediatrician in the Anglo-​
European-​American tradition of the twentieth century and the common screening
inventories used in well-​child pediatric care all derive from Piaget’s insights. The first
reported collaborative thinking about the intersections of developmental psychol-
ogy and emerging developmental neurosciences occurred in 1989 during a National
Institute of Child Health and Human Development/​National Institute of Mental
Health-​sponsored meeting in which Adele Diamond brought together developmen-
tal psychologists and neuroscientists (Diamond 1990). Subsequent studies confirmed
observations of variants in executive function in children under a variety of genetic
and environmental influences (Farah et al. 2006). Over the last decade, there has been
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160 What do new neuroscience discoveries in children mean for their open future?

a flourishing of research centered on detailed neuroimaging correlates of these behav-

ioral observations (Illes & Raffin 2002; Illes & Racine 2005). Further, there are emerg-
ing studies of the neurostructural changes associated with environmental and genetic
variations. Since some of these changes appear following in utero environmental expo-
sures, there are implications regarding the interactions between genetic endowment
and potential adverse prenatal and postnatal environmental influences on the eventual
capacity of children to have flourishing and productive lives.
The discovery of significant alterations in the normal structural development of the
brain in children, from the fetal period into adolescence, raises great concerns about
implications for behavior, cognitive functioning, and whether affected children are inevi-
tably destined for diminished function. This question of inevitability or determinism is a
key issue in the ethics of identity and personhood.
Because of the limitations of development and emotional immaturity on decisional
capacity in children, there has been a tendency among bioethicists, in general, to dis-
count the emerging expression of individual identity and self-​determination in the
pediatric age group. However, pediatric healthcare providers are acutely aware of the
transforming effect of serious and/​or chronic illness/​disability on accelerated insight, self-​
awareness, and in many instances nuanced ability for self-​determination (Campbell et al.
2012)  even with respect to critical end-​of-​life decisions. Transformation is not limited
to catastrophic illness and it has become apparent that children’s behaviors and world
views change in response to influences such as family networks, the nurturing of caring
family members, and other positive experiences (Weithorn & Campbell 1982; Weir &
Peters 1997). Therefore, the pediatric healthcare professional has been disposed to the
perception that children remain malleable and that potential can be optimized despite or
even in spite of genetic differences or neurostructural variances. However, the observa-
tions of neurostructural anomalies in the developing brain correlated with measurable
deficiencies in cognitive performance call into question whether such individuals are
owed more or less opportunity to express their self-​determination. What is the meaning
of self-​determination, in fact, in the context of neurostructural developmental abnormali-
ties? This question directly pertains to the concerns of pediatric bioethicists, who tend to
focus on eventual potential outcomes and have interests in the imprecise and unknowable
futures of children who may have experienced both genetic and environmentally deter-
mined compromise to neurocognitive function (Wilkinson 2013).
Specific questions of significance to pediatric bioethics emerge from recent work:
1. With the ample evidence that a variety of genetic determinants influence developing
brain structure and behaviors, are these determinants immutable? That is, if we iden-
tify developing sociopathy or psychopathy, are there social and policy implications that
may abridge individual liberty and the individual’s open future?
2. The socioeconomic and environmental pollution data are stunning. But can the data be
misconstrued or misused, or both, to support a case for genetic ancestry determinants
of poorer neurocognitive functioning? What safeguards do we as health researchers
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The notion of a child’s open future 161

and healthcare providers have a moral obligation to engage in to assure that this
extraordinary data is not used to oppress further already disadvantaged groups?
3. With the prospect of full understanding of both intrinsic and extrinsic determinants
of the mechanics of brain development in childhood rearing, we presume that inter-
ventions may be devised to normalize brain development and hence psychological
functioning. How do we define normalcy? Would fixing or tweaking neurocogni-
tive function eliminate diversity in personality, temperament, cognitive precocity, or
genius?
As a framework for examining these questions, I  will begin with a description of the
concept of the open future of the child (Feinberg 1980). Next will be a discussion of what
is accepted as evolving cognitive competence of children and adolescents, particularly
with respect to self-​awareness, insight, and decision-​making. The accelerated maturity
of healthcare decision-​making among adolescents experiencing lifelong chronic or life-​
limiting illnesses, or both, will also be described. Then I will summarize some of the recent
work among neuroscience colleagues on genetic and environmental influences on brain
development and behavior from the prenatal period through adolescence. An account
of the pediatric bioethical theory pertinent to this work will follow, providing a context
for discussion about how neuroscience findings might change how we look at the moral
status and evolving neurocognitive competency of affected children. Finally, I will discuss
the social justice implications and what social strategies ought to be put in place in order
to assure the most open future for not only affected children but also all of our children.

The notion of a child’s open future

In the context of a discussion of rights, the political and legal philosopher Joel Feinberg
distinguished the possession of rights (i.e., to autonomy, self-​determination) versus actual
exercise of those rights (Feinberg 1980, 1992). These are rights that are inherent to the
moral status of human beings who are in possession of full personhood. While children
are born with rights shared with adults, or all human persons, there are rights of self-​
determination that cannot be exercised until children acquire sufficient developmental
and cognitive maturity. This latter state usually means that they become of age through
the social or legal conventions (or both) of their culture. Until that time, the actions of
children are ordinarily constrained by their parents and caretakers. However, since chil-
dren are not the chattels of their parents, there are essential entitlements of childhood that
extend beyond the absolute authority of parents: basic rights to safety, well-​being, and pro-
tection from adversity. The presumption is that parents/​caregivers are the stewards of the
best interests and welfare of the children in their charge. Accordingly, parents and care-
takers are given substantial liberty around decision-​making across a variety of domains in
the rearing of their children, such as religion, lifestyle, and schooling. However, Feinberg
asserts that there are some specific rights that parents, caretakers, and society must safe-
guard in trust for the anticipated future capacities of their children. That is, children must
have their mature, adulthood capacities for self-​determination preserved.
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162 What do new neuroscience discoveries in children mean for their open future?

Feinberg proposed that societies have broad moral obligations to set into place laws
and policies which would assure the future of children’s potential self-​determination or
autonomy. Examples include legal prohibitions of physical and emotional abuse, and obli-
gations to avoid risky behaviors that endanger the welfare of children. Thus there are
minimum age standards for permitting cigarette smoking, imbibing of alcoholic bever-
ages, and driving an automobile. Once the minimal legal age of permission is passed,
individuals are free, more or less, to decide for themselves the level of risk they wish to
undertake on their own recognizance. The variations in societal determination of these
minimum ages for specific autonomous functions are an interesting reflection on a given
society’s beliefs about when children actually do come of age, and therefore may take on
the benefits of full autonomy as well as the risks of potential adverse outcomes from those
independent risk-​taking behaviors.
In the context of healthcare, this is most frequently taken to mean that parents or other
responsible parties (i.e., caregivers, guardians, and healthcare professionals) are obligated
morally to make healthcare decisions on behalf of the children in their charge which are
most likely to result in the greatest realization of their children’s eventual potential for
self-​determination and flourishing. Therefore, parents and caregivers are usually required
to participate in certain public health measures such as childhood immunizations, to pro-
vide adequate nutrition, and to seek healthcare for interval or chronic illnesses.
Nevertheless, particularly in a liberal society, there is wide discretion given to parents/​
guardians about the determination of the threshold of obligation toward the usual societal
norms. For instance, in some polities, parents/​guardians may forego routine childhood
immunizations for their children on the basis of religious liberty, or often a misplaced
anxiety about the very small risks of vaccines compared with the risks of adverse out-
comes following previously widespread viral diseases such as measles which can be asso-
ciated with risk for death and severe long-​term morbidities such as pan-​encephalitis.
On the other hand, the concerns of a liberal polity may result in misplaced criticism
about specific treatments of severely cognitively impaired individuals that are intended
to improve the quality of life of those individuals as well as facilitate the caregiving.
One example would be elective sterilization to eliminate risk of pregnancy in cognitively
impaired women, unable to consent to intercourse or to defend against rape. Another
example is the infamous case of the “Pillow Angel,” a profoundly encephalopathic and
neurocognitively diminished child, where growth attenuation treatments were pro-
vided with the intent to facilitate continued home versus institutional care (Gunther
& Diekema 2006). Critics asserted that the Pillow Angel possessed future reproductive
interests which were now foreclosed with the growth attenuation treatments (Liao et al.
2007; Peace & Roy 2014). For many healthcare professionals, as well as their parents, the
notion that a microcephalic child who had been non-​ambulatory and in a state of pro-
found static encephalopathy had any particular interests in the future, let alone repro-
ductive interests, is difficult to understand. These examples highlight some of the ethical
tensions within the practical application of the principles embedded in Feinberg’s child’s
open future concept.
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Developmental issues in childhood identity and self-determination 163

With this background, then, the new discoveries in pediatric neuroethics bring into
sharp relief some of the problems of self-​determination against a background of genetic
and environmental modulation of brain structure and behavior. The new neuroscience
can be interpreted to diminish substantially concepts of free will as well as call into ques-
tion the meaning of personal identity and personal authenticity, and ultimate moral
responsibility for actions. And the question is whether free will and autonomy can be
preserved in the face of the new neuroscience.

Developmental issues in childhood identity and

self-​determination
The contemporary standard of pediatric practice is to engage in transparency of commu-
nication with all patients about their healthcare status and needs in language appropri-
ate for the individual level of cognitive development and function. While it is clear that
parents or other legal caregivers/​responsible parties carry the burden of legal consent
for healthcare management or treatments, there are discrete advantages to inclusion of
patients in communication about their care. These advantages include improvements
in adherence, cooperation, and decreased anxiety about treatments on the part of the
patients. Furthermore, since maturation of insight and decision-​making capacity changes
with time and specific life experiences, pediatricians and social scientists have recognized
that adolescents who have had longstanding experience with personal chronic illness may
be particularly astute about their own self-​determination and therapeutic goals (Grisso
& Vierling 1978; Bishop 1980; Ladd & Forman 1995; Hester 2009). Ongoing debate per-
sists regarding how much weight ought to be given to adolescent patients’ judgments
about their own healthcare (Ross 1997) particularly with respect to high-​stake health
decisions. For instance, one of the greatest controversy surrounds the appropriateness
of allowing adolescent patients to forego potentially life-​saving procedures regardless of
the burdens or risks of those treatments. An example might be whether an adolescent,
or even younger child, with a failed solid organ transplant should be allowed to refuse a
second transplant. Those who advocate proceeding with such treatments even in the face
of adolescent objection, argue that to allow a minor to refuse life-​sustaining treatments
would be to foreclose that individual’s open future. In other words, minors who choose
for likely early death will not have any opportunity to become fully empowered adults
with presumed better grounds for making such decisions.
With the neuroscience evidence supporting impairment of insight, self-​awareness, and
judgment in individual children on the basis of genetic or environmental influences, or
both, how do the questions of capacity for decision-​making play out? Should individu-
als determined to be at increased risk for neurocognitive disability or psychopathy due
to observable alterations in brain structural development be deemed less competent
than their age-​matched peers? Given the many sorts of intelligence (Gray & Thompson
2004) individuals may exhibit, which particular intelligences should be deemed of greater
importance in making autonomous healthcare decisions, let alone all decisions pertinent
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164 What do new neuroscience discoveries in children mean for their open future?

to evolving independent living? Should fluid intelligence be privileged over crystalline

intelligence (Gray & Thompson 2004)? Should there be some sort of consensus taxonomy
or sliding scale that guides how much prerogative ought to be provided to children, ado-
lescents, and youth who are important stake holders in their health futures? What would
be the role of early educational intervention for individuals identified to be at risk for
judgment difficulties? Certainly health literacy is a sparse commodity among those indi-
viduals deemed to be within the normal neurocognitive range of capacity (IOM 2015).
Therefore, it would seem appropriate to consider strategies of education and policy for-
mulation which can enhance the capabilities of pediatric individuals of all capacities to
develop appropriate insight into their own needs and desires, thereby exercising appro-
priate judgment and choices as they mature. However, before attempting to deal with the
bioethics of the new neuroscience for children, it is necessary to review some of the more
recent findings of significance.

Recent work in pediatric neuroimaging in at-​risk populations

Children are continuously changing, morphologically and physiologically. They dem-
onstrate remarkable increases in neurocognitive capacity from birth until they achieve
full maturity. Along the way, brain structures change and evolve with concomitant
changes in behavior, personality, temperament, and different forms of intelligence. The
shape of these changes is determined by both intrinsic genetic endowment and the
experiences of living. In contrast to the neurocognitive state of adults, where growth
and development have already been achieved, and where adverse events may degrade
neurocognitive function significantly, the plasticity of the pediatric brain makes for
less predictable outcomes in the face of adverse events when considered against age
at time of insult and capacity for recovery/​compensation. Therefore, in childhood,
future neurocognitive function in the individual is open to varying degrees and may
be optimized through considered interventions. However, in order to develop effective
interventions, understanding must be achieved of both normal structural/​functional
development and of changes to the expected development in response to a variety of
external influences.
The neuroscientists and neurogeneticists of the Institute of the Developing Mind (IDM)
at Children’s Hospital Los Angeles, for example, are actively engaged in research pertain-
ing to factors that can alter neurocognitive potential in childhood. Much of the research
correlates brain structural differences with neurocognitive functional differences. The
domains of investigation include prenatal and postnatal influences, environmental fac-
tors, and genetic versus nurture factors. These projects are representative of the efforts
in pediatric neurosciences over the last decade and the findings from these projects pro-
voke considerable bioethical concerns about potential for maintaining the open futures
of children.
Considerable work has been reported on the association between brain structure abnor-
malities and psychopathy in adult males. For example, Yang and collaborators studied a
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Recent work in pediatric neuroimaging in at-risk populations 165

cohort of adolescents who are a part of the University of Southern California Risk Factors
for Antisocial Behavior Twin Study (Baker et al. 2002, 2006, 2013; Yang et al. 2012). In
an endeavor to separate genetic influences from environmental influences on developing
brain structure, 14-​year-​old twin pairs were studied: monozygotic pairs were compared
with dizygotic pairs, the latter of whom share only one-​half of their genetic endowment.
The investigators hypothesized that any environmentally derived differences in cortical
thickness would appear in regions of low heritability (i.e., the motor and sensory cortices).
As it turns out, 80% of interpersonal variations in cortical thickness could be explained
through genetic effects and occurred in later developing areas associated with higher-​
order functions in the prefrontal cortex (i.e., fluid intelligence). On the other hand, there
was evidence for environmental malleability in posterior parietal areas associated with
development of spatial attention, topographic information, and language (i.e., capacities
that are determined experientially).
Normal children and adolescents experience a rapid increase in cognitive processing
of sensory, motor, cognitive, and emotional information. These behavioral changes are
associated with changes in brain structure—​including synaptic pruning (i.e., controlled
reduction of the number of synapses) and myelination (i.e., increased axonal dimensions)
(Sowell et al. 1999, 2003; Selemon 2013; Houston et al. 2014). In order to characterize
variations from the normal pattern, the investigators (Yang et al. 2015) conducted struc-
tural magnetic resonance imaging (MRI) brain scanning of 14-​year-​olds and compared
these findings with serial measures of psychopathy with the Childhood Psychopathy Scale
made at ages 9–​10, 11–​13, 14–​15, and 16–​18 years. The investigators were interested in
changes in the psychopathy scores over time. They found that higher psychopathy scores
were associated with increased temporal cortical thicknesses, findings specific to adoles-
cents. There were gender-​related differences in regional variation in cortical thickness
as well (i.e., female subjects also showed decreased frontal cortical thickness). Increased
psychopathic tendencies over time in individuals, as measured with the Childhood
Psychopathy Scale, were associated with increased temporal cortical thickness. These
changes were more prominent in males versus females. Localization of these structural
anomalies to temporal lobe regions involved in complex social cognition and emotion
are consistent with the observed functional abnormalities in psychopathic tendencies.
Further, these observations are consistent with a neurodevelopmental origin of psychopa-
thy as opposed to or in addition to an experiential model of psychopathy. All the study
subjects were deemed to be healthy, in contrast to well-​studied adults who were already
known to have overt psychopathic behaviors (substance abuse, criminality). Therefore,
Yang and colleagues concluded that abnormal cortical development in the temporal lobes
is a likely biomarker of psychopathy in adolescents and may represent delayed maturation,
which is genetically driven, and results in social and moral dysfunction (Yang et al. 2015).
New and continuously improving treatment and neonatal intensive care techniques
have resulted in marked improvement in survival of preterm infants born at lower ges-
tational ages. Adverse neurological injury such as intracranial hemorrhage and isch-
emic injury (periventricular leukomalacia) are known to be associated with poorer
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166 What do new neuroscience discoveries in children mean for their open future?

neurological and neurocognitive outcomes. Accordingly, imaging techniques such as

cranial ultrasound, computed tomography scanning, and structural MRI cranial scan-
ning have become commonplace in the twenty-​first century neonatal intensive care unit
and those results are routinely used for outcomes prognostication (Wilkinson 2013).
However, even in the absence of routine cortical neuroimaging abnormalities, preterm
infants frequently exhibit abnormal cognitive, behavioral, and social function outcomes,
such as problems with executive function, attentional deficit activity disorder (ADHD),
and issues with empathy and social restraint as often exhibited in autism spectrum dis-
order. While there are clearly recognized genetic determinants of some of these behav-
ioral disorders, the incidence in preterm infants appears to be disproportionate. Leporé
and colleagues sought to determine if there were any deep brain structure anomalies
in preterm infants which could be determinants of later neurocognitive function (Lao
et al. 2016). They compared imaging of subcortical brain structures between apparently
healthy surviving preterm infants as compared with age-​matched control infants born at
term. They looked specifically at subcortical structures—​the thalamus and putamen—​
using surface-​based morphometry analysis. They found reduction in volume in all the
thalamic nuclei, more pronounced on the left than the right. In addition, connecting
pathways between thalamus and putamen (i.e., the dorsolateral prefrontal–​subcortical
circuit and the lateral orbitofrontal–​subcortical circuit) may be reduced in volume. It
is not clear if these changes are due to imposed injury such as hypoxemia and other
metabolic changes associated with preterm birth or due to a reduction of in utero stimu-
latory experience because of the shortened gestation. The relationship of such subcorti-
cal changes in brain morphological development and hypoxic-​ischemic injury to white
matter in preterm infants is not yet defined.
Although an ostensible motivation for these studies was to promote early identification
of risks for cognitive and behavioral disabilities, it is not at all clear that “early interven-
tion” from a behavioral perspective will prove to be effective in altering expected wors-
ened outcomes.
Environmental pollutants and toxins are of great concern for the public’s health. In
order to elucidate the impact of such pollutants on developing fetal brains and subse-
quent neurocognitive function and behavior, Peterson and his colleagues embarked on
carefully designed long-​term studies of maternal-​fetal pairs living in an urban setting
beginning in 1997 (Peterson et al. 2015). Nonsmoking pregnant women, predominantly
African American or Dominican, were recruited from prenatal clinics in New York City
which provide services to low-​income minority and recent immigrant communities. The
authors acknowledged that outdoor pollution sources tend to be concentrated in such
communities resulting in disproportionate exposure of these residents to outdoor pol-
lution. In addition, the pollutants in question, polycyclic aromatic hydrocarbons (PAH)
readily penetrate indoor residential environments; consequently, inhabitants of low-​
income urban neighborhoods cannot escape exposure. During the third trimester of
pregnancy, information about PAH exposures was collected through questionnaires and
from individual monitors carried by participants which sampled levels of the eight most
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Recent work in pediatric neuroimaging in at-risk populations 167

common PAH in each woman’s environment for 48 hours. More than 600 women partici-
pated in this phase of the study.
Children exposed to higher levels of PAH in utero showed a variety of neurodevel-
opmental problems at ages 3, 5, and 7 years (Perera et al. 2006, 2008, 2009, 2012). The
investigators then hypothesized that they could identify specific abnormalities in brain
structure associated with prenatal PAH exposure which resulted in the neurodevelop-
mental abnormalities (information processing speed, ADHD) seen in a subset of these
children at ages 7–​9 years (Peterson et al. 2015). They performed MRI on a subset of 40
children stratified into above-​and below-​median in utero PAH exposure. In addition
to the imaging, the Child Behavior Checklist and the Wechsler Scales of Intelligence for
Children (WISC-​IV) were administered. The differences between children with low intra-
uterine exposure versus high intrauterine exposure were striking: white matter reductions
were associated with higher PAH exposure, specifically in the left hemisphere. Therefore,
the left hemisphere in utero appears to be more vulnerable to the neurotoxic effects of
PAH. The investigators go on to link these observed changes to what is now known about
the transcriptional pathways that control brain hemispheric structure by week 10 of gesta-
tion. Of interest, the regions of white matter reduction in this cohort of children exposed
to high in utero PAH and who also had ADHD syndrome are qualitatively different
from white matter abnormalities observed in adolescent youth with ADHD syndrome
(Peterson et al. 2015). The authors speculate that environmental neurotoxins produce a
distinct subtype of ADHD.
The investigators recognized some of the implications relating to their study population
of impoverished, principally immigrant peoples and peoples of color in the urban neigh-
borhoods under investigation. However, through careful stratification of study subjects,
they were able to demonstrate independent environmental toxic effects on both brain
structure and neurocognitive function within this population. Therefore, any potential
arguments about intrinsic racial or ethnic differences could be dismissed.
That childhood experiences can modulate developmental functions, behavior and neu-
rocognitive capacity has been amply demonstrated (McLoyd 1998; Rosenzweig 2003;
Noble et al. 2007; Duncan & Magnuson 2012; Kim et al. 2013; Luby et al. 2013). However,
brain structural correlates of the neurocognitive, neurodevelopmental associations with
socioeconomic variables have not previously been demonstrated in any large num-
bers of study subjects. The collaborators of the Pediatric Imaging, Neurocognition, and
Genetics (PING) Study have examined these relationships among more than 1000 indi-
viduals between ages 3 and 20 years (Noble et al. 2015). Previous studies have looked at
brain cortical volume. However, changes in the normal sequence of cortical surface area
change may be more reflective over individual experiences. Normally, in contrast with
cortical volume, cortical surface area increases from infancy through early adolescence,
after which there is progressive shrinkage through middle adulthood. Genetic program-
ming of these changes is modulated by individual experience. Therefore, although nor-
mally cortical thickness decreases into adolescence, and thinness tends to be associated
with greater intelligence, cortical surface area increases with greater intelligence. Against
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168 What do new neuroscience discoveries in children mean for their open future?

the above-​mentioned background, the PING study group made the following observa-
tions: both parental education and family income were associated with increased corti-
cal surface area. Genetic ancestry was not a relevant factor. Subcortical structures, for
example, hippocampal size, are positively associated with parental educational achieve-
ment. Parental educational attainment was found to be linearly associated with cortical
surface area. Specifically, any increment of parental education was associated with a com-
mensurate increase in cortical surface area. The brain regions in question are important
in development of language, executive functions, and memory. Because of the logarith-
mic associations, the lower parental educational attainment and income, the greater the
impact on brain structure.
This study is particularly controversial and therefore it is not surprising that the results
elicited a considerable amount of media attention. The very tight coupling of socioec-
onomic status with brain structure seems to have struck a nerve in mainstream media
and within the greater North American public. Apparently, the specter of shrunken
brains among large segments of our population (i.e., our socioeconomically disadvan-
taged citizens and their children) created significant unrest (King 2015; Mohan 2015).
It is not yet clear whether that concern and unrest are sufficiently long-​lasting to result
in significant social policy changes and access to early educational and psychological
interventions.
Common ethical issues emerge across all of these studies. What do the data say about
personal identity? Is identity immutable if associated with structural changes in the brain?
Do all such changes translate to clinically significant abnormalities in information proc-
essing, insight, creativity, and fluid intelligence? How do these variants in brain develop-
ment play against the normal ontogeny of maturation of cognitive processes in children
and adolescents?

Bioethical and neuroethical implications

Bioethics is about relationships:  how we see each other, how we treat each other, and
what we owe to each other in terms of respect and moral seriousness. Relationships in
childhood are normally dynamic, changing continuously because infants and children
are changing continuously. Therefore, in order to understand what ethical harms children
who are already neurocognitively compromised may experience—​the additional neuro-
ethical piece—​it is worthwhile reviewing the basic bioethics issues of childhood.
Core issues in bioethics for children are centered on potentials: moral status, person-
hood, authenticity (i.e., persistence of personality over time) and judgment, and, sub-
sumed under rights or eventual rights—​self-​determination and decision-​making. Of
course, these are all key issues for bioethics in adults. But here, the concern is how to
ensure that each child has a flourishing future that is unlimited except for innate capac-
ity. These issues constitute our sense of self and self-​esteem and determine whether oth-
ers look at us as whole or damaged. The interactions between how we see ourselves and
others see us can be reinforcing, constructive, or destructive. I will look first at the large
category of rights for self-​determination and decision-​making.
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Bioethical and neuroethical implications 169

A key component for individual rights is the understanding that free will or at least the
possibility or potential for free will is an important determinant of individual person-
hood and worthy moral status. Without the possibility of free will, the concerns within
bioethics about self-​determination and respect for autonomy would be irrelevant, mean-
ingless. A discussion about the power of determinism (Rachels 2012) versus the actuality
of free will is well beyond the scope of this chapter, but the dichotomy of determinism (or
more properly, pre-​determinism) versus potential for eventual full autonomy is one of the
problems of the now demonstrated morphological aberrations in the brains of the young
throughout childhood.
Returning to Feinberg’s “open future of the child,” while theoretically compelling, much
of pediatric approaches to bioethics have involved pragmatic specifications about how to
implement appropriate decision-​making for minors in stewardship for the future mature
individual. There have been at least two significant competing models with some pro-
posed variants.
The most prevalent model in pediatrics is that articulated in the canonical work Deciding
for Others (Buchanan & Brock 1990). For individuals apparently either without compe-
tence or having lost their competence in the neurocognitive sense, surrogates can best
serve their charges by making decisions on their behalf using a “best interests standard”
(BIS) where the parents, or other legitimate responsible parties attempt to determine net
value among alternative choices which balance benefits versus the risks or burdens with
each choice. This standard requires an evaluation of quality of life considerations and the
authors stress that they mean quality of life, as it is significant to the presumed interests of
the individual in question as opposed to the interests of the family or the community at
large that may sway the decision-​making toward allocation of either more or less resources.
In other words, decisions on behalf of those deemed unable to decide for themselves should
be made solely on the basis of the worth or consequences of those decisions for those indi-
viduals and not on the basis of the perceived social utility of those individuals.
Although Buchanan and Brock were frequently speaking of individuals severely neu-
rocognitively disabled or those without developmental capacity for decision-​making,
depending on how we determine the threshold for neurocognitive incapacity, this surro-
gate decision-​making standard could be applied to some individuals now known to have
structural brain anomalies associated with genetic, socioeconomic, or environmental
adverse effects consisting of behavioral anomalies, processing difficulties, and sociopathy.
Further, Buchanan and Brock wrote separately of the specific problem of older children
who demonstrated evolving self-​awareness, maturation of abstract reasoning skills, exer-
cise of judgment and insight, and who would have increasing direct interests in their own
healthcare decision-​making.
Buchanan and Brock emphasized the priority of the individual’s interests over all other
parties. Therefore, they strictly privileged rights and interests of children/​minors over all
other interests including family and community interests.
On the other hand, others have weighed in on behalf of the priority of relationships and
the continuity thereof on whose interests should be first served? Murray speaks eloquently
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170 What do new neuroscience discoveries in children mean for their open future?

of the importance of the minor child’s place in the tapestry of relationships of the family
and then the social community (Murray 1996). Friedman Ross introduced her concept of
“constrained parental autonomy” (Ross 1998) as a means of bridging the divide between
pure parental prerogative and pure self-​interested primacy of their children’s interests
over and above the interests of the parents/​family and larger community. Friedman Ross
has contended that childhood autonomy cannot be appropriately expressed by children
due to inadequately developed maturity, lack of insight into consequences of decisions,
and perhaps inadequate foresight or imagination into the future. Therefore, she has stipu-
lated that parents must make all decisions in trust, premised on the requirement that the
constraints that parents must abide by relate to their obligations to provide a minimum of
supportive and protective care which can optimize or at least present the prospect of the
potential for maturation into full autonomous adulthood. Friedman Ross’s interpretation
of the child’s open future is that parents must engage in constraints to their children’s own
choices so as to optimize putative quality of the future child’s life. By doing so, parents
may promote the ongoing health and survival of their children until they can develop
sufficiently mature capacity to be empowered to make their own autonomous decisions.
Two extensive commentaries (Hester 2007; Salter 2012) on the value and utility of the
BIS shed a great deal of light on the pragmatic problems of applying the BIS. Salter has
produced a highly nuanced and detailed description of the BIS in its several versions. She
lists a variety of self-​regarding interests ascribed to children including both present and
future interests. The most pertinent of interests of children against the background of
neuroscience are those relating to cognitive-​developmental function both in the present
and in the future. Salter is also highly critical of the BIS because of the following prob-
lems: poorly defined terms, standards, and evaluation processes; there appears to be no
uniformly accepted understanding of criteria for determining the best interests resulting
in inconsistent and often too narrow application of the standard to specific cases; finally,
the standard does not allow for adequate respect for the family. Both Salter and Hester
reflect on cases where the specific contexts and circumstances are not amenable to solu-
tion through the BIS. Salter points out clearly that other interested parties, aside from the
child, for example, the healthcare providers and the parents, may not agree or have clarity
about what course of action(s) represent the child’s best interests.
Hester writes of the difficulties of ascribing interests to very young or compromised
infants, or both, because of the lack of any duration of lived experience. Therefore, he
observes that the tendency is to restrict the discussion about the best interest choices for
young infants to either avoiding net harm or to give all priority of decision-​making to
parents. He also asserts that parental interests may be connected to but not necessarily
identical to the cultural and social interests of the community at large in the welfare of
infants and children. Therefore, Hester believes that the sources of interests contributing
to decision-​making for very young children or children who may be neurocognitively
compromised should be expanded to encompass the larger community. Hester invokes
narrative as a means for ascertaining the relevant stories of the family, the child and the
larger community, which have bearing on healthcare decision-​making for the individual
 17

Bioethical and neuroethical implications 171

child. That is, only by identifying all of the relevant stakeholders can one determine what
are the real best interests for the individual child.
It is clear from these arguments that, as a prevalent/​dominant practice in deciding for
children, the BIS can weigh more heavily in the construction of a decision-​making future
for children with evidence of neurocognitive compromise or difference. That is, there is
more at stake in potential imposed constraints on the futures of compromised children.
The issues surrounding the emergence of personal identity and how others view the
individual emerging personality continue to be complex and difficult. As a counter to
the ambiguities of the BIS and the problems of recognizing developing individuation in
children, Lindemann has proposed a model of how personal identity is recognized by
others and how the perception of that identity as well as the maintenance of that per-
ception or recognition held over time, enables authenticity of the individual personality
(Lindemann 2014). She has described personhood as a composite of four elements: suf-
ficient mental activity is present to constitute a personality; aspects of the personality are
expressed bodily; others recognize those embodiments as expression of personality; and
others respond to what they perceive. Lindemann then goes on to describe how we see
ourselves and others as specific identities through “a web of stories depicting our most
important acts, experiences, characteristics, roles, relationships, and commitments. This
narrative tissue constitutes our personal identities, which play a crucial role in the prac-
tice of personhood” (Lindemann 2014, p.ix).
What Lindemann emphasizes is that our identities, and by connection, our moral status
as human beings, is determined first by how we are perceived by others, from the time
the gestating mother recognizes her emerging fetus, to the born child and emerging adult.
How individuals are perceived shapes how they view themselves, develop personality, and
how they engage in transactional activities or relationships with others: “Personal identi-
ties function as counters in our social transactions, in that they convey understandings of
what those who bear them are expected to do”(Lindemann 2014, p.ix). That is, how indi-
viduals are perceived results in responses, or reciprocal behaviors that either reinforce the
perceptions, edit those perceptions, eliciting further responses so that the development of
identity and personality is seen in a relational/​relationship context. Lindemann does not
directly discuss temperament (perhaps because that is intrinsic). But she does speak about
how the treatment of the other’s identity can be positive—​that is, supportive, reinforcing,
stimulating behaviors that lead to flourishing. On the other hand, the treatment of the
other can be negative, and result in the creation of what Lindemann refers to as a damaged
identity (Nelson 2001).
Lindemann’s model is quite potent in the context of identified neurostructural anomalies
in at-​risk children and youth for the following reasons: (1) at-​risk subjects may embody
abnormal behaviors, or psychopathies, associated with their brain anomalies; (2)  how
others perceive and respond to these behaviors can either reinforce negative behaviors or
shape more positive, more functional behaviors within the limits of the individual’s cogni-
tive capacity; and (3) targeted education and training of both at-​risk individuals and their
families/​community members could, over time, result in sustained alterations of behavior
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172 What do new neuroscience discoveries in children mean for their open future?

translating to authenticity in personality. Therefore, Lindemann would advocate devel-

opment of relational social structures that are protective and supportive of individual
personal identities.

Considerations of social justice

The other domain of bioethics, aside from the individual and personal, is that of the pub-
lic square. This is where the interests of the individual may intersect with the interests
of the greater polity. The recent findings of neuroimaging anomalies in the structure of
developing brains are worrisome. However, the acknowledged resilience and plasticity of
the immature central nervous system present opportunities, indeed, confer obligations to
create a social and cultural milieu, which can favor optimal growth and development of
all children, let alone those at significant risk for neurocognitive compromise. The new
neuroscience, because of the plethora of knowledge emerging about mechanisms of neu-
rocognitive compromise presents the prospects of new and more effective prevention and
possible treatments for these adverse conditions (Shonkoff & Levitt 2010). How can such
programs of early diagnosis and early intervention come about?
Models of social justice tend to be theoretical and abstract (Wenar 2013). However,
two parallel and somewhat related theories have introduced more pragmatic approaches
(Nussbaum 2003, 2004, 2006; Powers & Faden 2006). Part of the more practical nature
of these theories is the use of narrative in telling specific stories, which provide concrete
detail about individuals and subsets of individuals, which may inform justice policy
strategies.
Nussbaum has based her approach on some of the early work of Amartya Sen (Nussbaum
2003) and a critique of John Rawls (Nussbaum 2006). She addresses, in the latter work,
the weaknesses in social contract theories around disparities of access to social and health
goods where those who are disabled either lack voice or whose voices are dismissed.
Nussbaum proposes a noncontractarian view of basic entitlements owed to every indi-
vidual within a society. Nussbaum’s capabilities include the following:
1. Life (i.e., the ability to live)
2. Bodily health
3. Bodily integrity
4. Senses, imagination, thought (i.e., to engage in as fully cognitive function as possible)
5. Emotions (or valuation) or to form attachments, enjoy an affective life
6. Practical reason or to be able to engage in conceptual thought and critical reflection
on one’s life and future
7. Affiliation or to have relationships with others, other groups
8. Solidarity with other living creatures
9. Play
10. Control over one’s environment in both a social and political sense.
 173

Considerations of social justice 173

Implicit is the notion that all individuals are deemed to have personal identity and moral
worth. The capabilities 4 through 10 are particularly pertinent to the status of children
with neurocognitive variant or disability. Nussbaum’s prescription, then, is that identi-
fication of socially constructed barriers to expression or experience of these capabilities
ought to allow communities to develop policy and practices which optimize/​enhance
capabilities. The Americans with Disabilities Act (ADA) would be an example of the sort
of policy/​practice approach endorsed by Nussbaum. She undoubtedly views the ADA as
moving in the right direction, though not as comprehensive as she would like. Nussbaum’s
variant on Sen’s capabilities approach is far more expansive and is not limited to consider-
ations of physical or mental disability but also includes other forms of social and/​or eco-
nomic disparity. Recognizing the disproportionate burdens (time, money, labor) on the
part of caretakers of child with varying levels of neuro-​disability, Nussbaum extends her
capabilities approach to caretakers and other affiliated personnel who may be recruited
to help with the increased care needs of special needs children. By no means, should
we assume that the increased burden of care involves only those children with the most
severe disabilities. Children with educational and/​or social/​behavioral disabilities may
also require more resources for education, supervision, and treatment. And Nussbaum
would contend that a just society recognize such needs and accommodate in order that
both at-​risk children and their caretakers have flourishing lives:
Capabilities belong first and foremost to individual persons, and only derivatively to groups. The
approach espouses a principle of each person as an end. It stipulates that the goal is to produce
capabilities for each and every person, and not to use some people as a means to the capabilities of
others or of the whole. (Nussbaum 2011, p.35)

Well-​being is the key goal in an alternative theory of social justice (Powers & Faden 2006).
The premise is that a sound public health system can ensure a minimum sufficiency of
goods and resources to all members of the society so that well-​being can be achieved:
Our theory starts with the assumption that inequalities beget inequalities, and existing
inequalities—​in the social determinants of well-​being and ultimately in the essential dimensions
of well-​being themselves—​can compound, sustain, and reproduce a multitude of deprivations in
well-​being, bringing some persons below the level of sufficiency for more than one dimension.
(Powers & Faden 2006, p.7)
Powers and Faden assert that the moral imperative of public health practice is not just
regulatory and prescriptive but is also to ensure social justice through allocation and dis-
tribution practices. They have defined well-​being as a sufficiency of existence across a
number of dimensions which is similar to but not identical to the capabilities list:
1. Health
2. Personal security
3. Reasoning
4. Respect
5. Attachment
6. Self-​determination.
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174 What do new neuroscience discoveries in children mean for their open future?

They assert that the dimensions interact and that serious insufficiency of even one dimen-
sion tends to influence negatively the other dimensions of well-​being too. They do not
equate well-​being with absence of disease. They also identify, for some populations, such
as children, specific periods during the life cycle where public allocation decisions are
particularly important to ensure existing and developing well-​being. They identify early
infancy and early childhood as periods of great vulnerability in terms of suboptimal
development of reasoning skills that can impair cognitive function lifelong. These are
also periods during the life cycle of great opportunity for interventions that can optimize
practical reasoning skills, above and beyond intrinsic capacity. Because of the priority
assigned to the needs of children by Powers and Faden, they acknowledge that in a public
health system designed to assure the well-​being of all its citizens might result in conflicts
of priorities of allocation among subpopulations, for example, children versus the elderly
where there were constraints of resources.
There are always constraints on resources of one sort or another and Powers and Faden
propose strategies using quality of life potential, cost-​effectiveness analyses, and cost-​
utilization analyses to develop schemes for resource allocation which are fair and still
give priority to children’s needs. This is certainly a refreshing proposition for pediatric
healthcare providers! However, Powers and Faden also stipulate that context is important
in the final allocation decisions—​that is, if specific situations place individuals in other
age groups at greater risk to their well-​being, then it would be wrong to privilege children
always in terms of allocation of resources. Accounting of all dimensions of well-​being
needs to be analyzed closely in order to determine who should be privileged at particular
times and under particular circumstances. On the other hand, children tend to live longer
and therefore a suboptimal well-​being state would represent a greater burden to the indi-
vidual as well as the community if the needs of children were not addressed aggressively.
Presumably this stance would apply even more so for children identified to have risk for
poor neurocognitive outcomes.
With these marginally less abstract theories to consider, what we are left with are some
common conclusions: all children are owed optimal services in the form of education,
training, comprehensive care, suitable living conditions, and environments designed to
promote flourishing. Because of the increased burdens associated with providing addi-
tional services to compensate for additional neurocognitive risks, services for support of
families and caretakers should be allocated as well. In concrete terms, neither Nussbaum
nor Powers and Faden provided real descriptions of comprehensive capabilities or social
justice schemes.

Conclusion
Have we made any progress in answering the three questions posed at the beginning of
this paper?
1. How might genetic determinants of brain structure influence social policy to abridge
individual liberty and the individual’s open future?
 175

Conclusion 175

2. What are the moral obligations of health researchers and healthcare providers to ensure
that socioeconomic and environmental pollution data not be misconstrued to oppress,
further, already disadvantaged groups by ascribing poorer neurocognitive outcomes to
genetic ancestry?
3. How should normalcy be defined and would correction of neurocognitive function
eliminate diversity in personality, temperament, cognitive precocity, or genius?
For question 1, yes, there are risks of biased perceptions and creation, in Lindemann’s words,
of damaged identities that foreclose many possibilities for remediation through education,
training, and improvement of the rearing environment in childhood. Social and policy
measures which could foster damaged identities are intuitively obvious, such as scapegoat-
ing and restriction of access to appropriate educational and other support services to such
children and their families. On the other hand, we are currently in an era of great libertari-
anism among the families of children who are neurocognitively compromised and fami-
lies are often tremendous advocates on behalf of their special needs children. However,
resources are not distributed at a federal level, but rather at individual states levels, in the
United States, so that access to those resources are certainly not universally available and
are highly variable according to a priori conditions determined by various insurance plans
or state policy. Further, mental health services are notoriously poorly supported.
For question 2, there is no doubt that researchers and clinicians have obligations to
ensure that the data are gathered and reported with sufficient controls so as to eliminate
misconstrual of results and to minimize the possibility of adding social oppression to the
plight of children and families who are less fortunate. Both Peterson and Sowell were able
to implement sufficient controls to disabuse any notions that the neurocognitive impair-
ments observed in their study populations could be ascribed to race, ethnicity or culture.
These are practices that ought to be a part of the design of all such studies.
For question 3, there are no answers yet. This question and all the implications will have
to wait for the next edition of this book.
To conclude, while much of the content of this chapter has been theoretical, there are
some pragmatic interventions that ought to be considered at both individual and societal
levels. They draw upon the different aspects of and strengths of neuroethical inquiry and
methods, and what they can offer looking ahead:
1. Minimization of prenatal exposure to neurotoxins (Lanphear et al. 2005; Mezzacappa
et  al. 2011), and of all environmental sources of neurotoxins since adverse effects
on neurofunction are not limited to fetuses or children (Illes et  al. 2014; Cabrera
et al. 2016).
2. Focus on maximal educational achievement across all socioeconomic classes for the
purposes of enhancing the likelihood of economic achievement that may ameliorate
the functional consequences of brain growth anomalies among children and adoles-
cents (Diamond & Lee 2011; Schonert-​Reichl et al. 2015).
3. Promotion of a societal focus on improving the capabilities of all members of the
polity—​whether using the model of Nussbaum or the public health model of Powers
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176 What do new neuroscience discoveries in children mean for their open future?

and Faden—​with the intent to ameliorate the effects of socioeconomic disparities: bet-

ter education, better nutrition, and better quality of life could reduce the likelihood of
neurocognitive compromise on basis of social disparities.
4. Establishment of strategies at the individual level to promote construction of positive
identities for all individuals, and especially for those known to be at risk for neuro-
cognitive problems. Even individuals who exhibit psychopathic behaviors may have
insight (Horstkötter et al. 2012) and may be more or less open to supportive networks
that may increase their ability to lead flourishing and successful lives.

References
Baker, L.A., Barton, M., and Raine, A. (2002). The Southern California Twin Register at the University
of Southern California. Twin Research, 5, 456–​459.
Baker, L.A., Barton, M., Lozano, D.I., Raine, A., and Fowler, J.H. (2006). The Southern California Twin
Register at the University of Southern California: II. Twin Research and Human Genetics, 9, 933–​940.
Baker, L.A., Tuvblad, C., Wang, P., et al. (2013). The Southern California Twin Register at the
University of Southern California: III. Twin Research and Human Genetics, 16, 336–​343.
Bishop, S. (1980). Children, autonomy and the right to self-​determination. In: Aiken, W. and Lafollette,
H. (Eds.) Whose Child? Children’s Rights, Parental Authority, and State Power, pp.154–​176. Totowa,
NJ: Littlefield, Adams & Co.
Buchanan, A.E. and Brock, D.W. (1990). Deciding for Others: The Ethics of Surrogate Decision-​Making.
New York: Cambridge University Press.
Cabrera, L.Y., Tesluk, J., Chakraborti, M., Matthews, R., and Illes, J. (2016). Brain matters: from
environmental ethics to environmental neuroethics. Environmental Health, 15, 1–​5.
Campbell, A.T., Derrington, S.F., Hester, D.M., and Lew, C.D. (2012). Her own decision: impairment
and authenticity in adolescence. Journal of Clinical Ethics, 23, 47–​55.
Diamond, A. (1990). Introduction: the development and neural bases of higher cognitive
functions. In: The Development and Neural Bases of Higher Cognitive Functions, pp.xiii–​lvi.
New York: New York Academy of Sciences.
Diamond, A. and Lee, K. (2011). Interventions shown to aid executive function development in
children 4 to 12 years old. Science, 333, 959–​964.
Duncan, G.J. and Magnuson, K. (2012). Socioeconomic status and cognitive functioning: moving from
correlation to causation. Wiley Interdisciplinary Reviews: Cognitive Science, 3, 377–​386.
Farah, M.J., Noble, K.G., and Hurt, H. (2006). Poverty, privilege, and brain development: empirical
findings and ethical implications. In: Illes, J. (ed.) Neuroethics: Defining the Issues in Theory, Practice,
and Policy, pp.277–​287. New York: Oxford University Press.
Feinberg, J. (1980). The child’s right to an open future. In: Aiken, W. and Lafollette, H. (Eds.) Whose
Child? Children’s Rights, Parental Authority, and State Power, pp.124–​153. Totowa, NJ: Littlefield,
Adams & Co.
Feinberg, J. (1992). Freedom & Fulfillment: Philosophical Essays. Princeton, NJ: Princeton
University Press.
Gray, J.R. and Thompson, P.M. (2004). Neurobiology of intelligence: science and ethics. Nature Reviews
Neuroscience, 5, 471–​482.
Grisso, T. and Vierling, L. (1978). Minors’ consent to treatment: a developmental perspective.
Professional Psychology, 9, 412–​427.
 17

References 177

Gunther, D.F. and Diekema, D.S. (2006). Attenuating growth in children with profound developmental
disability: a new approach to an old dilemma. Archives of Pediatrics & Adolescent Medicine, 160,
1013–​1017.
Hester, D.M. (2007). Interests and neonates: there is more to the story than we explicitly acknowledge.
Theoretical Medicine and Bioethics, 28, 357–​372.
Hester, D.M. (2009). Adolescent decisionmaking, part i: introduction. Cambridge Quarterly of
Healthcare Ethics, 18, 300–​302.
Horstkötter, D., Berghmans, R., De Ruiter, C., Krumeich, A., and De Wert, G. (2012). “We are also
normal humans, you know?” Views and attitudes of juvenile delinquents on antisocial behavior,
neurobiology and prevention. International Journal of Law and Psychiatry, 35, 289–​297.
Houston, S.M., Herting, M.M., and Sowell, E.R. (2014). The neurobiology of childhood structural brain
development: conception through adulthood. Current Topics in Behavioral Neurosciences, 16, 3–​17.
Illes, J. (Ed.) (2006). Neuroethics: Defining the Issues in Theory, Practice, and Policy. Oxford: Oxford
University Press.
Illes, J. and Racine, E. (2005). Imaging or imagining? A neuroethics challenge informed by genetics.
American Journal of Bioethics, 5, 5–​18.
Illes, J. and Raffin, T.A. (2002). Neuroethics: an emerging new discipline in the study of brain and
cognition. Brain and Cognition, 50, 341–​344.
Illes, J., Davidson, J., and Matthews, R. (2014). Environmental neuroethics: changing the environment
changing the brain. Recommendations submitted to the Presidential Commission for the Study of
Bioethical Issues. Journal of Law and the Biosciences, 1(2), 221–​223.
IOM (2015). Health Literacy: Past, Present, and Future: Workshop Summary. Washington, DC: The
National Academies Press.
Kim, P., Evans, G.W., Angstadt, M., et al. (2013). Effects of childhood poverty and chronic stress on
emotion regulatory brain function in adulthood. Proceedings of the National Academy of Sciences of
the United States of America, 110, 18442–​18447.
King, N. (Director) (2015). Socioeconomic Status Could be Affecting Childrens’ Brains. Los Angeles,
CA: American Public Media.
Kohlberg, L. (1981). The Philosophy of Moral Development: Moral Stages and the Idea of Justice (Essays
on Moral Development, Vol. 1). San Francisco:, CA: Harper & Row.
Ladd, R.E. and Forman, E.N. (1995). Adolescent decision-​making: giving weight to age-​specific values.
Theoretical Medicine, 16, 333–​345.
Lanphear, B.P., Vorhees, C.V., and Bellinger, D.C. (2005). Protecting children from environmental
toxins. PLoS Medicine, 2, e61.
Lao, Y., Wang, Y., Shi, J., Ceschin, R., Nelson, M., Panigrahy, A., and Leporé, N. (2016). Thalamic
alterations in preterm neonates and their relation to ventral striatum disturbances revealed by a
combined shape and pose analysis. Brain Structure and Function, 221(1), 487–​506.
Liao, S.M., Savulescu, J., and Sheehan, M. (2007). The Ashley treatment: best interests, convenience,
and parental decision-​making. Hastings Center Report, 37, 16–​20.
Lindemann, H. (2014). Holding and Letting Go. New York: Oxford University Press.
Luby, J., Belden, A., Botteron, K., et al. (2013). The effects of poverty on childhood brain development: the
mediating effect of caregiving and stressful life events. JAMA Pediatrics, 167, 1135–​1142.
McLoyd, V.C. (1998). Socioeconomic disadvantage and child development. American Psychologist, 53,
185–​204.
Mezzacappa, E., Buckner, J.C., and Earls, F. (2011). Prenatal cigarette exposure and infant learning
stimulation as predictors of cognitive control in childhood. Developmental Science, 14, 881–​891.
Mohan, G. (2015). Can money buy yours kids a bigger brain? Los Angeles Times, March 30.
178  1

178 What do new neuroscience discoveries in children mean for their open future?

Murray, T.H. (1996). The Worth of a Child. Berkeley, CA: University of California Press.

Nelson, H.L. (2001). Damaged Identities: Narrative Repair. New York: Cornell University Press.
Noble, K.G., McCandliss, B.D., and Farah, M.J. (2007). Socioeconomic gradients predict individual
differences in neurocognitive abilities. Developmental Science, 10, 464–​480.
Noble, K.G., Houston, S.M., Brito, N.H., et al. (2015). Family income, parental education and brain
structure in children and adolescents. Nature Neuroscience, 18, 773–​778.
Nussbaum, M. (2003). Capabilities as fundamental entitlements: sen and social justice. Feminist
Economics, 9, 33–​59.
Nussbaum, M.C. (2004). Beyond the social contract: capabilities and global justice. an Olaf Palme
lecture, delivered in Oxford on 19 June 2003. Oxford Development Studies, 32, 3–​18.
Nussbaum, M.C. (2006). Frontiers of Justice: Disability, Nationality, Species Membership. Cambridge,
MA: Harvard University Press.
Nussbaum, M.C. (2011). Creating Capabilities: The Human Development Approach. Cambridge,
MA: Harvard University Press.
Peace, W.J. and Roy, C. (2014). Scrutinizing Ashley X: presumed medical “solutions” vs. real social
adaptation. Journal of Philosophy, Science & Law, 14, 33–​52.
Perera, F.P., Rauh, V., Whyatt, R.M., et al. (2006). Effect of prenatal exposure to airborne polycyclic
aromatic hydrocarbons on neurodevelopment in the first 3 years of life among inner-​city children.
Environmental Health Perspectives, 114, 1287–​1292.
Perera, F.P., Li, Z., Whyatt, R., et al. (2008). Prenatal airborne polycyclic aromatic hydrocarbon
exposure and child IQ at age 5 years. Pediatrics, 124, e195–​202.
Perera, F.P., Li, Z., Whyatt, R., et al. (2009). Prenatal airborne polycyclic aromatic hydrocarbon
exposure and child IQ at age 5 years. Pediatrics, 124, e195-​e202.
Perera, F.P., Tang, D., Wang, S., et al. (2012). Prenatal polycyclic aromatic hydrocarbon (PAH) exposure
and child behavior at age 6-​7 years. Environmental Health Perspectives, 120, 921–​926.
Peterson, B.S., Rauh, V.A., Bansal, R., et al. (2015). Effects of prenatal exposure to air pollutants
(polycyclic aromatic hydrocarbons) on the development of brain white matter, cognition, and
behavior in later childhood. JAMA Psychiatry, 72, 531–​540.
Piaget, J. (1926). The Language and Thought of the Child. Paris: Kegan Paul, Trench, Trubner & Co.
Piaget, J. (1997). The Moral Judgment of the Child. New York: Simon & Schuster.
Powers, M. and Faden, R. (2006). Social Justice: The Moral Foundations of Public Health and Health
Policy. New York: Oxford University Press.
Rachels, J. (2012). The case against free will. In: Rachels, J. and Rachels, S. (Eds.) Problems from
Philosophy (3rd edn.). New York: McGraw Hill.
Rosenzweig, M.R. (2003). Effects of differential experience on the brain and behavior. Developmental
Neuropsychology, 24, 523–​540.
Ross, L.F. (1997). Health care decisionmaking by children is it in their best interest? Hastings Center
Report, 27, 41–​46.
Ross, L.F. (1998). Children, Families, and Health Care Decision Making. New York: Oxford
University Press.
Salter, E.K. (2012). Deciding for a child: a comprehensive analysis of the best interest standard.
Theoretical Medicine and Bioethics, 33, 179–​198.
Schonert-​Reichl, K.A., Oberle, E., Lawlor, M.S., et al. (2015). Enhancing cognitive and social-​
emotional development through a simple-​to-​administer mindfulness-​based school program for
elementary school children: a randomized controlled trial. Developmental Psychology, 51, 52–​66.
Selemon, L.D. (2013). A role for synaptic plasticity in the adolescent development of executive function.
Translational Psychiatry, 3, e238.
 179

References 179

Shonkoff, J.P. and Levitt, P. (2010). Neuroscience and the future of early childhood policy: moving from
why to what and how. Neuron, 67, 689–​691.
Sowell, E.R., Peterson, B.S., Thompson, P.M., Welcome, S.E., Henkenius, A.L., and Toga, A.W. (2003).
Mapping cortical change across the human life span. Nature Neuroscience, 6, 309–​315.
Sowell, E.R., Thompson, P.M., Holmes, C.J., Batth, R., Jernigan, T.L., and Toga, A.W. (1999).
Localizing age-​related changes in brain structure between childhood and adolescence using
statistical parametric mapping. NeuroImage, 9, 587–​597.
Weir, R.F. and Peters, C. (1997). Affirming the decisions adolescents make about life and death.
Hastings Center Report, 27, 29–​40.
Weithorn, L.A. and Campbell, S.B. (1982). The competency of children and adolescents to make
informed treatment decisions. Child Development, 53, 1589–​1598.
Wenar, L. (2013). John Rawls. In: Zalta, E.N. (Ed.) Stanford Encyclopedia of Philosophy (Winter 2013
edn.). Stanford, CA.
Wilkinson, D. (2013). Death of Disability?: The “Carmentis Machine” and Decision-​Making for Critically
Ill Children. Oxford: Oxford University Press.
Yang, Y., Joshi, A.A., Joshi, S.H., et al. (2012). Genetic and environmental influences on cortical
thickness among 14-​year-​old twins. Neuroreport, 23, 702–​706.
Yang, Y., Wang, P., Baker, L.A., et al. (2015). Thicker temporal cortex associates with a developmental
trajectory for psychopathic traits in adolescents. PLoS ONE, 10, e0127025.
180

Chapter 10

Neuroprognostication after severe
brain injury in children: Science fiction
or plausible reality?
Sarah S. Welsh, Geneviève Du Pont-​Thibodeau,
and Matthew P. Kirschen

Introduction
Neuroprognostication with regard to functional and cognitive recovery after brain injury
in children is highly complex, and occurs as a continuous, iterative process throughout the
initial resuscitation, acute, and subacute and rehabilitative phases of injury and recovery.
It requires constant and vigilant attention to translation of prognostication to meaningful
action for parents and families making clinical decisions on behalf of their children. This
translation is fraught with the implications for a child’s cognitive and physical potential,
any particular family’s set of goals and acceptable outcomes for that individual child, and
the context driven by personal experience and media exposure within which each family
centers the medical team’s prognostic framework (Racine & Bell 2008).
The spectrum of causes for brain injury in children is broad. For select etiologies, such
as hypoxic-​ischemic injury after cardiac arrest or traumatic brain injury, epidemiological
and observational data exist which can guide initial prognostic discussions. For less com-
mon disorders such as infectious or autoimmune encephalitis, sepsis-​associated encepha-
lopathy, or status epilepticus, estimating a child’s potential for neurologic recovery can be
far more challenging as the outcomes are less predictable, and dependent on the response
to targeted therapy. A major challenge to accurate and timely prediction of both global
and specific neurologic potential after brain injury in children is the ability of the young,
developing brain to form new neuronal connections and updated structure–​function
associations. This process is highly individualized and variable, with the same apparent
injury producing widely different clinical outcomes. Physicians typically have confidence
in their prognostic abilities at the deep ends of the spectrum of injury—​they are able to
diagnose brain death and what lies very close to it, and they are comfortable with diagnos-
ing mild injury with normal or near-​normal neurologic outcomes—​but they struggle to
elucidate the many variations of gray that lie between those two divergent ends.
In this chapter, we utilize a clinical case to outline the phases of injury and recovery
through which a child progresses after sustaining a severe brain injury. Understanding
 18

Phases of injury and recovery after severe brain injury 181

these phases is crucial to elucidating how and where newer technologies may have the
greatest influence on our prognostic capabilities. We describe the potential role of current
technologies, including functional neuroimaging, in neuroprognostication after brain
injury, and examine ethical issues that may arise as these instruments are transitioned
from the research lab into clinical practice. Finally, we envision how current and future
technologies could be applied to improve neuroprognostication accuracy and physician
and family confidence in those assessments.

Phases of injury and recovery after severe brain injury

Resuscitation phase
Case scenario:  An 8-​year-​old previously healthy boy was found unresponsive and submersed in a
pool. He was a strong swimmer and seen by his mother about 5 minutes prior playing with friends.
Emergency medical services initiated cardiopulmonary resuscitation (CPR) and inserted an endotra-
cheal tube. He was transported to a local emergency room with CPR ongoing. Return of spontaneous
circulation was achieved after approximately 25 minutes of CPR and multiple doses of epinephrine. At
the time of transfer to a pediatric intensive care unit (PICU), he had ongoing hemodynamic instability
and was comatose with no movement to painful stimuli, absent cough and gag reflex, and enlarged
pupils that were minimally responsive to light.

During the resuscitation phase, which often traverses several hours, pediatric critical care
physicians are methodically and systematically stabilizing critical organ systems includ-
ing the brain. This may require invasive procedures to insert devices for close physiologic
monitoring, CPR, or institution of therapies such as extracorporeal membrane oxygen-
ation (ECMO) for maximal cardiopulmonary support. This is a stressful and anxious time
for both physicians and families. Discussions between medical staff and families during
this tenuous time are typically focused on orientation to the ICU environment, planned
procedures and interventions, and presumed injury severity, although data regarding the
extent of the brain injury is limited often to a clinical exam and an early head comput-
erized tomography (CT) scan. While head CT performed early after injury may fail to
show the full extent of brain injury, loss of gray–​white matter differentiation, basilar cis-
tern effacement, and sulcal effacement are in general associated with poor outcome after
pediatric out-​of-​hospital cardiac arrest (Starling et al. 2015). Similarly, a physical exam
performed during or immediately after resuscitation can be misleading with respect to
the degree and permanence of brain injury. There is often limited time for in-​depth dis-
cussions regarding neurologic outcome during an intense resuscitation, especially when
survival is paramount.
Data exist to assist with survival prediction during the resuscitation phase depending
on the etiology of brain injury, and can be further refined based on individual clinical
characteristics (Kessler et al. 2011; Girotra et al. 2013). Additionally, the mortality trend
for pediatric cardiac arrest has been improved over recent years with early recognition
and CPR, emphasis on high-​quality resuscitation, and post-​resuscitation care (Topjian
et al. 2013). Thus, especially in pediatrics, it is often unclear how long to continue CPR
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182 Neuroprognostication after severe brain injury in children

or a resuscitation. Technology that could be applied noninvasively at the bedside during

a resuscitation that allowed for quantification of brain injury and an estimation of neuro-
logic outcome could be invaluable in guiding medical teams regarding when to limit or
withdraw medical interventions including CPR.

Acute phase
Case scenario, continued: In the PICU, he required mechanical ventilation with high pressures due to
severe lung injury and high-​dose vasopressor infusions for hemodynamic support secondary to cardiac
dysfunction. He remained comatose with no response to stimuli and intermittently absent brainstem
reflexes. A head CT scan obtained the following day showed subtle loss of gray–​white differentiation
with crowding of the basal cisterns, but no herniation or midline shift. A continuous electroencepha-
logram (EEG) was abnormal, with disorganization, but no epileptiform discharges, and some periods
of preserved sleep architecture.

After surviving the initial resuscitation, patients progress to the acute phase, which typi-
cally lasts for several days. This period of multisystem instability requires close physi-
ologic monitoring and observation, and the institution of therapies aimed at mitigating
and preventing secondary or ongoing brain injury. A complete discussion of these neu-
roprotective and neurorestorative therapies (e.g., therapeutic hypothermia) is beyond the
scope of this chapter, although the neuroprognostication process must account for the
presence and timing of these treatments (Perman et al. 2012). The efficacy of these thera-
pies depends on the etiology of brain injury, and is the subject of many completed and
ongoing clinical trials in adults and pediatrics (Holzer 2002; Nielsen et al. 2013; Moler
et al. 2015).
During this acute phase in the ICU, parents frequently ask probing questions regard-
ing their child’s potential functional and cognitive outcomes (Box 10.1). Will the child
wake up? Will s/​he speak, interact, smile, walk? The answers to these questions often
directly guide decisions about care. Intensivists and neurologists partner together dur-
ing this phase to provide information to families regarding the suspected degree of brain
injury, discuss potential treatment options, and ascertain the family values for the child
(Kirschen et  al. 2014; Kirschen & Walter 2015). Communicating and managing prog-
nostic uncertainty can be especially challenging during this acute phase (Marcin et  al.
1999, 2004).
Information about a patient’s neurologic status during this phase is typically based on
a child’s physical exam, possible head CT, and continuous EEG recordings. The neuro-
logic exam and EEG recordings are often confounded by analgesic and sedative infu-
sions, which are used routinely in the pediatric ICU environment. EEG background and
presence of subclinical seizures have been associated with poor neurologic outcome and
increased mortality after cardiac arrest (Abend et  al. 2009; Topjian et  al. 2016). More
definitive neuroimaging such as magnetic resonance imaging (MRI) to characterize the
extent of the brain injury is not often feasible during this phase due to the critical nature
of the patient and the inability for safe transport to the scanner suite. Serum biomark-
ers which measure neuronal and astrocyte destruction (e.g., neuron-​specific enolase and
 183

Phases of injury and recovery after severe brain injury 183

Box 10.1  Key questions from parents of children with severe

brain injury

◆ Will my child wake up?

◆ What will my child be able to do?
• Will s/​he be able to dress, feed, and toilet him or herself? (Functional potential)
• Will s/​he be able to stand, walk, or run? (Gross motor potential)
• Will s/​he be able to talk or communicate in any way? (Language and emotional
potential)
• Will s/​he be able to attend school, graduate from college, hold a job? (Cognitive
potential)
◆ Can my child currently feel pain?
◆ How aware is my child now? Can s/he hear our voices? Does s/he know that
I am here?

S100B) have been studied in select pediatric populations, but are not validated or incor-
porated into prognostic algorithms as they are in adults (Topjian et al. 2009; Berger et al.
2010). Clinical characteristics about a child’s cardiac arrest and physiologic data obtained
during the resuscitation and acute phases have also been correlated with survival and
neurologic outcome (Girotra et al. 2013; Topjian et al. 2013, 2014; van Zellem et al. 2015).
Various guidelines exist to assist with neurologic prognosis in patients who remain
comatose after survival from cardiac arrest during this acute phase, although these
have only been developed and validated in adults. For example, in 2006, the American
Academy of Neurology released a sequential algorithm to predict poor neurologic out-
come and thus guide decision-​making that focused on the clinical exam, somatosen-
sory evoked potentials, and biomarkers obtained within 72 hours of the arrest, but did
not take into account the advent of targeted temperature management (i.e., therapeutic
hypothermia), EEG assessment, or advanced imaging techniques (Wijdicks et al. 2006).
Thus, the European Resuscitation Council and the European Society of Intensive Care
Medicine issued a revised algorithm in 2014, incorporating the patient’s clinical exam,
EEG, biomarkers, somatosensory evoked potentials, and neuroimaging including CT and
MRI. A poor outcome according to those guidelines is “very likely” if the patient has no
pupillary or corneal reflexes, and bilaterally absent N20 somatosenory-​evoked potentials
(SSEPs). A poor outcome is “likely” with the presence of myoclonic status, high neuron-​
specific enolase levels, burst suppression or status epilepticus on EEG and/​or diffuse
anoxic injury on CT/​MRI (even in the absence of abnormalities in pupillary exam or
SSEPs). The algorithm also recommends only initiating prognostic testing after an appro-
priate period post confounders such as hypothermia and residual sedation has elapsed
(Greer et al. 2014; Sandroni et al. 2014; Sandroni & Nolan 2015; Hindle et al. 2015).
184

184 Neuroprognostication after severe brain injury in children

No formal guidelines or algorithms have been developed in pediatrics to assist with

prognosticating in comatose survivors of cardiac arrest or other types of severe brain
injury. One study found that delaying prognostication for several days post injury, and
basing prognosis on duration of CPR, components of the clinical exam, MRI findings,
and SSEPs, had the highest positive predictive value for poor prognosis. Specifically, CPR
greater than 10 minutes, Glasgow Coma Scale score less than 5, absent pupillary response,
bilaterally absent N20 SSEPs, abnormal EEG, and watershed/​basal ganglia/​brainstem
injuries on MRI were highly predictive of poor outcome (Abend & Licht 2008).
Unfortunately, current predictors of long-​term neurologic function differentiate only
against a “poor” neurologic outcome, usually defined as death, severe neurologic disabil-
ity, or persistent vegetative state. Physicians can only provide families with a categorized
prediction of their child’s predicted neurologic outcome—​whether it will be favorable or
unfavorable—​without being able to define the subtleties that can considerably affect fami-
lies’ decision of care. Families often carry the burden of having to make life-​altering deci-
sions for their child based on somewhat elusive predictive models and risk estimations.
The acute phase may also contain a critical period of physiological instability, during
which time withholding or withdrawal of life-​sustaining therapies has a higher likeli-
hood of leading to death. This period is sometimes referred to as the window of oppor-
tunity, and is one reason why emphasis is often placed on the need for accurate and
timely prognosis (Wilkinson 2009, 2011; Kirschen & Walter 2015). Prognostic certainty
can often be improved by delaying clinical decisions; however, children may no longer
require life-​sustaining therapies at that time, and thus survive with profound neurologic
injury. Additionally, newer therapies aimed at neuroprotection after brain injury may
not have sufficient time to demonstrate effectiveness until after this window has passed.
Technologies aimed at improving diagnostic and prognostic accuracy during this acute
phase would be an invaluable asset to physicians, families, and patients. This is espe-
cially crucial since some data show that the neurologic capabilities of some patients with
hypoxic-​ischemic brain injury from cardiac arrest can change in both positive and nega-
tive directions over time (Michiels et al. 2016).

Subacute phase
Case scenario, continued: Magnetic resonance imaging (MRI) of the brain 72 hours post injury
showed mild signal abnormality in the bilateral thalami with subtle restricted diffusion, indicating
some ischemia in these brain regions. He was extubated 4 days after injury. On exam over the follow-
ing weeks he was non-​verbal, lacked purposeful movements, was unable to follow commands, and
had frequent episodes of posturing. Electrocardiogram (ECG) showed a prolonged corrected QT (QTc)
interval, and family history revealed long QT syndrome in a maternal aunt and death by drowning in
a maternal cousin (a prolonged QT interval is a cardiac rhythm abnormality that may be associated
with sudden death).

In the subacute phase of brain injury and recovery, patients typically demonstrate signs
that they will breathe and maintain sufficient hemodynamic stability to survive inde-
pendently of technological support, although some patients require more prolonged
 185

Phases of injury and recovery after severe brain injury 185

mechanical ventilation. This phase is often characterized by a disordered state of con-

sciousness. Disorders of consciousness are a spectrum of clinical syndromes that result
from brain injury that compromises wakefulness, or self-​and environmental aware-
ness, or both (Box 10.2). This alteration in consciousness can be acute and transient, or
may vary in permutations up to and including irreversible and permanent. Most of the
advanced neuroimaging techniques used to assess neurologic outcome potential have
been employed in patients with a disorder of consciousness during this subacute phase, as
patients are clinically stable enough to undergo the imaging procedure.
Patients in a vegetative state, recently renamed unresponsive wakefulness syndrome,
may appear awake, but will not demonstrate any evidence of self-​and environmental
awareness and do not show any voluntary motor responsiveness (Calabro et al. 2016). In
these patients, auditory or painful stimuli may activate primary somatosensory cortices,
but not higher-​order associative areas (Laureys et al. 2000, 2002). In contrast, minimally
conscious patients will demonstrate evidence of self-​or environmental awareness with a
variable spectrum of voluntary behaviors such as visual tracking, localization of a painful
stimulus, or may even follow simple commands (Calabro et al. 2016). The natural history
of brain recovery is the progression from a vegetative state to that of a minimally con-
scious state, followed by a confused and amnesic phase, and finally to a post-​confusional
functional recovery phase (Katz et al. 2009). The degree of recovery and of residual func-
tionality, if any, is highly variable and dependent on the underlying etiology of the brain
injury. For example, patients who sustain traumatic brain injury will have improved tra-
jectories for neurologic recovery compared to non-​traumatic brain injured patients (Katz
et al. 2009). Patients who have sustained a hypoxic-​ischemic injury typically have a more
diffuse and global brain injury, whereas patients with trauma have a more heterogeneous

Box 10.2  Disorders of consciousness

◆ Delirium: often temporary state of confusion, anxiety, decreased awareness of self

and the environment, can be hyperreactive to stimuli
◆ Coma: an eye-​closed pathologic state of unresponsiveness from which individuals
cannot be aroused to wakefulness by stimuli
◆ Unresponsive wakefulness syndrome (or vegetative state; “persistent” after being
present for more than one month):  an eye-​open state of wakefulness without
awareness
◆ Minimally conscious state: a chronic state of poor responsiveness to stimuli, but
evidence of awareness of themselves and environment is present
◆ Locked-​in syndrome: the patient is conscious and aware of self and the environ-
ment, but is outwardly behaviorally unresponsive.
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186 Neuroprognostication after severe brain injury in children

pattern of brain injury, with areas of unaffected neural tissue interspersed with the injured
tissue (Fins 2011).
Making the correct clinical assessment of consciousness is essential, as it directly impacts
decisions of care, rehabilitation, and prognostication (He et al. 2014; Bender et al. 2015).
Knowing whether a patient is conscious or aware of their environment certainly plays a
crucial role in families’ decision-​making process. Adult physicians commonly utilize the
standardized Coma Recovery Scale-​Revised clinical tool to categorize degrees of impaired
consciousness, and in particular, to distinguish the vegetative from the minimally con-
scious patients (Giacino et al. 2004). Making these diagnoses is a very challenging task
for the clinician, as discerning reflexive movements from intermittent and episodic vol-
untary movements can be subjective and dependent on the timing of exam. Furthermore,
patients may suffer from cognitive (aphasia, apraxia) or sensory impairments (auditory
or visual) limiting their ability to interact. The inability to elicit responsiveness does not
necessarily mean that the patient is not conscious. Misdiagnosing patients in vegetative
state when they are in fact minimally conscious has been reported to occur in up to 40%
of cases (Childs et al. 1993; Andrews et al. 1996; Wilson et al. 2002; Schnakers et al. 2009;
Calabro et al. 2016).
Appreciating the wide disparity in adult practitioners’ reliability and accuracy in
diagnosing these disorders makes conferring these diagnoses in pediatric patients that
much more challenging. First, this difficulty in outcome prediction is magnified by any
preexisting chronic neurologic or developmental condition (Kirschen & Feudtner 2012;
Kirschen & Walter 2015). Second, the broad range of normal developmental stages in
childhood further complicates neurologic status assignment, especially for young chil-
dren. And third, clinical exams based on the age and developmental stage of the child
can be incredibly challenging and produce highly variable results, particularly in a child’s
response to painful or uncomfortable stimuli.
In the prior section focusing on prognosticating during the acute phase of injury,
we discussed how physicians often focus on the period of cardiopulmonary instability
as an optimal time to discuss outcome prediction since withholding or withdrawal of
life-​sustaining therapies during this window will likely result in death. A large num-
ber of families are unable to make such an irreversible decision during the highly
emotional and stressful initial days after a child’s injury, especially since they are hop-
ing for a better-​than-​expected outcome. However, this initial period of physiologic
instability is not the only opportunity families have to limit or withhold aggressive
care. Thus, technologies that could enhance prognostic accuracy and certainty during
this subacute phase would continue to be of significant value. They could provide vital
information for a family seeking treatment options aligned with their values for the
child, which may include limiting or withholding care, or proceeding with aggressive
brain-​centered rehabilitation. Options for limiting or withholding care may include
removal of an endotracheal or tracheostomy tube that some children still require in
the subacute phase, and discussions regarding goals of care for future illnesses and
hospitalizations. Additionally, for some children who permanently lack conscious
 187

Advanced neuroimaging techniques in outcome prediction 187

awareness, withdrawal of artificial hydration and nutrition can be ethically permis-

sible (Diekema et al. 2009).

Advanced neuroimaging techniques in outcome prediction

To aid in the neuroprognostication process, researchers have turned to advanced neuro-
imaging techniques to attempt to determine consciousness beyond the current clinical
inspection for purposeful behavior. Several imaging techniques have demonstrated the
ability to detect activity in high-​level associative cortical centers in otherwise vegetative-​
appearing patients, which could be suggestive of awareness. These techniques include
positron emission tomography (PET scans; measuring metabolic activity including glu-
cose uptake and oxygen extraction), magnetoencephalography (MEG; assessing electri-
cal activity in the brain able to generate a magnetic field), MR spectroscopy (magnetic
resonance evaluation of cell turnover/​energetic function), MR diffusion tensor imaging
(measuring the density and integrity of white matter tracts), functional MRI (fMRI; quan-
tifying blood oxygenation level-​dependent (BOLD) images), and electroencephalography
(Fins et al. 2008; Owen 2013; Northoff & Heiss 2015).
Functional MRI allows the visualization of areas in the brain with high functional
connectivity, elevated cerebral blood flow, and high rate of glucose metabolism (Wu
et  al. 2015). It has been showed to elicit areas responsible for information integra-
tion, an essential function of consciousness (Tononi 2004; Tononi & Koch 2008).
Multiple small studies have shown these areas to be disrupted in patients with acute
brain injury (Achard et al. 2006; Liang et al. 2013; Tomasi et al. 2013). These islands of
functional brain seem to exist in some persistently vegetative patients, suggesting that
they may have some retained consciousness (Laureys et al. 2000, 2002; Wu et al. 2015).
Minimally conscious patients may retain some cognition and may be able to process
language despite their inability to interact and communicate appropriately (Schiff
et  al. 2005). In one study, spoken narratives by family members to minimally con-
scious patients resulted in large-​scale network activation similarly to healthy controls,
but this activation did not occur when narratives were presented by the same family
member without linguistic content. These findings suggest that patients may have a
preserved ability to process language without being consciously aware. In fact, studies
in patients under anesthesia demonstrated that speech perception and word process-
ing continued to occur during anesthesia and sleep despite the absence of conscious
awareness (Owen et al. 2006).
Given the preservation of some language capabilities, fMRI has been further
employed to attempt to interact with a patient in a vegetative state. For example, a 23-​
year-​old vegetative woman from a traumatic brain injury was asked to perform two
mental tasks: the first was to imagine herself playing tennis, and the other one was to
imagine visiting every room in her house. These mental tasks demonstrated increased
activation in supplementary motor area, and parahippocampal gyrus, the posterior
parietal cortex, and the lateral premotor cortex, respectively. Those same areas were
18

188 Neuroprognostication after severe brain injury in children

also observed in healthy volunteers performing the same task. This patient demon-
strated via fMRI brain activation maps that she was able to understand and respond to
commands (Owen et al. 2006). Monti and colleagues were able to elicit similar responses
in 4 of 23 patients previously diagnosed as being vegetative (Monti et al. 2010). In a
separate study, this team asked a patient that had been in a vegetative state for 5 years
to imagine playing tennis to communicate one answer (e.g., yes) and to imagine mov-
ing around the rooms of his home to communicate the alternative answer (e.g., no).
The patient then correctly answered five personalized questions (e.g., his father’s name)
confirming that he was conscious, and able to successfully recall historical details of his
life (Monti et al. 2010; Owen 2013).
Functional MRI has also shown promising results in predicting functional recovery in
patients clinically diagnosed as being in a vegetative state. The detection of activity in
higher-​level associative cortices predicts recovery with 93% specificity and 69% sensi-
tivity (Di et al. 2008). The strength of functional connectivity of whole-​brain networks
also correlates with neurologic recovery. A recent study of nearly 100 patients with vary-
ing degrees of impaired consciousness and 34 healthy controls demonstrated a correla-
tion between functional connectivity strength, consciousness, and recovery. Functional
connectivity strength could predict recovery of consciousness with 81% accuracy (Wu
et al. 2015). These studies have identified a population of patients that demonstrate some
evidence of preserved cognitive function, consciousness, and awareness of self and the
environment, but without the ability to communicate with the outside world (Wu et al.
2015). This syndrome, newly termed functional locked-​in syndrome, raises the possibility
that some vegetative patients are in fact conscious, aware of their environment, and able
to understand speech.

Pediatric advanced neuroimaging studies

Several studies have sought to extend these functional neuroimaging protocols to
detect language and higher-​order cognitive processing to pediatric patients with a
disorder of consciousness after severe brain injury (Ashwal et al. 2014; Roberts et al.
2014). Nicholas and colleagues performed a study in which a 7-​year-​old girl in a mini-
mally conscious state from a traumatic brain injury was presented names (her own
name and an unfamiliar name) using familiar (her mother) and unfamiliar voices.
Activation was detected in the primary auditory cortex, a site commonly activated
during auditory language processing tasks in healthy controls. Activation maps to the
patient’s own name versus an unfamiliar name, and using familiar versus unfamiliar
voices, were inconsistent with adult studies using the same paradigm. She demon-
strated activity in cortical midline structures and dorsolateral prefrontal cortex to her
own name, which are thought to be activated in response to self-​related stimuli, and
when making evaluations of self (Nicholas et al. 2014; Wang et al. 2015). Further stud-
ies in children of varying ages and developmental stages are needed to build on these
results and move this field forward.
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Advanced neuroimaging techniques in outcome prediction 189

Ethical considerations
The ramifications of these recent findings are fraught with ethical issues. Such neuroimag-
ing studies suggest that a patient who has clinically been deemed to be in an unresponsive
vegetative state may in fact demonstrate consciousness and be capable of interacting with
their environment. This possibility forces us to question the autonomy and decision-​mak-
ing ability of patients with disorders of consciousness. It also raises questions about per-
ceived quality of life, and whether evidence for covert consciousness argues for ongoing
aggressive medical care or compassionate withdrawal of life-​sustaining treatments. While
only a small subset of these patients may retain sufficient cognitive neural networks to
perform the types of tasks required in these studies, there is still a significant leap between
imagining motor tasks and answering questions about a person’s past, and demonstrat-
ing adequate understanding to provide informed consent or express a person’s wishes for
complex clinical decision making. If technology were to advance through this gap, could
it be used to assess pain, emotions such as anxiety, fear, or depression, and whether a
patient feels hunger or thirst? If so, perhaps medical teams would more effectively be able
to titrate care to actual patient wishes rather than by proxy.
Prior to transitioning this research-​based technology into routine clinical practice, we
as researchers and clinicians must first feel confident that the behavioral stimuli presented
map to known anatomical locations. We must be mindful during this process that normal
structure–​function relationships have been developed in the adult population and may
not be directly transferable to the developing brain, or a brain that has begun to func-
tionally reorganize as it recovers from a brain injury. Second, we must be sure that any
particular patient or group of patients will respond to a similar stimulus in a consistent,
replicable manner. Lastly, we currently have no way of understanding whether or not
a meaningful, replicable, and consistent response indicating awareness is predictive of
future functional recovery for any given patient (Wilkinson et al. 2009; Weijer et al. 2014).
Jox and colleagues formatted a deft explanation of this ethical and clinical conundrum
based on three possible outcomes of functional neuroimaging: (1) neuroimaging shows
less evidence of consciousness or awareness than found on clinical exam, which may allow
families to feel more comfortable with limitations or withholding of life-​sustaining tech-
nology, but may strain the therapeutic relationship with the clinician if she is more opti-
mistic about the patient’s potential outcome; (2) neuroimaging shows more evidence of
awareness than found on clinical exam, which may on one hand encourage more aggres-
sive treatment, but on the other hand may create false hope for a more complete recovery
or prompt a family to withhold technologic support if there is perceived awareness of pain
or suffering; or (3) neuroimaging shows the same evidence of awareness as clinical exam,
which may also strain the physician-​family therapeutic relationship with a perception of
“useless” and expensive testing (Jox et al. 2012). Regardless, as we currently hold neither a
complete understanding of functional neuroanatomy, nor a meaningful ethical construct
of interpreting covert consciousness, we are faced with data that we are unable to reliably
act upon (Lutkenhoff et al. 2015; Kowalski et al. 2015; Wintermark et al. 2015a, 2015b).
190

190 Neuroprognostication after severe brain injury in children

The field of functional neuroimaging holds great promise to assist with the assess-
ment and potential clinical management of patients with disordered consciousness after
severe brain injury. It may contribute objective data to aid with diagnostic classification
of patients and provide families with a more concrete understanding of a patient’s capa-
bilities. It may have implications for assisting patients with pain management, commu-
nicating wants and needs, and end-​of-​life decisions of care. Additionally, when repeated
serially after injury, functional imaging may provide crucial information about neuronal
recovery and reorganization over time from brain injury, and could potentially be used to
monitor the response of the brain to medications such as amantadine and zolpidem that
have been shown to produce and accelerating neurologic recovery (Giacino et al. 2014).

Envisioning future directions for neuroprognostication

Current frameworks for estimating neurologic outcome after severe brain injury are lim-
ited to a dichotomous poor or not likely to be poor metric. They are influenced by both
patient and family factors, and physician-​related factors including age, clinical experi-
ence, and medical specialty (Racine et al. 2009; Finley Caulfield et al. 2010; Perman et al.
2012). The development or application of technology that contributes meaningful objec-
tive data to the neuroprognostication process that can be applied clinically at the bed-
side would be an invaluable resource to physicians, families, and patients. In this section,
we will review theoretical applications of current technology that have the potential to
improve outcome prediction and aid families in the medical decision-​making process.
We envision these novel applications of current technologies to be of greatest utility in the
acute and subacute phases of injury and recovery.
An initial step in advancing current techniques could be the creation of a multimodal-
ity database that incorporates signals from several neuromonitoring and neuroimaging
devices, and follows trends from soon after injury through recovery. These signals could
be compared to a similar database generated from typically developing children over
time. By using EEG and fMRI data, a functional map of each individually injured brain
could be generated, and changes in signals and activation patterns over time could be cor-
related with improvements in consciousness, awareness, behavior, and cognition. Once
enough permutations of injuries with varying location and extent have been computa-
tionally analyzed, it is conceivable that data from a child with a new brain injury could be
entered into the system and modeled for how that injury pattern will evolve and recover.
This model would account for both normal brain development over time as well as the
variable neuronal plasticity that occurs during recovery from brain injury. The model may
be able to estimate, with some degree of certainty, the expected functional recovery of the
patient. This information would be valuable for parents struggling with clinical decisions
and determining goals of care that are in line with the values they have for their child.
These brain-​derived signals could also provide information regarding a child’s current
perception of their environment and their degree of discomfort, pain, or hunger. This
information could be transmitted to the medical team and family to improve clinical
 19

Envisioning future directions for neuroprognostication 191

care and shared decision-​making. A  variety of platforms could be used to convey this
information. Dramatic improvements in virtual reality technology have led to the ability
to simulate a 360-​degree representation of a space using a head-​mounted display and a
mobile phone. These systems have already been applied in medicine and the neurosci-
ences to help physicians and patients enhance their understanding of disease processes
and therapeutic options. For diseases such as multiple sclerosis and migraine headache,
three-​dimensional virtual reality systems allow entry into the central nervous system to
visualize how the immune system has become dysregulated and neuronal transmission
impaired. Procedural fields have used these platforms to demonstrate how catheter-​based
systems bore through blood clots or deploy stents. One could envision a scenario in
which information gleaned from neuromonitoring and functional neuroimaging tech-
niques could be uploaded onto a virtual reality platform to model a child’s perceptions
and awareness, and allow parents the opportunity to experience this for themselves. How
does the child perceive him-​or herself in the ICU? Is there pain? What brings pleasure
or comfort? While this simulated environment may generate intense emotional responses
from parents and family members, it may help clarify how they choose to apply the values
they have for their child when making medical decisions.
Further information about brain function may be available through depth electrodes
that can be surgically implanted in patients after severe acquired brain injury. These elec-
trodes have primarily been used for seizure focus localization in patients being evaluated
for epilepsy surgery, but more recently have been placed in patients after traumatic brain
injury or subarachnoid hemorrhage to screen for subclinical seizures (Claassen et  al.
2013; Vespa et al. 2016). Just as signals from these electrodes are more sensitive than rou-
tine scalp EEG to detect some types of seizures, these signals may carry additional infor-
mation about awareness or cognition that could be incorporated into functional models
and prediction algorithms.
By amalgamating these brain-​derived signals, one could also create a meaningful
interface that calculates not only the likelihood of overall survival, but answers crucial
questions that could influence clinical decisions during the acute and subacute phases of
injury. Will my child walk again after this injury? Will he or she regain consciousness?
Recognize me? Smile and interact with me? Speak and understand language? For some
parents, answers to these questions, even if delivered with some degree of uncertainty,
would help them make these unfathomable decisions. Finally, the groundbreaking work
with neural control of movement in animals and humans with powered prosthetics may
provide an opportunity to create translational communication devices for children with
disorders of consciousness. Such devices could truly facilitate communication of wants
and desires in patients with covert awareness from brain injury.
These platforms to convert neurally derived signals into tangible reality for physicians
and families are accompanied by considerable ethical considerations. While many of
these technologies are currently in the domain of science fiction, the rapid growth of the
neuroimaging and neuromonitoring fields may make these concepts plausible reality in
the near future. They would require extensive investigation and vetting in the research
192

192 Neuroprognostication after severe brain injury in children

domain prior to translation into the clinical arena. Additionally, these techniques will not
be without inherent limitations and caveats, and the generated data and user interface
will be susceptible to a wide spectrum of interpretation. Given the power of images and
their influence in medical decision-​making, it will be essential that families have a clear
understanding of exactly what they are and are not viewing (Racine et al. 2005, 2006).
Experiencing a virtual tour of their child’s severely injured brain with lack of neural con-
nections, abnormal neurotransmitter levels, and impaired blood flow, may be considered
emotionally manipulative and unethical if used with the intent to encourage withdrawal
of life-​sustaining therapies, in the case of, for example, a family with deeply religious
views valuing the preservation of life under any circumstances.

Conclusion
The neuroprognostication process is uncomfortable and anxiety provoking for many phy-
sicians. Conferring an overly optimistic prognosis may result in the prolonged survival of
a neurologically devastated child, while an overly pessimistic prediction may result in a
family withdrawing life-​sustaining therapies in a child with a potentially more favorable
neurologic outcome. The challenges associated with outcome prediction are increased
with young children, especially when a child has an underlying neurologic or neurode-
velopmental condition prior to brain injury. Predictions of neurologic outcome should
be evidence-based whenever possible; however, to date, no single clinical exam feature,
laboratory value, biomarker, or neuroimaging finding is highly reliable. Many intensivists
and neurologists have memorable patients for whom initial outcome prediction was inac-
curate, reaffirming both the challenging nature of the process and the incredible adapt-
ability of the pediatric brain after injury.
The patient described in the case scenario survived his drowning and cardiac arrest.
Several experienced physicians counseled the family about his poor prognosis for neuro-
logic recovery given the ischemic injury to his thalami bilaterally, and his failure to make
clinical improvements in the weeks after his injury. After months of intense inpatient
rehabilitation, he has returned to school and is performing near grade level with some
scholastic accommodations. He requires ongoing speech, physical, and occupational
therapies, and has a full-​time aid to help with his activities of daily living. His follow-​up
MRI showed sequelae of hypoxic-​ischemic injury, with abnormal signal in the periven-
tricular white matter and thalami bilaterally and generalized volume loss.
His example is not uncommon. While these types of patients illustrate the diffi-
culty physicians have in accurately predicting functional outcome within the gray
areas between a truly devastating brain injury and mild injury with minimal sequelae,
they are a constant reminder that improved technology is essential to aid the neu-
roprognostic process. Our ability to provide an accurate and timely estimation of
potential neurologic recovery directly impacts decision-​making during all phases of
injury. Functional neuroimaging provides a platform that may be able to detect covert
awareness, predict neurologic recovery, and allow seemingly unresponsive patients to
 193

References 193

communicate. This technique, however, is often not feasible during the acute phase of
injury due to the patient’s clinical instability. Future directions and technologies for
neuroprognostication may require synthesizing brain-​derived signals from multiple
sources and relaying that data to digital platforms easily accessible to physicians and
families. These emerging techniques are on the verge of transforming our perception
and understanding of human consciousness and cognition after severe brain injury.
The associated ethical considerations are immense and should be discussed prospec-
tively with stakeholders from both the medical community and the public. Clinical,
scientific, and ethical caution is needed as these evolving technologies transition from
science fiction to plausible reality.

References
Abend, N.S. and Licht, D.J. (2008). Predicting outcome in children with hypoxic ischemic
encephalopathy. Pediatric Critical Care Medicine, 9(1), 32–​39.
Abend, N.S., Topjian, A., Ichord, R., et al. (2009). Electroencephalographic monitoring during
hypothermia after pediatric cardiac arrest. Neurology, 72(22), 1931–​1940.
Achard, S., Salvador, R., Whitcher, B., Suckling, J., and Bullmore, E. (2006). A resilient, low-​frequency,
small-​world human brain functional network with highly connected association cortical hubs.
Journal of Neuroscience, 26(1), 63–​72.
Andrews, K., Murphy, L., Munday, R., and Littlewood, C. (1996). Misdiagnosis of the vegetative
state: retrospective study in a rehabilitation unit. BMJ, 313(7048), 13–​16.
Ashwal, S., Tong, K.A., Ghosh, N., Bartnik-​Olson, B., and Holshouser, B.A. (2014). Application of
advanced neuroimaging modalities in pediatric traumatic brain injury. Journal of Child Neurology,
29(12), 1704–​1717.
Bender, A., Jox, R.J., Grill, E., Straube, A., and Lule, D. (2015). Persistent vegetative state and
minimally conscious state: a systematic review and meta-​analysis of diagnostic procedures.
Deutsches Ärzteblatt International, 112(14), 235–​242.
Berger, R.P., Bazaco, M.C., Wagner, A.K., Kochanek, P.M., and Fabio, A. (2010). Trajectory analysis
of serum biomarker concentrations facilitates outcome prediction after pediatric traumatic and
hypoxemic brain injury. Developmental Neuroscience, 32(5-​6), 396–​405.
Calabro, R.S., Milardi, D., Cacciola, A., et al. (2016). Moving into the wide clinical spectrum of
consciousness disorders: pearls, perils and pitfalls. Medicina (Kaunas), 52(1), 11–​18.
Childs, N.L., Mercer, W.N., and Childs, H.W. (1993). Accuracy of diagnosis of persistent vegetative
state. Neurology, 43(8), 1465–​1467.
Claassen, J., Perotte, A., Albers, D., et al. (2013). Nonconvulsive seizures after subarachnoid
hemorrhage: multimodal detection and outcomes. Annals of Neurology, 74(1), 53–​64.
Di, H., Boly, M., Weng, X., Ledoux, D., and Laureys, S. (2008). Neuroimaging activation studies in the
vegetative state: predictors of recovery? Clinical Medicine (London), 8(5), 502–​507.
Diekema, D.S., Botkin, J.R., and Committee on Bioethics (2009). Clinical report: forgoing medically
provided nutrition and hydration in children. Pediatrics, 124(2), 813–​822.
Finley Caulfield, A., Gabler, L., Lansberg, M.G., et al. (2010). Outcome prediction in mechanically
ventilated neurologic patients by junior neurointensivists. Neurology, 74(14), 1096–​1101.
Fins, J.J. (2011). Neuroethics, neuroimaging, and disorders of consciousness: promise or peril?
Transactions of the American Clinical and Climatological Association, 122), 336–​346.
194

194 Neuroprognostication after severe brain injury in children

Fins, J.J., Illes, J., Bernat, J.L., Hirsch, J., Laureys, S., and Murphy, E. (2008). Neuroimaging and
disorders of consciousness: envisioning an ethical research agenda. American Journal of Bioethics,
8(9), 3–​12.
Giacino, J.T., Kalmar, K., and Whyte, J. (2004). The JFK Coma Recovery Scale-​Revised: measurement
characteristics and diagnostic utility. Archives of Physical Medicine and Rehabilitation, 85(12),
2020–​2029.
Giacino, J.T., Fins, J.J., Laureys, S., and Schiff, N.D. (2014). Disorders of consciousness after acquired
brain injury: the state of the science. Nature Reviews Neurology, 10(2), 99–​114.
Girotra, S., Spertus, J.A., Li, Y., et al. (2013). Survival trends in pediatric in-​hospital cardiac arrests: an
analysis from Get With the Guidelines-​Resuscitation. Circulation Cardiovascular Quality and
Outcomes, 6(1), 42–​49.
Greer, D.M., Rosenthal, E.S., and Wu, O. (2014). Neuroprognostication of hypoxic-​ischaemic coma in
the therapeutic hypothermia era. Nature Reviews Neurology, 10(4), 190–​203.
He, J.H., Yang, Y., Zhang, Y., et al. (2014). Hyperactive external awareness against hypoactive internal
awareness in disorders of consciousness using resting-​state functional MRI: highlighting the
involvement of visuo-​motor modulation. NMR in Biomedicine, 27(8), 880–​886.
Hindle, E.M., Dunn, M., Gillies, M., and Clegg, G. (2015). Neuroprognostication following out of
hospital cardiac arrest –​a retrospective study of departmental practice. Resuscitation, 94, e5–​6.
Holzer, M. (2002). Mild therapeutic hypothermia to improve the neurologic outcome after cardiac
arrest (Hypothermia after Cardiac Arrest Study Group). New England Journal of Medicine, 346(8),
549–​556.
Jox, R.J., Bernat, J.L., Laureys, S., and Racine, E. (2012). Disorders of consciousness: responding to
requests for novel diagnostic and therapeutic interventions. Lancet Neurology, 11(8), 732–​738.
Katz, D.I., Polyak, M., Coughlan, D., Nichols, M., and Roche, A. (2009). Natural history of recovery
from brain injury after prolonged disorders of consciousness: outcome of patients admitted to
inpatient rehabilitation with 1-​4 year follow-​up. Progress in Brain Research, 177, 73–​88.
Kessler, S.K., Topjian, A.A., Gutierrez-​Colina, A.M., et al. (2011). Short-​term outcome prediction by
electroencephalographic features in children treated with therapeutic hypothermia after cardiac
arrest. Neurocritical Care, 14(1), 37–​43.
Kirschen, M.P. and Feudtner, C. (2012). Ethical issues. In: Abend, N. and Helfaer, M. (Eds.) Pediatric
Neurocritical Care, pp.485–​493. New York: Demos Medical Publishing.
Kirschen, M.P. and Walter, J.K. (2015). Ethical issues in neuroprognostication after severe pediatric
brain injury. Seminars in Pediatric Neurology, 22(3), 187–​195.
Kirschen, M.P., Topjian, A.A., Hammond, R., Illes, J., and Abend, N.S. (2014). Neuroprognostication
after pediatric cardiac arrest. Pediatric Neurology, 51, 663–​668.
Kowalski, R.G., Buitrago, M.M., Duckworth, J., et al. (2015). Neuroanatomical predictors of awakening
in acutely comatose patients. Annals of Neurology, 77(5), 804–​816.
Laureys, S., Faymonville, M.E., Degueldre, C., et al. (2000). Auditory processing in the vegetative state.
Brain, 123 (Pt 8), 1589–​1601.
Laureys, S., Faymonville, M.E., Peigneux, P., et al. (2002). Cortical processing of noxious
somatosensory stimuli in the persistent vegetative state. NeuroImage, 17(2), 732–​741.
Liang, X., Zou, Q., He, Y., and Yang, Y. (2013). Coupling of functional connectivity and regional
cerebral blood flow reveals a physiological basis for network hubs of the human brain. Proceedings of
the National Academy of Sciences of the United States of America, 110(5), 1929–​1934.
Lutkenhoff, E.S., Chiang, J., Tshibanda, L., et al. (2015). Thalamic and extrathalamic mechanisms of
consciousness after severe brain injury. Annals of Neurology, 78(1), 68–​76.
Marcin, J.P., Pollack, M.M., Patel, K.M., Sprague, B.M., and Ruttimann, U.E. (1999). Prognostication
and certainty in the pediatric intensive care unit. Pediatrics, 104(4 Pt 1), 868–​873.
 195

References 195

Marcin, J.P., Pretzlaff, R.K., Pollack, M.M., Patel, K.M., and Ruttimann, U.E. (2004). Certainty and
mortality prediction in critically ill children. Journal of Medical Ethics, 30(3), 304–​307.
Michiels, E., Quan, L., Dumas, F., and Rea, T. (2016). Long-​term neurologic outcomes following
paediatric out-​of-​hospital cardiac arrest. Resuscitation, 102, 122–​126.
Moler, F.W., Silverstein, F.S., Holubkov, R., et al. (2015). Therapeutic hypothermia after out-​of-​hospital
cardiac arrest in children. New England Journal of Medicine, 372(20), 1898–​1908.
Monti, M.M., Vanhaudenhuyse, A., Coleman, M.R., et al. (2010). Willful modulation of brain activity
in disorders of consciousness. New England Journal of Medicine, 362(7), 579–​589.
Nicholas, C.R., Mclaren, D.G., Gawrysiak, M.J., Rogers, B.P., Dougherty, J.H., and Nash, M.R. (2014).
Functional neuroimaging of personally-​relevant stimuli in a paediatric case of impaired awareness.
Brain Injury, 28(8), 1135–​1138.
Nielsen, N., Wetterslev, J., Cronberg, T., et al. (2013). Targeted temperature management at 33
degrees C versus 36 degrees C after cardiac arrest. New England Journal of Medicine, 369(23),
2197–​2206.
Northoff, G. and Heiss, W.D. (2015). Why is the distinction between neural predispositions,
prerequisites, and correlates of the level of consciousness clinically relevant?: Functional brain
imaging in coma and vegetative state. Stroke, 46(4), 1147–​1151.
Owen, A.M. (2013). Detecting consciousness: a unique role for neuroimaging. Annual Review of
Psychology, 64, 109–​133.
Owen, A.M., Coleman, M.R., Boly, M., Davis, M.H., Laureys, S., and Pickard, J.D. (2006). Detecting
awareness in the vegetative state. Science, 313(5792), 1402.
Perman, S.M., Kirkpatrick, J.N., Reitsma, A.M., et al. (2012). Timing of neuroprognostication in
postcardiac arrest therapeutic hypothermia. Critical Care Medicine, 40(3), 719–​724.
Racine, E. and Bell, E. (2008). Clinical and public translation of neuroimaging research in disorders of
consciousness challenges current diagnostic and public understanding paradigms. American Journal
of Bioethics, 8(9), 13–​15.
Racine, E., Bar-​Ilan, O., and Illes, J. (2005). fMRI in the public eye. Nature Reviews Neuroscience, 6(2),
159–​164.
Racine, E., Bar-​Ilan, O., and Illes, J. (2006). Brain imaging: a decade of coverage in the print media.
Science Communication, 28(1), 122–​142.
Racine, E., Dion, M.J., Wijman, C.A., Illes, J., and Lansberg, M.G. (2009). Profiles of neurological
outcome prediction among intensivists. Neurocritical Care, 11(3), 345–​352.
Roberts, R.M., Mathias, J.L., and Rose, S.E. (2014). Diffusion tensor imaging (DTI) findings
following pediatric non-​penetrating TBI: a meta-​analysis. Developmental Neuropsychology ,
39(8), 600–​637.
Sandroni, C. and Nolan, J.P. (2015). Neuroprognostication after cardiac arrest in Europe: new timings
and standards. Resuscitation, 90, A4–​5.
Sandroni, C., Cariou, A., Cavallaro, F., et al. (2014). Prognostication in comatose survivors of cardiac
arrest: an advisory statement from the European Resuscitation Council and the European Society of
Intensive Care Medicine. Resuscitation, 85(12), 1779–​1789.
Schiff, N.D., Rodriguez-​Moreno, D., Kamal, A., et al. (2005). fMRI reveals large-​scale network
activation in minimally conscious patients. Neurology, 64(3), 514–​523.
Schnakers, C., Vanhaudenhuyse, A., Giacino, J., et al. (2009). Diagnostic accuracy of the vegetative and
minimally conscious state: clinical consensus versus standardized neurobehavioral assessment. BMC
Neurology, 9, 35.
Starling, R.M., Shekdar, K., Licht, D., Nadkarni, V.M., Berg, R.A., and Topjian, A.A. (2015). Early
head CT findings are associated with outcomes after pediatric out-​of-​hospital cardiac arrest.
Pediatric Critical Care Medicine, 16(6), 542–​548.
196

196 Neuroprognostication after severe brain injury in children

Tomasi, D., Wang, G.J., and Volkow, N.D. (2013). Energetic cost of brain functional connectivity.
Proceedings of the National Academy of Sciences of the United States of America, 110(33),
13642–​13647.
Tononi, G. (2004). An information integration theory of consciousness. BMC Neuroscience, 5, 42.
Tononi, G. and Koch, C. (2008). The neural correlates of consciousness: an update. Annals of the
New York Academy of Sciences, 1124, 239–​261.
Topjian, A.A., Lin, R., Morris, M.C., et al. (2009). Neuron-​specific enolase and S-​100B are associated
with neurologic outcome after pediatric cardiac arrest. Pediatric Critical Care Medicine, 10(4),
479–​490.
Topjian, A.A., Berg, R.A., and Nadkarni, V.M. (2013). Advances in recognition, resuscitation, and
stabilization of the critically ill child. Pediatric Clinics of North America, 60(3), 605–​620.
Topjian, A.A., French, B., Sutton, R.M., et al. (2014). Early postresuscitation hypotension is associated
with increased mortality following pediatric cardiac arrest. Critical Care Medicine, 42(6), 1518–​1523.
Topjian, A.A., Sanchez, S.M., Shults, J., Berg, R.A., Dlugos, D.J., and Abend, N.S. (2016). Early
electroencephalographic background features predict outcomes in children resuscitated from
cardiac arrest. Pediatric Critical Care Medicine, 17(6), 547–​557.
Van Zellem, L., Utens, E.M., Legerstee, J.S., et al. (2015). Cardiac arrest in children: long-​term health
status and health-​related quality of life. Pediatric Critical Care Medicine, 16(8), 693–​702.
Vespa, P., Tubi, M., Claassen, J., et al. (2016). Metabolic crisis occurs with seizures and periodic
discharges after brain trauma. Annals of Neurology, 79(4), 579–​590.
Wang, F., Di, H., Hu, X., et al. (2015). Cerebral response to subject’s own name showed high prognostic
value in traumatic vegetative state. BMC Medicine, 13, 83.
Weijer, C., Peterson, A., Webster, F., et al. (2014). Ethics of neuroimaging after serious brain injury.
BMC Medical Ethics, 15, 41.
Wijdicks, E.F., Hijdra, A., Young, G.B., Bassetti, C.L., and Wiebe, S. (2006). Practice
parameter: prediction of outcome in comatose survivors after cardiopulmonary resuscitation (an
evidence-​based review): report of the Quality Standards Subcommittee of the American Academy of
Neurology. Neurology, 67(2), 203–​210.
Wilkinson, D. (2009). The window of opportunity: decision theory and the timing of prognostic tests
for newborn infants. Bioethics, 23(9), 503–​514.
Wilkinson, D. (2011). The window of opportunity for treatment withdrawal. Archives of Pediatrics and
Adolescent Medicine, 165(3), 211–​215.
Wilkinson, D.J., Kahane, G., Horne, M., and Savulescu, J. (2009). Functional neuroimaging and
withdrawal of life-​sustaining treatment from vegetative patients. Journal of Medical Ethics, 35(8),
508–​511.
Wilson, F.C., Harpur, J., Watson, T., and Morrow, J.I. (2002). Vegetative state and minimally
responsive patients –​regional survey, long-​term case outcomes and service recommendations.
NeuroRehabilitation, 17(3), 231–​236.
Wintermark, M., Coombs, L., Druzgal, T.J., et al. (2015a). Traumatic brain injury imaging research
roadmap. AJNR American Journal of Neuroradiology, 36(3), E12–​23.
Wintermark, M., Sanelli, P.C., Anzai, Y., et al. (2015b). Imaging evidence and recommendations for
traumatic brain injury: conventional neuroimaging techniques. Journal of the American College of
Radiology, 12(2), e1–​14.
Wu, X., Zou, Q., Hu, J., et al. (2015). Intrinsic functional connectivity patterns predict
consciousness level and recovery outcome in acquired brain injury. Journal of Neuroscience,
35(37), 12932–​12946.
 197

Chapter 11

No pain no gain: A neuroethical place

for hypnosis in invasive intervention
Elvira V. Lang

A true story
A magnetic resonance imaging (MRI) technologist, let’s call her AX, who had been
trained in nonpharmacologic sedation techniques to help her claustrophobic patients
through their tests, needed treatment of her varicose veins. Her vascular specialist was
to use a minimally invasive procedure during which a laser or radiofrequency probe is
inserted in the vein to heat its inner lining and damage the vessel wall so that it closes
off. To ease the sensation, local anesthetic is applied sequentially along the entire course
of the vein from the groin level down to below the knee. AX wanted to be comfortable
and brought with her a colleague who had been trained in the same nonpharmacologic
sedation techniques with which she was familiar. The doctor clearly did not want AX’s
colleague in the procedure room. He kept warning AX that the local anesthetic would
be stinging and burning—​repeating the expectations of hurt even after AX asked him to
not use such wording since it was not helpful, and that she was prepared for the proce-
dure. The doctor couldn’t help himself and kept insisting that things would hurt until AX
looked directly at him and told him, “You got this all wrong. I will just experience a deli-
cious sense of tingling.” This had the desired effect and the doctor became and remained
silent. The procedure continued uneventfully and AX was proud of having been able to
help herself.
This short interaction harbors ethics considerations which may even be at odds with
each other depending on whether one analyzes the scenario from the point of moral-
ity ethics, concerning right or wrong behaviors, general societal belief systems, bioethics
used by medical review boards in terms of beneficence/​maleficence, risk/​liability of vari-
ous approaches, and professional standard of care based on prevailing values and prac-
tices. Further dilemmas arise when beliefs and expectations of patient and healthcare
professional clash with each other and with scientific evidence, societal norms, or observ-
able behaviors. This chapter examines how such interrelationships can shape the experi-
ence of acute pain versus comfort during medical procedures. Can there be gain without
pain? Should there be?
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198 No pain no gain

Talking about pain
“Will it hurt?” How this question, whether asked or implied, is handled from the point of
view of the recipient and the purveyor of potentially painful stimuli is deeply rooted in
belief systems and cultures of practice. Introducing upcoming stimuli with wording such
as, “This shouldn’t hurt that much,” or “It’s just like a bee sting,” “This is going to be the
worst part,” “A stick and a burn,” or sympathizing, “That wasn’t that bad?” are rampant in
the medical environment and produce the opposite effect—​more pain (Blankfield 1991;
Lang et al. 2005; Cyna & Lang 2011). Research has shown that using the word “pain” or
other verbiage with negative emotional content such as “sting” or” burn” will significantly
increase pain and anxiety, even when preceded by “not much” or “little” (Lang et al. 2005).
The mind is only able to call upon the image of something, not of nothing, just as one can
imagine bananas but not no-​bananas. Even if I were to tell you not to think of bananas
(or pink elephants), their image and perhaps some appetite for bananas may have come to
mind even though I suggested not to think of such.
Implicitly, the use of such negative suggestions before and during potentially uncomfort-
able procedures is sanctioned by the lack of official guidelines by professional governance
bodies to replace it with more positive suggestions (Blease 2012). One should think that
by inflicting more pain through one action as compared to another less hurtful one vio-
lates the medical ethics principle of nonmaleficence: to do no harm. In clinical practice,
the maleficence potential is to be balanced against the beneficence principle: is the risk of
greater harm justified by a greater good? In the case of negative suggestions this is not the
case, at least not for the patient. So why is the use of negative suggestions so common?
There are various reasons that words and phrases with negative emotional content have
become embedded in the vocabulary of many frontline medical caregivers. For some, it
may be a desire to be perfectly honest with the patient along a general ethical principle
of full disclosure. One procedure nurse once told me she likes to describe the upcom-
ing procedure as more painful since she knows it is not the case and the patient will be
relieved and feel good about the experience (an aspect of beneficence) as well as thank her
for great care (a more questionable motive). Practitioners may truly believe, from training
or experience, that the patient will feel pain and it is only fair to give forewarning. Feeling
it then as a duty to warn the patient of the upcoming hurt and finding confirmation in
the resulting report (more pain than if nothing had been said) will tend to perpetuate the
belief in the need for warning in the future. It may even cause the practitioner to increase
the negatively worded warning thus perpetuating and driving up the spiral of healthcare
provider-​induced pain.
Familiarity with routine ways of eliciting a response from patients about their experi-
ence of pain may be another powerful reason that practices do not change. Nurses and
other medical personnel are required to query patients about their pain levels (Joint
Commission on Accreditation of Healthcare Organizations 2016). Typically 0–​10 pain
scales are used. To make sure patients know about these instruments they may contain
bright red pointers, a bold header such as “Pain Assessment Tool,” and may be prominently
 19

Expecting and experiencing pain 199

posted in the treatment areas. The intent of better pain assessments in the hospital and
ambulatory environment was a good one—​to reduce suffering; the choice of advertise-
ment of these instruments in clinical practice, however, may lead to the opposite effect.
There are simple solutions to the beneficence/​nonmaleficence equation for this aspect.
One study that assessed whether asking patients instead for their comfort levels after
cesarean section found that this simple change in wording resulted in the women also
reporting their overall postoperative experience as less bothersome or unpleasant com-
pared to those being asked to rate their pain (Chooi et al. 2013). In the clinical trials I was
involved with, we would introduce the customary hospital 0–​10 pain scale with the ques-
tion, “How is your comfort level on a scale of 0–​10 with 0=no pain at all and 10= worst
possible.” At least this avoided setting an expectation that there should be pain. AX’s story
also highlights what may happen when expectations of pain are at a variance between
healthcare/​stimulus provider and recipient thereof. Do patients have a right to their own
experience? Do they, as has happened in the case, have to be convinced that they are
“wrong” and that it will hurt even when they present with a declared set of anodyne skills
in which the provider does not believe or is unfamiliar with? Is it ok to trust the patient’s
perceptions even if they run counter to the provider’s beliefs?

Expecting and experiencing pain

Feeling pain is not a static or predictable experience. The same type of stimulus or medi-
cal condition does not provoke the same sensation of hurt in different people (Burgstaller
et al. 2016). Thus the same level of tissue injury or physical severity of stimulus may lead
to a response of 8 out of 10 in one person and a response of 2 out of 10 in another.
Functional brain imaging has shown the patient’s self-​report of pain in terms of suffering
or being affected by the sensation correlates well with activation of pain-​related process-
ing in their brain (Peyron et al. 2000; Hayashi et al. 2016). Patients’ self-​reports of pain
thus should be trusted.
The pain experience depends on a variety of factors. Beside the stimulus intensity, set-
ting, meaning, and expectations play a considerable role and their effect also can be docu-
mented with neuroimaging (Atlas & Wager 2012). Words can be powerful in shaping a
negative experience as pointed out earlier. Words can also be powerful in shaping positive
expectations. A recent meta-​analysis showed moderate to large effect sizes on reduction
of experienced acute pain after verbal suggestions that promoted expectations of pain
relief (Peerdeman et al. 2016). Effects were particularly prominent when associated with
an active treatment such as placing an intravenous (IV) line or needles. Such verbal sug-
gestions surrounding pain expectations have been shown just by themselves to produce
associated changes in pain-​related brain activity and connectivity that then subsequently
diminish the negative effects of painful stimuli (Hashmi et al. 2014).
Societal norms or individual perceptions can create beliefs of “no pain, no gain.” The term
is particularly prized in the fitness movement where sufferance and feeling the burn are
valued on the road to the ideal body sculpt and physical/​mental toughness. Furthermore,
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200 No pain no gain

aspects of the Puritan legacy may lead to the consideration of pain as deserved, and
attempts to alleviate suffering as moral weakness (Kilwein 1989). While individuals are
free to choose their actions, the situation becomes ethically more challenging when the
standards of the community or healthcare professionals are forced on individual patients,
and when hurtful approaches are rationalized on moral-​ethical grounds.
When an individual who is engaged in researching and learning skills in how to adapt
expectations positively encounters a healthcare professional with a different perception
of what is appropriate (such as AX and the doctor in our story) both may be behaving
morally and true to their convictions even though in this case the patient is subjected to
maleficence based on research evidence. Conversely, when a patient’s beliefs embrace a
high-​risk approach, inappropriate in the eye of conventional medicine—​such as refusing
blood transfusions or antibiotics for fear of spiritual/​religious doom—​how much physical
sufferance is acceptable for the higher spiritual good? Lawsuits and ethics boards struggle
over these questions and often there are no good answers. On occasion, it may even be
that the aversion of a professional caregiver to inflict pain at all is in the gray area of what
is ethically justifiable and what is not.

Inflicting pain
Is it ethical to inflict pain? Having been an interventional radiologist all my life, perform-
ing image-​guided surgery on mostly awake patients, it is clear that it is sometimes neces-
sary to violate tissue boundaries to be able to proceed with treatment. Even just applying
lidocaine can be interpreted as painful by the patient. Again, belief systems will dictate
whether avoiding potential pain altogether is justifiable, thereby making oneself feel good,
while letting a treatable condition go untreated and endangering a patient’s health or life.
The ethical solution could be to not choose a profession where this may be a dilemma
but there is also an ethical consideration to having only the disinhibited provide care.
Certainly history has sufficient examples of atrocious behavior of physicians for the sake
of science.
What of the dentist who is a soft-​hearted individual who will only proceed if the local
anesthetic produces complete numbness? I had the unfortunate experience to observe
this when my husband, who in the beginning cloud of Alzheimer’s, wasn’t able to clearly
distinguish between pressure and hurt when tested with a clanking instrument on a tooth
fragment to be extracted. It was very clear that all would have been fine, based on a prior
visit he had to the same dentist, and with me being there with him. However, the dentist
was so scared that it would hurt that he would not do the extraction and let an underly-
ing abscess smolder for another day until a colleague at a different practice was able to
achieve the goal.

The pitfalls of empathy

Modern medical training highly stresses empathy; to feel for a patient is presumed to be
the sign of a good provider. As a shared sense of suffering, empathy can even be found
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Reducing the pain of others 201

in laboratory animals and is present to varying degrees in humans (Singer et  al. 2004;
Goubert et al. 2005; Mogil 2012; Chen et al. 2015). Higher levels of empathy, however, do
not necessarily produce better medical outcomes. In a study with nurses in cardiovascular
units, levels of empathy among the staff did not correlate with patients’ pain perception or
the amount of medication administered (Watt-​Watson et al. 2000). Misbeliefs and associ-
ated behavior were independent of the nurses’ levels of empathy.
Seeing another person suffer may result in either withdrawal from the situation to avert
one’s own suffering, or behaviors that may be considered helpful in the given cultural
environment but in themselves can be deleterious. We once had to halt a clinical trial
because patients in the empathic attention control group had significantly more adverse
events than those patients either left alone or supported with guidance in the self-​hypnotic
relaxation group (Lang et al. 2008). Review of taped interactions between providers and
patients suggested that increased efforts of being nice likely provided more distraction
from the patient’s own internal coping mechanisms or may have signaled that things were
more risky than perhaps portrayed, keeping adrenergic stimulation up. Thus just feeling
for someone, as desirable, ethical, and humanly noble as this might be, not knowing how
to express it may actually be hurtful.
In the context of this study I recall a taped interaction in which one of the nurses
approached the patient on the procedure table and kindly stroked his hair. The psycholo-
gist on the team pointed out that such an approach should be avoided since it placed the
patient at a child-​like level and, in addition, risked potentially evoking past abuse. After
all, we worked in a setting ideally suited to elicit such a memory: a darkened interven-
tional radiology lab with the patient naked under surgical drapes, immobilized, and with
little control while the procedure determined health and well-​being. I also recall how dif-
ficult it was to convince the nursing staff that this was not great care and that unsolicited
touching or touching without obtaining permission was inappropriate. It was a case of
reducing the risk of the patient feeling uncomfortable or reliving old trauma versus the
beneficence of good intentions in the hope of improving the experience through touch.

Reducing the pain of others

When going to the dentist, having surgery, or preparing for any other medical procedure,
have you ever wondered who determines whether and how much drug you receive for
managing pain and anxiety? You might think that your needs or your doctor’s are the
critical factors but that is not necessarily the case. A study in which the same physicians
performed the same procedure for evaluation of the blood vessels with the same protocols
at three different hospitals was able to illustrate that the culture of an institution is the
overriding factor (Lang et al. 1998). The nursing staff did not rotate among the hospitals
and supposedly was to provide medications under the umbrella of physician’s orders. The
amount of intravenous drugs given was relatively constant within any given hospital but
significantly different among hospitals varying by a factor of as much as 3 with regard to
pain medication. There was no correlation with patients’ age, sex, medical condition, or
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202 No pain no gain

physician identity, or with patients’ levels of pain and anxiety. One might conclude that
local hospital culture or habit was the driving force. This approach bears the risk of over-
medicating individuals whose metabolism and constitution is sensitive to small dosages
of sedatives and analgesics, with possibly fatal or serious adverse effects on breathing and
blood pressure, and undertreating individuals who either experience greater pain and
who need more medication for the same amount of pain relief.
The wide variety in the approach to drug usage for pain management during medi-
cal procedures is not limited to healthcare providers (McDermott et al. 1993) but is also
reflected in patient expectations. Patients risk not to be given enough credence when,
based on their own biases, healthcare professionals expect a different response in terms of
pain severity as the one the patient indicated. Higher than expected pain ratings from the
patient may be interpreted as drug-​seeking behavior and withholding of needed medica-
tion, or possibly even as personal offense when the patient indicates pain but refuses drugs.
The medically ethical approach for a caregiver to minimize sufferance would be to be
responsive to the patients’ needs rather than one’s own assumptions. Ethical behavior,
though, relies on rational decisions. Encounters with nursing staff having to perform
repeated painful dressing changes on author Dan Ariely in his youth led him to research
human decision-​making in this setting and become a major contributor to the field of
behavioral economics (Ariely 2010). He concluded that humans behave predictably
irrationally—​a feature well exploited by the advertising industry. He describes his experi-
ence that the nurses tended to rather quickly rip the bandages off his heavily burnt skin
rather than removing them slowly from the edges. They believed that a short spike in
excruciating pain was better for the patient than a lengthier but less severe approach.
There was no scientific evidence behind the nurses’ behavior who were in general kind
and generous individuals. Even when years later he presented scientific evidence based
on his own experiments that people feel less pain when treatments are carried out with
lower intensity and longer duration, no change in practice ensued. When he asked one of
his more trusted nurses for a reason, she explained that pulling the bandages fast might
be more understandable if it were indeed the nurses’ way of shortening their own tor-
ment. Even after the discussion produced agreement that practice should be changed on
the burn unit, the change never happened. The nurses, with all their experience and true
compassion for their patients, kept misunderstanding the consequences of their behav-
iors and repeatedly made the wrong irrational decisions for their patients.
Pain management goes to the core of the self of healthcare professionals who often
choose their vocations for wanting to help others and the biases emerge along the way
through personal experience, customary behaviors, and social norms in their respec-
tive environments. However, convictions about specific approaches run deep. I had the
opportunity to observe the interpersonal clashes after a hospital merger when staff from
two interventional radiology units had to work together. One team had been used to
injecting relatively large amounts of sedatives and narcotics for procedures, the other
relatively smaller amounts. Nursing staff of the lower-​use site would accuse their col-
leagues of being drug pushers and the nursing staff of the higher-​use site would return the
 203

Societal influence 203

compliment by accusations of lack of caring. The fact that, as division chief, I introduced
nonpharmacologic adjuncts to pain management only helped insofar as forming an alli-
ance of high-​and low-​users against this new threat to entrained practice patterns. It took
about half a year and weekly meetings supported by the hospitals’ skilled organizational
development facilitators to arrive at a new common and patient-​centered practice.

Societal influence
In years past, most medical procedures and treatments were ordered by a physician and
carried out in an appropriate hospital or office setting with very little consultation with
the patient. What was offered was accepted as necessary, including any accompanying
pain or discomfort. The attitude that the doctor knows best has eroded and the belief that
the healthcare system will provide what is best for the patient has been largely shattered.
Social norms, based on mutual trust between healthcare providers and recipients, are
increasingly being replaced by material norms, expectations of quality outcomes in return
of value for healthcare expenditures.
With healthcare reform in the United States and focus on National Quality Strategies,
patients are being considered more as consumers, clients, and customers (Van Fleet &
Peterson 2016), a concept that is clearly uncomfortable for some healthcare profession-
als (Leng 2015). However, the switch to a consumer’s market has pushed the element
of patient satisfaction into the forefront of various tools that evaluate medical facilities,
including those used by the Centers for Medicare and Medicaid Services (CMS) when
weighing reimbursement to hospitals for patient care (Centers for Medicare and Medicaid
Services 2009, 2011). In the United States, patient satisfaction rankings contribute 30% to
the overall quality scores. Hospitals ranking below the 50th national percentile are fined
1–​2% of all payments through CMS, which is significant considering hospital margins
commonly range between 1% and 5%.
Pain management and communication play prominently in the US patient satisfac-
tion surveys (Lang et al. 2013). Questions include “How often was your pain well con-
trolled?” “How often did the hospital staff do everything they could to help you with
your pain?” The emphasis on “everything” acknowledges that drugs are not the only way
opening the way to include nonpharmacologic approaches. Effective January 1, 2015, the
Joint Commission on Accreditation of Healthcare Organizations clarified its Standard
PC.01.02.07 on managing patient’s pain in that both pharmacologic and nonpharmaco-
logic strategies have a role in the management of pain.
The new emphasis on nonpharmacologic adjuncts is driven in part by the opioid epi-
demic. In 2014, opioids killed more than 28,000 people in the United States alone, with
more than half involving prescription drugs (Centers for Disease Control and Prevention
2016). With greater pressure on medical professionals to see more patients in less time,
it is often easier to prescribe large amounts of narcotics rather than to sit and discuss
what else may work to improve comfort after dental or other surgery and risk a possible
subsequent unreimbursed call or repeat visit of the same patient. Recent laws that attempt
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204 No pain no gain

to prohibit prescription of narcotics beyond a certain number of days can be helpful in

preventing overdoses but at the same time also risk leaving patients in need of them, such
as terminal cancer patients stranded in how to get their prescriptions weekly from the
pharmacy. Education in pain and opioid management is now mandatory in many states,
an example of how legal pressure can lead practitioners to engage in socially and morally
responsible behavior. At least this requires them to understand about the problem and
learn new skills to fix it.

Changing the dynamics of pain

During medical procedures and tests, pain increases linearly over time relatively indepen-
dent of stimulus severity and the amount of drugs given (Lang et al. 2014). The increase in
pain over time may be explained by several mechanisms. In a setting of ambiguity, human
nature tends to choose the worst possible interpretation born out of a protective mecha-
nism of the subconscious (Ewin & Eimer 2006). Once a painful stimulus has occurred,
one also tends to be more attentive to external cues that could indicate pain even when
there is none (Bayer et al. 1998). Expectation then further shapes pain-​intensity process-
ing in the brain (Atlas & Wager 2012). If expectation is changed based on cues of a prior
pain experience, neurobiological changes in the brain take place in the pain-​related cir-
cuitry, such that stimuli that come with suggestions of hurt will be experienced more
painfully than when preceded by nonpainful stimuli or absence of cues of pain (Keltner
et al. 2006; Atlas et al. 2010). At the same time, brain regions are activated that are not only
associated with pain perception but also affected by processes such as conflict, negative
affect, and response inhibition (Atlas & Wager 2012).
Thus by changing expectations or other mechanisms of pain processing, a more com-
fortable experience may be created. As research with three large-​scale prospective ran-
domized trials demonstrated, it is possible to reframe the mind’s approach to processing
events during medical procedures through relatively simple means at the onset of the
interaction (Lang et  al. 2000, 2006, 2008). Using advanced rapport and a 1–​3-​minute
script at the time patients were brought into their procedure suite prevented the process-
ing that led to an increase of pain over time, remaining effective even for hours of proce-
dure time to come. The effectiveness of a combination of positive-​type suggestions and
guidance in hypnotic or imagery-​focused techniques has also been shown by other inves-
tigators (Kroger & DeLee 1957; Weinstein & Au 1991; Everett et al. 1993; Faymonville
et al. 1995; Meurisse et al. 1999; Montgomery et al. 2002; Liossi & Hatira 2003; Kupers
et al. 2005; Elkins et al. 2006; Liossi et al. 2006; Montgomery et al. 2007). One may thus
wonder why these techniques are not used more broadly?

Shaping the experience
The proverbial term of the white coat trance, with the associated higher blood pressure
and heart rate is an indication that the medical encounter itself produces a state of height-
ened suggestibility. One can consider the patient to be already in a state of self-​hypnosis
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Shaping the experience 205

and being highly susceptible to everything that is said or not being said or the suggestive
power of external cues. Thus, just as any negatively voiced statement or negative sugges-
tion can make the experience worse in the sense of a nocebo, mere avoidance of such
negative suggestions improves the experience, and helpful suggestions can improve the
experience just as the expectations coming with placebo treatment.
Of particular benefit is the fact, as shown in our studies, that shaping the patient’s expe-
rience at the onset of the provider interaction is the critical step and may be all that is
needed, even for procedures that last for hours (Lang et al. 2000, 2006, 2008). The ele-
ments of this process are rapport, relaxation, and reframing in conjunction with aware-
ness of what is said, injection of hypnoidal language, and, depending on the need of the
situation, reading of a formal self-​hypnotic relaxation script or comparative unscripted
induction of a relaxed state.
One truly does not know how a patient will experience a stimulus or treatment, and
there is the tendency to project one’s own expectations onto the other person in concor-
dance with one’s own belief system. In going further to assess how the patient’s pain expe-
rience can be improved, we found that the very first step is to establish rapport. Once in
rapport, it makes it much easier to communicate and find the right words spontaneously
and without awkwardness (Marchant 2016). For this reason we place heavy emphasis on
advanced rapport skills when training medical teams in nonpharmacologic calmative and
analgesic techniques (Lang 2012; Norbash et al. 2016).
Advanced rapport skills entail adapting to the patient’s body position, for example,
bending over toward sitting patients, but may also mean adapting to their emotional state,
such as speaking louder or in an agitated manner if they do so, or softer if they are more
subdued and then lead by modeling to a more resourceful state (Lang & Laser 2009). The
same methods are found in some of the sales literature (Boothman 2010) and the question
is often raised during workshops we give to medical professionals whether this would not
be manipulative and therefore unethical.
Often the individuals that object the most to intentional matching with another person
are the ones who do so very naturally on their own. Is it unethical to do something inten-
tionally that one does by natural instinct? The answer will most likely be in the intent of
the outcome, whether to deceive or to help. However, an interesting phenomenon hap-
pens in that regard. People who match each other, whether intentionally or not, are in
rapport and are more open to each other’s suggestions and leads. So even if one may start
with less than best intentions, being so-​to-​speak willing to walk in the other person’s
shoes may produce a better mutual understanding than intentional lack of matching.
Feelings and external expression thereof are interrelated. For example, the application
of botulinum toxin (Botox®) into the forehead muscles above the nose, mainly done for
cosmetic reasons, has been found to have as a side effect the reduction in depression of
the recipient, giving credence to a facial feedback mechanism on emotion (Wollmer et al.
2014). Furthermore, the facial expression of one person will affect the conversation part-
ner in the sense of an emotional contagion (Hatfield & Cacioppo 1994). What may start as
mimicry or matching ends as feeling in similar ways. If done intentionally, thus one could
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206 No pain no gain

make another person feel worse, which could ethically be considered as objectionable, or
make the other person feel better. However, when this requires an intentional effort, as we
find in our training, it tends to be interpreted as more manipulative when done to make a
patient feel more resourceful, as compared to when executed without noticing by radiat-
ing off the stress from work and making other people feel equally stressed.

Language
In the interest of full disclosure, consenting and listing of side effects of treatments has to
be honest to enable a person to determine which risk ratio to accept with a treatment as
compared to no treatment or alternative treatment. If done in a collaborative approach,
discussing what will be done to manage potential complications and what omission of
proceeding may evoke with the same conditions, patients can arrive at a decision that feels
right for them (Lang 2014b). After the medical consent is given, full focus on avoidance
of nocebo effects and use of more positive language is in order. How can this be achieved
in practical terms?
Avoiding upfront use of verbiage with negative emotional content is a first step. Use
of neutral statements such as, “I will give you the local anesthetic,” is a further step up
the comfort ladder, and mentioning the likelihood of a reasonably expectable desirable
outcome can help even further, such as, “I will give you the anesthetic and the area should
become numb shortly” (Lang et al. 2005; Dutt-​Gupta et al. 2007; Varelmann et al. 2010).
Consider the difference between such a statement and “I will stick you with a needle”
(Lang 2014a).
At the other end of the suggestive spectrum are placebo statements that are known to
the user to be untrue and may constitute a moral dilemma. One of the most impressive
demonstrations of placebo, where need and belief coincide in a powerful combination,
occurred at the warfront in World War II when Henry Beecher ran out of morphine while
treating wounded American soldiers. Desperate to be supportive, nurses would inject
saline, describing it as a potent pain killer. It worked in about 40% of the cases.
With regard to the use of placebo, the American Medical Association urges practitio-
ners to be “extremely thorough in obtaining consent from patients” (American Medical
Association 1997) echoed by the ethics code of the UK General Medical Council equally
insisting on complete openness. Blease argues that medical treatment always occurs in the
framework of interpersonal interactions between staff and patients and is influenced by
the beliefs of those involved in the power of the treatment thus making the term “positive
care effects” more appropriate than “placebo effect” (Blease 2012). “Positive care effects”
may also take away the stigma that some perceive to be associated with a “sugar pill” or an
element of deception. Although the literature suggests that even open labeling of placebo,
for example revealing the placebo nature of a treatment doesn’t interfere with its success
in pain management and can still result in a 50% success rate (Kam-​Hansen et al. 2014).
One can see how the element of known deception in some placebo approaches could
interfere with the patient–​provider relationship. After all, one really doesn’t know what
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Procedure hypnosis 207

the patient will experience and thus it is wise to avoid suggesting that something will
not or does not hurt or feel in a particular way. One way around this dilemma is the
use of permissive language leaving options for an outcome, indications that something,
for example, “might happen,” “could happen,” or “would be interesting to notice.” This
approach is often associated with Milton Erickson a psychiatrist and psychologist who
greatly shaped modern hypnosis. The permissive approach avoids the possibility that a
prediction fails and thereby undermines the trust a patient may have in the healthcare
professional. It also adheres to a dictum in my own practice, to leave to the patients the
right to their own experience. On the spectrum between purely neutral descriptors to the
possible integration of stimuli in a deeper hypnotic experience is a language approach
I like to call hypnoidal language. It is still fairly conversational while moving suggestions
up to the next level of desired outcomes. Giving a choice, “Would you prefer the IV on
the right arm or the left arm?” gives the patient a sense of control that otherwise may be
lacking. Double binds target a combination of desired results but leave the perception of
a choice without being authoritarian: “Some people first close their eyes, then they relax;
others first relax then close their eyes.” A sentence using presupposition of outcome in
response to a patient’s complaint may be, “I don’t know when it will stop hurting, in a
minute, in two minutes, in three minutes, or … NOW [emphasized].”
Offering choices for an experience can serve as a distraction by occupying the mind
about what the sensation might be, thereby leading away from the more catastrophizing
expectations, “You might feel some warmth or coolness, and then it should become numb
where it needs to be.” Including confusional elements can further help to take the mind
off spinning around negative recurring thoughts. As such we use in our script or when
announcing injections something like, “You might feel some warmth, or coolness. And
some people even describe a delicious sense of tingling.” The issue is that nobody really
knows how a delicious sense of tingling feels, and the statement is sufficiently surprising
that it helps to end unhelpful interactions, whether when voiced by the healthcare profes-
sional or by the patient, as in the example with AX above. Since AX’s report I have had to
use the “delicious tingling” reference myself once with a surgeon treating me in a similar
scenario and I can attest that it does shut off unwelcome negative suggestions by others.
Should we have asked our doctors’ consent to such confusional induction to reset their
own fears? Having requested them to stop in their unhelpful predictions of discomfort
should have sufficed, and by the time a procedure is started one can assume all partici-
pants are already in a trance-​like state.

Procedure hypnosis
Going one step further when guiding patients in nonpharmacologic pain and anxiety
management is to have the patient associate with a pleasant scenario and integrate all
stimuli. This tends to be mostly acceptable as long as it is called imagery, visualization, or
meditation, but beware of using the word that actually would describe it best, “hypnosis,”
a state of focused concentration where awareness of outside stimuli become muted. To
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208 No pain no gain

distinguish such use of language from hypnotherapy, where psychotherapy is bundled

with hypnosis, I  prefer the term “procedure hypnosis” as a practice limited to health-
care professionals who routinely engage in “sedation without medication” in their daily
practice.
There is considerable uproar in the American Society of Clinical Hypnosis (ASCH)
about the use of “lay” hypnosis. The idea is that nobody except a mental healthcare
professional, social worker, doctor, or master’s degree nurse should be trained even in
basic skills that could help their patients through everyday procedures. Thus, the front-
line providers of medical care such as nurses, medical technologists (such as AX whom
I trained), and first responders who deal on a daily basis with highly distressed patients
not only should not be allowed to be trained, but anyone who would train them would
be charged with unethical behavior and expelled from the ASCH. The Society of Clinical
and Experimental Hypnosis and International Society of Clinical Hypnosis have been
more open and accepted the reality that frontline providers such as bachelor-​level nurses
are ideal candidates to learn and be taught such techniques. In this ongoing debate, an
argument of ethics is used to prevent approaches that would provide better outcomes to
patients in an effort to preserve trade superiority.
The premise is again that one does not need permission to conduct negative hypno-
sis in terms of powerful negative suggestions with their associated worse outcomes as
compared to being allowed to use or being trained in evidence-​based methods that have
been tested in the environment. As our research has shown, the use of targeted hypnoi-
dal language and advanced rapport skills can be applied quite effectively and safely by
licensed medical professionals who are the frontline but do not have advanced medical
degrees. Training of just a few such individuals can change the experience for the better
of tens of thousands of patients over the course of a year as we have shown in a recent
study after training personnel in three MRI facilities (Norbash et al. 2016). Studies show
positive outcomes after training: a better patient experience, shorter procedures, and
greater safety—​fewer adverse events.
Looking at the use of nonpharmacologic pain and anxiety management techniques,
there is much at stake by wanting to limit practice to mental healthcare professionals
and to exclude others who are at the frontline of medical, surgical, and dental healthcare
delivery. Not only are there not enough mental healthcare professionals to cover routine
medical encounters, their time may not be well spent as extras in the critical first 90 sec-
onds to a few minutes of patient encounters to enable the upcoming medical treatments
or tests as compared to their regular patient approach of spending 45–​60-​minute sessions
on the couch for deeper exploration of lives and behaviors. This is not necessary for pro-
cedure hypnosis.
Not allowing frontline medical professionals to be trained overlooks tremendous
societal cost. Outside hospitals the opioid crisis is raging. Extrapolating the risk of IV
conscious sedation as found in a large collaborative study with greater than 21,000
 209

Conclusion 209

endoscopies (Arrowsmith et  al. 1991)  to 8.7  million invasive medical procedures, it is
predicted that 47,000 patients will suffer serious cardiorespiratory complications and
2600 patients will die each year in the United States alone. This number does not take into
account the fatalities in dental offices using IV drug sedation (Yagiela 2001; Bennett et al.
2015). In addition, the cost of patient anxiety poses a considerable burden. The inability
of patients to complete their MRI exams, leaving capacity unused, wastes about $310 mil-
lion USD annually by conservative estimates (Norbash et al. 2016). These losses could be
largely avoided by team training of medical personnel in nonpharmacologic calmative
and analgesic techniques (Lang & Rosen 2002). Here the question of societal ethics clearly
comes into play when considerable sums of healthcare expenditures are wasted because
of preconceived notions. The situation is further aggravated by the fact that rationing of
pain medication now occurs even in prestigious hospitals, mostly without the patient’s
knowledge. A recent article in The New York Times described that all sorts of drugs includ-
ing anesthetics, pain killers, antibiotics, and cancer drugs that may be produced only by
few companies because of poor profit margin, may suddenly become unavailable during
production shortages, and that the practice of doctors of triaging and rationing critical
medications have become the new normal (Fink 2016).

Conclusion
There is ample scientific evidence about the power of words and how small changes in
behavior and wording can make huge differences in terms of medical outcomes and
patient satisfaction. Any change, however small, will likely encounter resistance from
engrained practice patterns often under the guise of the proposal violating prevailing eth-
ics or not being authentic. It can be a dilemma when scientific findings counteract one’s
deepest held beliefs about how another person’s discomfort should be managed or when
one’s own coping mechanisms clash with different preferences of friends or colleagues.
The resulting disagreement becomes even more critical in a patient–​provider relationship,
which is inherently unequal. While giving a patient control can be therapeutic in itself for
the patient, giving up control without giving up responsibility can be a challenge for the
healthcare professionals accustomed to a more patriarchal model.
With patients’ empowerment toward expectation of greater patient-​ centered care
comes the recognition that patient satisfaction is not just a “customer” gimmick. Rather,
it is intertwined with quality in any kind of healthcare system and can enhance patients’
willingness to follow treatment recommendations and save healthcare expenditures.
The hope is that continued documentation of the efficacy of nonpharmacologic calm-
ative and analgesic techniques in well-​conducted clinical trials will overcome these hur-
dles and further stepwise integration in medical practice will facilitate the needed culture
change of Western medical practice. The aim is to make gains for all concerned without
unnecessary pains.
210

210 No pain no gain

References
American Medical Association (1997). Opinion 2.075—​The Use of Placebo Controls in Clinical Trials.
Available from: http://​www.ama-​assn.org/​ama/​pub/​physician-​resources/​medical-​ethics/​code-​
medical-​ethics/​opinion2075.page? [accessed March 8, 2016].
Ariely, D. (2010). Predictably Irrational, Revised and Expanded Edition: The Hidden Forces that Shape
our Decisions. New York: Harper Perennial.
Arrowsmith, J.B., Gerstman, B.B., Fleischer, D.E., and Benjamin, S.B. (1991). Results from the
American Society for Gastrointestinal Endoscopy/​U.S. Food and Drug Administration collaborative
study on complication rates and drug use during gastrointestinal endoscopy. Gastrointestinal
Endoscopy, 37, 421–​427.
Atlas, L.Y. and Wager, T.D. (2012). How expectations shape pain. Neuroscience Letters, 520, 140–​148.
Atlas, L.Y., Bolger, N., Lindquist, M.A., and Wager, T. D. (2010). Brain mediators of predictive cue
effects on perceived pain. Journal of Neuroscience, 30, 12964–​12977.
Bayer, T.L., Coverdale, J.H., Chiang, E., and Bangs, M. (1998). The role of prior pain experience and
expectancy in psychologically and physically induced pain. Pain, 74, 327–​331.
Bennett, J.D., Kramer, K.J., and Bosack, R.C. (2015). How safe is deep sedation or general anesthesia
while providing dental care? Journal of the American Dental Association, 146, 705–​708.
Blankfield, R.P. (1991). Suggestion, relaxation, and hypnosis as adjuncts in the care of surgery
patients: a review of the literature. American Journal of Clinical Hypnosis, 33, 172–​186.
Blease, C. (2012). The principle of parity: the “placebo effect” and physician communication. Journal of
Medical Ethics, 38, 199–​203.
Boothman, N. (2010). Convince Them in 90 Seconds or Less: Make Instant Connections that Pay Off in
Business and Life. Chapel Hill, NC: Workman Publishing Company.
Burgstaller, J.M., Schuffler, P.J., Buhmann, J.M., et al. (2016). Is there an association between pain and
magnetic resonance imaging parameters in patients with lumbar spinal stenosis? Spine, 41(17),
E1053–​1062.
Centers for Disease Control and Prevention (2016). Injury Prevention & Control: Opioid Overdose.
Available from: http://​www.cdc.gov/​drugoverdose/​ [accessed April 16, 2016].
Centers for Medicare and Medicaid Services (2009). Roadmap for Implementing Value Driven
Healthcare in the Traditional Medicare Fee-​for-​Service Program. Available from: http://​www.cms.hhs.
gov/​QualityInitiativesGenInfo/​downloads/​VBPRoadmap_​OEA_​1-​16_​508.pdf [accessed December
5, 2012].
Centers for Medicare and Medicaid Services (2011). Hospital Value-​Based Purchasing Program (VBP).
Washington, DC: Medicare Learning Network. Available from: http://​www.cms.gov/​Hospital-​Value-​
Based-​Purchasing [accessed January 20, 2013].
Chen, J., Li, Z., Lv, Y.F., et al. (2015). [Empathy for pain: a novel bio-​psychosocial-​behavioral laboratory
animal model]. Sheng Li Xue Bao, 67, 561–​570.
Chooi, C.S., White, A.M., Tan, S.G., Dowling, K., and Cyna, A.M. (2013). Pain vs comfort scores after
Caesarean section: a randomized trial. British Journal of Anaesthesia, 110, 780–​787.
Cyna, M.A. and Lang, E.V. (2011). How words hurt. In: Cyna, M., Andrew, M.I., Tan, S.G.M.,
and Smith, F. (eds.) Handbook of Communication in Anaesthesia and Critical Care, pp.30–​37.
Oxford: Oxford University Press.
Dutt-​Gupta, J., Bown, T., and Cyna, A.M. (2007). Effect of communication on pain during intravenous
cannulation: a randomized controlled trial. British Journal of Anaesthesia, 99, 871–​875.
Elkins, G., White, J., Patel, P., Marcus, J., Perfect, M.M., and Montgomery, G.H. (2006). Hypnosis to
manage anxiety and pain associated with colonoscopy for colorectal cancer screening: Case studies
and possible benefits. International Journal of Clinical and Experimental Hypnosis, 54, 416–​431.
 21

References 211

Everett, J.J., Patterson, D.R., Burns, G.L., Montgomery, B., and Heimbach, D. (1993). Adjunctive
interventions for burn pain control: comparison of hypnosis and ativan: the 1993 Clinical Research
Award. Journal of Burn Care & Research, 14, 676–​683.
Ewin, D.M. and Eimer, B.N. (2006). Ideomotor Signals for Rapid Hypnoanalysis. Springfield, IL: Charles
C. Thomas Publishers.
Faymonville, M.E., Fissette, J., Mambourg, P.H., Roediger, L., Joris, J., and Lamy, M. (1995). Hypnosis
as adjunct therapy in conscious sedation for plastic surgery. Regional Anesthesia, 20, 145–​151.
Fink, S. (2016). Drug shortages forcing hard decisions on rationing treatments. New York Times,
January 29.
Goubert, L., Craig, K.D., Vervoort, T., et al. (2005). Facing others in pain: the effects of empathy. Pain,
118, 285–​288.
Hashmi, J.A., Kong, J., Spaeth, R., Khan, S., Kaptchuk, T.J., and Gollub, R.L. (2014). Functional
network architecture predicts psychologically mediated analgesia related to treatment in chronic
knee pain patients. Journal of Neuroscience, 34, 3924–​3936.
Hatfield, E. and Cacioppo, J. T. 1994. Emotional Contagion (Studies on Emotion and Social Interaction).
New York: Cambridge University Press.
Hayashi, K., Ikemoto, T., Ueno, T., et al. (2016). Higher pain rating results in lower variability
of somatosensory cortex activation by painful mechanical stimuli: an fMRI study. Clinical
Neurophysiology, 127, 1923–​1928.
Joint Commission On Accreditation Of Healthcare Organizations (2016). Joint Commission Statement
on Pain Management. Available from: https://​www.jointcommission.org/​joint_​commission_​
statement_​on_​pain_​management/​ [accessed February 8, 2016].
Kam-​Hansen, S., Jakubowski, M., Kelley, J.M., et al. (2014). Altered placebo and drug labeling changes
the outcome of episodic migraine attacks. Science Translational Medicine, 6, 218ra5.
Keltner, J.R., Furst, A., Fan, C., Redfern, R., Inglis, B., and Fields, H.L. (2006). Isolating the
modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging
study. Journal of Neuroscience, 26, 4437–​4443.
Kilwein, J.H. (1989). No pain, no gain: a Puritan legacy. Health Education Quarterly, 16, 9–​12.
Kroger, W.S. and Delee, S.T. (1957). Hypnoanesthesia for cesarean section and hysterectomy. JAMA,
163, 442–​444.
Kupers, R., Faymonville, M.E., and Laureys, S. (2005). The cognitive modulation of pain: hypnosis-​and
placebo-​induced analgesia. Progress in Brain Research, 150, 251–​269.
Lang, E.V. (2012). A better patient experience through better communication. Journal of Radiology
Nursing, 31, 114–​119.
Lang, E.V. (2014a). How (Not) to Place an IV. Comfort Talk d/​b/​a/​Hypnalgesics, LLC. Available
from: http://​www.youtube.com/​watch?v=526N-​3Xqkwg [accessed February 8, 2016].
Lang, E.V. (2014b). Managing Your Medical Experience: The Information You Need Plus Self-​Hyonosis for
Finding Comfort With Your Tests and Treatments. Middletown, DE: Create Space.
Lang, E.V. and Laser, E. (2009). Patient Sedation Without Medication. Rapid Rapport and Quick
Hypontic Techniques. A Resource Guide for Doctors, Nurses, and Technolgists. Raleigh, NC: Lulu.
Lang, E.V. and Rosen, M.P. (2002). Cost analysis of adjunct hypnosis with sedation during outpatient
interventional radiologic procedures. Radiology, 222, 375–​382.
Lang, E.V., Chen, F., Fick, L.J., and Berbaum, K.S. (1998). Determinants of intravenous conscious
sedation for arteriography. Journal of Vascular and Interventional Radiology, 9, 407–​412.
Lang, E.V., Benotsch, E.G., Fick, L.J., et al. (2000). Adjunctive non-​pharmacological analgesia for
invasive medical procedures: a randomised trial. Lancet, 355, 1486–​1490.
Lang, E.V., Hatsiopoulou, O., Koch, T., et al. (2005). Can words hurt? Patient-​provider interactions
during invasive procedures. Pain, 114, 303–​309.
21

212 No pain no gain

Lang, E.V., Berbaum, K.S., Faintuch, S., et al. (2006). Adjunctive self-​hypnotic relaxation for outpatient
medical procedures: a prospective randomized trial with women undergoing large core breast
biopsy. Pain, 126, 155–​164.
Lang, E.V., Berbaum, K.S., Pauker, S.G., et al. (2008). Beneficial effects of hypnosis and adverse effects
of empathic attention during percutaneous tumor treatment: when being nice does not suffice.
Journal of Vascular and Interventional Radiology, 19, 897–​905.
Lang, E.V., Yuh, W.T., Ajam, A., et al. (2013). Understanding patient satisfaction ratings for radiology
services. AJR American Journal of Roentgenology, 201, 1190–​1195.
Lang, E.V., Tan, G., Amihai, I., and Jensen, M.P. (2014). Analyzing acute procedural pain in clinical
trials. Pain, 155, 1365–​1373.
Leng, S (2015, February). Patients are not customers. Here are 6 reasons why. KevinMD.com. Available
from: http://​www.kevinmd.com/​blog/​2015/​02/​patients-​not-​customers-​6-​reasons.html [accessed
February 8, 2016].
Liossi, C. and Hatira, P. (2003). Clinical hypnosis in the alleviation of procedure-​related pain in
pediatric oncology patients. Journal of Clinical and Experimental Hypnosis, 51, 4–​28.
Liossi, C., White, P., and Hatira, P. (2006). Randomized clinical trial of local anesthetic versus a
combination of local anesthetic with self-​hypnosis in the management of pediatric procedure-​
related pain. Health Psychology, 25, 307–​315.
Marchant, J. (2016). The Cure: A Journey into the Science of Mind Over Body. New York: Crown.
McDermott, V.G.M., Chapman, M.E., and Gillespie, I. (1993). Sedation and patient monitoring in
vascular and interventional radiology. British Journal and Radiology, 66, 667–​671.
Meurisse, M., Hamoir, E., Defechereux, T., et al. (1999). Bilateral neck exploration under
hypnosedation. A new standard of care in primary hyperparathyroidism? Annals of Surgery, 229,
401–​408.
Mogil, J.S. (2012). The surprising empathic abilities of rodents. Trends in Cognitive Sciences, 16,
143–​144.
Montgomery, G.H., David, D., Winkel, G., Silverstein, J.H., and Bovberg, D.H. (2002). The
effectiveness of adjunctive hypnosis with surgical patients: a meta-​analysis. Anesthesia & Analgesia,
94, 1639–​1645.
Montgomery, G.H., Bovbjerg, D.H., Schnur, J.B., et al. (2007). A randomized clinical trial of a brief
hypnosis intervention to control side effects in breast surgery patients. Journal of the National
Cancer Institute, 99, 1304–​1312.
Norbash, A., Yucel, K., Yuh, W., et al. (2016). Effect of team training on improving MRI study
completion rates and no show rates. Journal of Magnetic Resonance Imaging, 44(4), 1040–​107.
Peerdeman, K.J., Van Laarhoven, A.I., Keij, S.M., et al. (2016). Relieving patients’ pain with expectation
interventions: a meta-​analysis. Pain, 157, 1179–​1191.
Peyron, R., Laurent, B., and Garcia-​Larrea, L. (2000). Functional imaging of brain responses to pain.
A review and meta-​analysis. Clinical Neurophysiology, 30, 263–​288.
Singer, T., Seymour, B., O’Doherty, J., Kaube, H., Dolan, R.J., and Frith, C.D. (2004). Empathy for pain
involves the affective but not sensory components of pain. Science, 303, 1157–​1162.
Van Fleet, D.D. and Peterson, T.O. (2016). Improving healthcare practice behaviors. International
Journal of Health Care Quality Assurance, 29, 141–​161.
Varelmann, D., Pancaro, C., Cappiello, E.C., and Camann, W.R. (2010). Nocebo-​induced hyperalgesia
during local anesthetic injection. Anesthesia & Analgesia, 110, 868–​870.
Watt-​Watson, J., Garfinkel, P., Gallop, R., Stevens, B., and Streiner, D. (2000). The impact of nurses’
empathic responses on patients’ pain management in acute care. Nursing Research, 49, 191–​200.
 213

References 213

Weinstein, E.J. and Au, P.K. (1991). Use of hypnosis before and during angioplasty. American Journal of
Clinical Hypnosis, 34, 29–​37.
Wollmer, M.A., Kalak, N., Jung, S., et al. (2014). Agitation predicts response of depression to botulinum
toxin treatment in a randomized controlled trial. Frontiers in Psychiatry, 5, 36.
Yagiela, J.A. (2001). Making patients safe and comfortable for a lifetime of dentistry: frontiers in office-​
based sedation. Journal of Dental Education, 65, 1348–​1356.
214

Chapter 12

Placebo beyond controls: The

neuroscience and ethics
of navigating a new understanding
of placebo therapy
Karen S. Rommelfanger

Why discuss placebos in neuroethics?

Neuroethics as a field exists because the brain enjoys a privileged position unlike any
other organ. For better or worse, the predominant belief is that the brain is synonymous
with personality and the essence of who people are; the brain is not an object, but a sub-
ject and agent (Roskies 2007; Racine et al. 2010). Adina Roskie’s appraisal of the impact of
neuroscience in society holds that “the rhetorical force of the neuroscientific understand-
ing, rather than what it can actually reveal … causes the potential ethical issues to arise”
(Roskies 2007, p.S54). Kathinka Evers advocates not for a total reduction of the human
experience to the material brain, but that a valuable integration of neuroscience into ethi-
cal discussions might be toward an “informed materialism” that could be used to “oppose
both dualism and naïve reductionism” (Evers 2007, p.S48). The role that individuals feel
their brains play in their lives, from free will to personhood, is culturally bound and
informs fundamental personal and societal values and impacts ethical decision-​making
from when a person comes into being and to when a person is pronounced to be dead
(Adam et al. 2015; Yang & Miller 2015). In this chapter, I discuss placebo as a case study
of neuroethical inquiry. I explore how neuroscience evidence informs and advances exist-
ing ethical debates, and how these debates have real-​world impacts on daily well-​being.

Introduction
The powers of placebo are long known. In the popular imagination, placebos have become
synonymous with snake oil, deception and lying, and other nefarious immoral endeavors
(the primary exception being a mother’s kiss to the bumps and bruises of childhood). The
scientific and medical community has assumed a stance that placebos are by definition
inert and their use should be reserved to that of an experimental control; therapeuti-
cally, placebo use is condemned as a transgressive practice and punishable based on the
assumed deception necessary with placebo administration—​a breach of ethical conduct.
 215

What are placebos? 215

This stance is now being challenged by the emerging scientific evidence demonstrating
that placebos are far from inert as well as by studies revealing widespread, although largely
clandestine, therapeutic use (Sherman & Hickner 2008; Tilburt et al. 2008; Kermen et al.
2010; Rommelfanger 2013a). Perhaps even more surprising is the frequently reported
patient approval of therapeutic use of placebos even under the context of deception
(Lynoe et al. 1993; Fassler et al. 2011; Hull et al. 2013; Pugh et al. 2016). For those who
unequivocally believe deception is immoral, emerging data suggest that placebo effects
can be maintained even without deception (Kaptchuk et  al. 2010; Schafer et  al. 2015).
Collectively, these new data on placebo require reappraisal.

What are placebos?

History
In the medical context, placebo is typically described as an inert treatment of no reme-
dial value that is given to reinforce a patient’s expectation to get well (Diederich & Goetz
2008; Finniss et al. 2010). It seems that simply the act of taking an intervention meant for
healing—​with a suggestion that medicine might work—​can improve patient outcomes.
With such clinical effects, why has the research and development of placebo therapies not
been the subject of more open conversation in clinical care?
The powerful therapeutic benefits of placebo have made it a long-​standing subject of
bewilderment and ethical scrutiny. As far back as 1621, in the Anatomy of Melancholy
Robert Burton wrote that “a silly chirurgeon, doth more strange cures than a rational phy-
sician … because the patient puts his confidence in him” (Burton 1621). In 1807, Thomas
Jefferson described therapeutic placebo as a pious fraud, yet, “one of the most successful
physicians … used more of bread pills, drops of colored water, and powders of hickory
ashes, than all other medicines put together” (Ford 1898). Arguments about the ethics of
therapeutic placebos during the nineteenth and twentieth centuries have remained largely
faithful to the following problem: placebos seem to work, but not in the right way—​an
argument that has pervaded medicine for more than 200  years (Brody 1982). Patients
may report being or feeling better after placebo intervention, yet placebos are by defini-
tion inert. The restorative effect requires deceptive manipulation of a vulnerable patient’s
mind by implanting false beliefs about an inert remedy to overcome the inert properties
of placebos.
In popular imagination, neither the placebo nor its effect is considered real. Placebos
are conceptualized as inert and their powerful effects are caused by the imagination of the
individual under their influence. Indeed, the effects are fundamentally a product of the
mind. In this conceptual framework, the affected person is influenced by expectation and
false belief, an insult to otherwise rational intelligence (a greater affront is when a person
is duped by a trusted authority and violated in a vulnerable state). In coming to recognize
the power differential historically held in the practice of medicine, there has been a sig-
nificant shift away from paternalism in medical practice and today a key ethical principle
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216 Placebo beyond controls

in medicine is to ensure the patient has autonomy and is self-​determining (Beauchamp

& Childress 2009). This is achieved largely through transparency in and shared decision-​
making between the healthcare provider, patients, and their families, seemingly the
antithesis of placebo therapy.
This evolution of anti-​paternalism and patient empowerment has not been without its
challenges. A well-​noted and natural tension in placebo use lies between the principles
of beneficence and respect of autonomy (Beauchamp & Childress 2009). If placebo use
requires deception and efficacy in the patient’s best interest, is it not the physician’s obliga-
tion to deceive? Adding to the complexity of the placebo story, patients report supporting
deception, permissible particularly in therapeutic encounters with unresolved chronic
conditions (Lynoe et al. 1993; Fassler et al. 2011; Hull et al. 2013; Pugh 2015). Perhaps
in the context of placebo therapy, shared decision-​making between patient, families, and
providers might provide some level of resolution (Brody et al. 2012). What information
needs to be shared and under what contexts are topics discussed later in this chapter.

Placebos in practice
Placebo therapy use is a global phenomenon, and according to some reports, up to 97%
of physicians administer placebo therapeutically (Fassler et  al. 2010; Fent et  al. 2011;
Meissner et al. 2012; Howick et al. 2013). Fifty percent of US physicians have used pla-
cebo in clinical practice (Sherman & Hickner 2008; Tilburt et al. 2008) for an array of
disorders from gastrointestinal and immune disorders to cancer and neurological disor-
ders (Sherman & Hickner 2008). Placebo treatments include saline, sugar pills, vitamins,
over-​the-​counter analgesics, antibiotics, and sedatives (Tilburt et  al. 2008). Physicians
often describe placebo therapies as “a substance that may help and will not hurt” or “it
is medication” or “it is medicine with no specific effect,” “a medicine not typically used
for your condition but might benefit you,” or might say, “This may help you, but I am
not sure how it works” (Sherman & Hickner 2008; Tilburt et al. 2008). These statements
demonstrate a mode of communicating information that falls somewhere on a spectrum
between acceptable professional norms of oversimplifying treatment descriptions (i.e.,
physician states that a pill is akin to an antibiotic or antihistamine) to deliberate attempts
at verbal misdirection.

Professional values
While placebo therapy has been widely employed across the globe (Hrobjartsson & Norup
2003; Tilburt et al. 2008; Fassler et al. 2010; Fent et al. 2011; Meissner et al. 2012; Howick
et al. 2013), this practice is quite contrary to the values self-​professed to be held by profes-
sional medical associations such as the American Medical Association (AMA)—​although
the AMA only in 2006 categorically prohibited deceptive placebo use (Bostick et al. 2008;
Blease 2012). Interestingly, no pronouncement has been made by similar global organiza-
tions and the AMA’s stance is by far the most explicit and stringent.
According to the Report of the AMA Council on Ethical and Judicial Affairs, placebo is
defined as “a substance that the physician believes had no known specific pharmacological
 217

What are placebos? 217

activity against the condition being treated” (Bostick et al. 2008, p.58). The Council states
that placebo use with deception “directly conflicts with contemporary notions of patient
autonomy and the practice of shared decision making (Bostick et al. 2008, p.59). Aside
from the harm of violating the patient–​physician alliance, the Council argue that patients
may also encounter nocebo effects, adverse side effects rather than the positive effects
associated with placebo use. These statements reveal the inherent professional and con-
ceptual confusion about placebo in two ways. First, the authors warn against placebos as
treatments with no specific pharmacological activity that may be accompanied by legiti-
mate adverse effects, implying that while benefits are somehow fake, the harms are some-
how real. Second, the placebos are defined by the physician’s belief that the placebo has
no known specific pharmacological activity, not characterized or defined by the scientific
evidence that might explain mechanisms of placebo. However, in the concluding state-
ments of the report, the Council states that placebos “may be used in clinical practice to
determine a diagnosis or appropriate treatment in the face of clinical uncertainty,” but that
physicians should avoid deception. The report also recommends that physicians should
avoid placebos, but are nonetheless supported in their attempt to elicit a “placebo-​like
effect through the skillful use of reassurance and encouragement … In this way, the physi-
cian builds respect and trust, promotes the patient-​physician relationship, and improves
health outcomes” (Bostick et al. 2008, p.60). One may well wonder, which is it? Do pla-
cebos violate the patient–​physician relationship and cause harm or do placebos build
respect and trust and improve health outcomes? Perhaps it is no wonder in this linguistic
equivocation that clinicians find themselves in practice clandestinely using placebo.
The AMA has also created explicit guidelines in the form of an Opinion under their
Code of Medical Ethics on the clinical use of placebos. In their Opinion statement there
is one loophole for deception under the condition that the patient is informed at some
point that placebo will be used but that the patient will be blind to the precise timing of
its implementation (AMA 2007). In this case the Opinion appears to sanction a kind of
deception that requires patient ignorance of some details such as timing with the patient’s
approval. Again such an Opinion also highlights lingering ambiguity about the role both
of deception in routine practice and for deceptive placebo use. The AMA Council report
states that “physicians may utilize placebos within their clinical practice without relying
on the act of deception” (Bostick et al. 2008). This statement in the Council Report in
combination with the Opinion seems to suggest that there is some form of acceptable
deception, or appears to suggest that authorized deception is not really deception (Blease
et al. 2016), just like placebos are not really placebos if the physician does not believe they
are, as with the case of active placebos where active agents such as vitamins or off-​label
prescriptions are given as placebo.
How and why does the prevalent use of (deceptive) therapeutic placebo prevail even in
the absence of solidarity from professional medical societies? Have physicians betrayed
their oaths to care for patients and to try to make them well or improve their quality of
lives? Is there an ethical framework that would make such a behavior morally permissible?
A consequentialist approach where the ends justify the means seems to explain popular
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218 Placebo beyond controls

physician use of placebo therapy. A deontological approach championing the duty not to
lie about an inert treatment seems to drive concerns for deception. The result is a rela-
tively widespread use of placebo in a clandestine manner or a compromised use of active
placebos that utilize off-​label or reduced doses of real drugs (Sherman & Hickner 2008;
Tilburt et al. 2008; Rommelfanger 2013a). While these arguments around placebo are not
new, the definition and what we know about placebos must be updated with the accumu-
lating body of evidence showing specific neurobiological effects from placebo (Benedetti
2014) as well as the necessity—​or lack thereof (Blease et al. 2016)—​for deception with
placebo administration. These data will be discussed in “Explanations for placebo effects.”
Just as remarkably absent as the neuroscience data in these ethical evaluative schemas,
is the patient’s voice and her reflections about the use of placebo therapy. These data too
must be incorporated into our future reappraisals of placebo therapy and in determina-
tions of what is best for individual patients.

Explanations for placebo effects

Prejudicial terminology and placebo
Much of ethical demise of placebo is owed to its conceptual entanglements.
In 2011, Miller and Brody outlined common conceptual distinctions of placebo that
produce misunderstanding about the placebo; such awkward terminology undermines
a critical understanding of placebo in medicine and almost universally work to devalue
placebo (Miller & Brody 2011). These conceptual framings serve as policing agents for
an outdated and outmoded Cartesian model that attempts to separate the mind from
the body, a view that is so prevalent in the practice of Western medicine. These terms are
summarized as follows.
The first is verum (what is true) versus placebo. If verum is truth, placebo is necessarily
positioned as false. Another confusing set of terms, often used in clinical trials, is active
versus inactive wherein the inactive agent is considered placebo. Such a distinction is
misguided because, as discussed, placebo controls are used because of their activity and
known–​unknown arbiters to any drug effect. Another framing to describe clinical effects
is to distinguish specific from nonspecific effects where placebo effects are designated
as nonspecific contamination of desired clinical effects. In this framework, it follows
that a disease is not really a legitimate diagnosable disease until the specific biochemical
pathways are understood. Reporting of symptoms is not enough. The need for specificity
seems to coincide with redefining of diseases with “specificity and specificity of mecha-
nism” (Rosenberg 2002, p.243) and by extension, a specific therapy (Rosenberg 2002).
Rosenberg calls this the “Tyranny of Diagnosis.”
By extension, utilizing nonspecific therapies—​such as off-​label use of drugs or even
something like acupuncture—​whose mechanism is not understood is to practice med-
icine that was not scientifically grounded. However, the nature of practicing medicine
is full of ambiguity. The goal of research with scientific studies is to identify generaliz-
able findings. This scientific strategy will not necessarily map cleanly onto real-​world
 219

Explanations for placebo effects 219

individual experience and illness. In fact, those who subscribe to such a model are guilty
of reducing the human experience in a way that devalues the individual patient’s sub-
jective experience while over-​privileging objective measures. The long-​suffering road of
pain researchers who have struggled to find objective measures that can replace subjective
reports of pain demonstrate the downfall of such a strategy.
Another way of conceptualizing placebo is to suggest that placebos are largely effects
of context (Miller & Kaptchuk 2008). So much so, perhaps, that Di Blasi and colleagues
suggest that placebo effects would more appropriately be referred to as “context effects”
(Di Blasi et al. 2001). It would seem that the ritual around the intervention, rather than
the intervention itself, is what determines the placebo effect. Anthropologist Daniel
Moerman advocates for a reconceptualization of placebo effects as meaningful responses,
and in doing so one can avoid the ethical quandaries of both placebo itself and the embed-
ded connotations of deception (Moerman 2002; Moerman & Jonas 2002). With Western
biomedicine, technological interventions are privileged and the placebo is understood as
the non-​technological context, somehow a nonspecific variable and background noise.
Placebo effects, in other words, are psychological contamination (Colloca & Benedetti
2005). A discussion of how context impacts learning and expectation associated with pla-
cebo is discussed further in “Mechanisms of placebo.”
Regardless, placebo, conceptualized as nonspecific and subjective phenomena, has
demonstrably specific and objectively measurable effects. Given these demonstrable
effects, should placebos be given more credibility as a viable intervention? Can we over-
come the historical linguistic trappings with placebo and its counterparts? The term pla-
cebo is in grave need of updating and perhaps at best only serves as an anachronistic
placeholder, like thingamajig, a relic of a troubled legacy of misunderstanding.

Mechanisms of placebo
Placebo effects can be thought of in terms of mechanisms of expectation, learning, and
conditioning (Colloca & Miller 2011b). In Colloca and Miller’s model, placebo is a vehicle
for therapy not because of its internal properties, but because they are a collection of
salient signals or symbols. An intervention, whether considered a placebo or not, can-
not be separated from the context in which it is given. Colloca and Miller point out that,
“The patient does not come to the clinical encounter as a blank slate but with a history of
experiences and memories evoked by prior responses to signals related to the milieu of
therapy” (Colloca & Miller 2011b, p.1860). In this sense, placebo effects are not unique
to placebo interventions per se and can happen with any clinical intervention—​with or
without physical placebo.
According to a classical conditioning framework, repeated exposure to contextual fac-
tors that coincide with ingestion of a medication—​such as visual, tactile, and gustatory
stimuli (unconditioned stimuli)—​become associated conditioned stimuli (Pavlov 1927;
Colloca & Miller 2011b). Placebos, as a consequence, are in turn able to elicit condi-
tioned responses in the presence of their conditioned stimuli. For example, were one to
visit a physician’s office and receive pain relief from an injection of an anti-​inflammatory
20

220 Placebo beyond controls

drug, a syringe can become the conditioned stimulus—​it becomes the symbol for pain
relief. Then future observation of the syringe (or injection from the syringe regardless
of its content) at a doctor’s office may then elicit pain relief for a patient so conditioned
(Montgomery & Kirsch 1997; Colloca & Miller 2011b).
Learning associations for placebo, like any learning, allows for environmental cues or
elements to be connected with social cues. There appear to be several different cues or
conditions that can elicit a placebo response. These include verbal cues, prior experi-
ence, observation, and social learning, each of which lead to expectation and conditioned
learning (Colloca & Miller 2011b). Early studies explored the effect of verbal language on
bronchoconstriction in patients with asthma (Luparello et al. 1968, 1970). When patients
were instructed to inhale a solution (of nebulized saline) and told that the solution was
an allergen, nearly half of the patients demonstrated increased airway resistance. When
the same patients were instructed to inhale the same solution (again of nebulized saline)
and told that the solution was a medicine for asthma, airway bronchoconstriction was
reversed. In an additional study, carbachol, a bronchoconstrictor, was given to patients
who were told that it was a bronchoconstrictor. These patients had greater effects than
when patients were told carbachol was indeed a bronchodilator. In another series of stud-
ies for postoperative pain relief, patients (who were told that a placebo was a potent pain
reliever) were able to reduce their opioid intake more than patients who were told nothing
about the analgesic effect of the placebo or patients who were told that they might receive
a placebo or pain reliever (Pollo et al. 2001). Verbal suggestion also has been shown to
have significant placebo (and nocebo, or negative, unpleasant effects) effects in an experi-
mental model of itch (Van Laarhoven et al. 2011).
One example of conditioning by prior experience was demonstrated by Benedetti and
colleagues. Participants given placebo for migraine relief were able to experience subjec-
tive pain relief accompanied by the same profile of significant biochemical effects (albeit
not as dramatic) of increased growth hormone release and decreased cortisol release
(Benedetti et al. 2003). The placebo was only able to elicit this response after prior admin-
istration of the migraine medication, that is, no effect was seen if placebo was admin-
istered before administration of migraine medication. This effect was also independent
of verbal instructions about the placebo/​migraine medication that would have primed
expectations. Similar conditioned placebo responses have been seen with immunosup-
pressors (Goebel et al. 2002, 2005), dopamine agonists (De La Fuente-​Fernandez et al.
2001; Benedetti et  al. 2004; Lidstone et  al. 2010), and benzodiazepines (Petrovic et  al.
2005). Conditioned placebo responses have also been modeled in nonhuman animal
studies in mice (Guo et al. 2010) and rats (Zhang et al. 2013; Lee et al. 2015). Interestingly,
in one follow-​up study, Guo and colleagues suggest that placebo effects can be trans-
ferred from one domain to another, from pain to emotion in their rodent model (Guo
et al. 2011).
In a recent placebo analgesia study involving rodents, Lee and colleagues attempted to
parse out learning neurophysiology from analgesia physiology (Lee et al. 2015). Rodents
were trained in a conditioned place preference paradigm to associate a place/​room with
 21

Explanations for placebo effects 221

low or high pain induced by heat. Rats then formed an association between the room
cue (one room had a rough floor with a black and white wall and the other room had
black wall with a soft floor) and the pain stimulus following exposure to the room. Given
the choice post training, the rats came to prefer the room that had preceded lower pain
exposure during training. The pain response was measured with hind paw withdrawal to
a stimulus. Longer latencies are associated with lower pain. Administration of the dopa-
mine antagonist haloperidol blocked cue learning preference for the room preceding low
pain exposure. Both dopamine and opioid antagonist naloxone blocked the expression of
placebo analgesia as measured by biomarkers in the ventral tegmental area and nucleus
accumbens. From these data, researchers concluded that dopamine pathways were critical
in the acquisition of association of cues with the placebo response. Corroborating human
study data (Wager et al. 2007), Zhang and colleagues further concluded through direct
microinjections of various subtype opioid antagonists into the rat anterior cingulate cor-
tex, an area associated with registered physical pain, that mu-​opioid receptors mediate
placebo analgesia (Zhang et al. 2013).
Prior experience with active drugs or even placebos can influence the magnitude of sub-
sequent placebo responses (Colloca & Benedetti 2006). In one study of placebo analgesia,
two groups of participants were exposed to painful stimuli. In one group, individuals were
told they were given an analgesic agent while the researcher simulated a placebo effect by
surreptitiously reducing the intensity of the painful stimuli. In a second group the inten-
sity of the painful stimuli was not reduced. When both groups were given the placebo
again, but without reduction of painful stimuli, the participants who initially were primed
to believe the placebo was an effective pain reliever by surreptitiously reducing inten-
sity of the painful stimuli in the initial exposure, experienced a greater placebo response.
These placebo responses and the anticipation of analgesia were correlated to activity in
the dorsolateral prefrontal cortex suggesting that anticipation of placebo involves higher-​
order cognitive activities such as executive functioning and perception (Lui et al. 2010).
In another study by Lidstone and colleagues, participants with Parkinson’s disease, told
a numerical probability of receiving dopamine therapy while always receiving placebo,
demonstrated significant dopamine release in both the nigrostriatal system that is charac-
teristically impacted in Parkinson’s disease, as well as the mesoaccumbens, a node in the
reward pathway, when the probability was high (75%) (Lidstone et al. 2010). The strength
of expectation by giving participants a numerical expectation value impacted the degree
of dopamine release in both the dorsal striatum associated with therapeutic dopamine
release, and ventral striatum, associated with reward/​expectation mediated dopamine
release (Lidstone et al. 2010). Cortical excitability has also been associated with expecta-
tion of treatment (Lou et al. 2013).
Reward learning is the subject of significant study for drug addiction, attention defi-
cit hyperactivity disorder, and basic learning mechanisms. Critical to reward learning is
the recruitment of the ventral striatum (Schultz 2006), a region also thought to underlie
placebo effects (De La Fuente-​Fernandez et al. 2004) by moderating salience and expecta-
tion. Dopamine release in the ventral striatum has been identified with placebo analgesia
2

222 Placebo beyond controls

(Scott et al. 2008) as well as in response to the probability of receiving active drug as men-
tioned earlier (Lidstone et al. 2010).
While some scholars have attempted to draw clear distinctions between expectancy
and conditioning (Kirsch 2004; Stewart-​Williams & Podd 2004)—​that is, conditioning
requires unconscious participation while expectancy may require conscious processing—​
it is also recognized by critics (Kirsch 2004) that some form of conditioning likely under-
lies critical aspects of the generation of expectancy. Classical conditioning is also likely to
involve a higher order of cognition in order to form logical and perceptual relationships
between events, stimuli, and representations (Shanks 2010).
Amanzio and Benedetti attempted to dissect components of expectation-​based anal-
gesia and conditioning-​based analgesia, eliciting recruitment of specific neurophysi-
ological changes related to pain analgesia (Amanzio & Benedetti 1999). In this human
study, expectations of receiving pain relievers that work by two different mechanisms
induced opioid-​and nonsteroidal anti-​inflammatory drug (NSAID)-​mediated pla-
cebo analgesia respectively. However, conditioned responses recruited specific neu-
rophysiological responses dependent on the type of analgesia; morphine-​induced
opioid-​mediated pain relief was blocked by the opioid antagonist naloxone and
NSAID-​mediated analgesia was not blocked by naloxone. Importantly, the research-
ers found that the two components were intertwined and that reduced expectancy. By
telling participants they would receive an NSAID rather than morphine while they
were being given the opioid antagonist that blocks opioid-​mediated pain relief, the
conditioned placebo analgesia response was reduced but not eliminated (Amanzio &
Benedetti 1999). In this case, the expectation that the drug was a pain reliever still
resulted in placebo analgesia likely though a specific NSAID-​mediated mechanism (as
a conditioned response to the NSAID) that could not be blocked by an antagonist for
another pain reliever (morphine).
Finally, Colloca and Miller note models of social learning for placebo (Colloca &
Miller 2011a), rather than direct first-​hand experience as described in the studies previ-
ously described. The magnitude of the placebo response for those who were conditioned
through observing pain relief in another was similar to conditioned placebo responses
via first-​hand experience (Colloca & Benedetti 2009). In addition, those participants with
higher empathy scores had greater placebo responses upon observing placebo pain relief.
Another form of social learning with placebo can occur through patient–​provider inter-
action. Placebo effects have been shown to be augmented when participants had more
supportive practitioner engagement as enacted though active listening (e.g. repeating
patients’ words and asking for clarification) and attempts to behave in a warm, friendly,
and empathetic (e.g., by saying, “I understand how this could be difficult for you”) way as
well as setting positive expectations (e.g., saying, “I believe this will have a positive impact
for you”) and 20 seconds of thoughtful silence after interventions (Kaptchuk et al. 2008).
It seems the ritual of therapeutic encounters provides a learning mechanism wherein
patients can learn to produce placebo responses through having an interaction with a
healer/​clinician (Miller et al. 2009). In this model of “interpersonal healing,” the doctor’s
 23

Explanations for placebo effects 223

beliefs about the efficacy of treatment can be extremely influential on the patient’s expec-
tation and placebo response to an intervention.
Societal influence and impact of branding can influence placebo effects. In a recent
study on placebo analgesia for migraine, by Kam-​Hansen and colleagues, investigators
noted that placebo bottles labeled as “Maxalt” reduced headache severity as well as Maxalt
labeled as placebo (Kam-​Hansen et  al. 2014). Further placebo, labeled as placebo, was
more effective in reducing headaches than no treatment at all. A recent study exploring
the price attached to a medication for Parkinson’s showed that patients told they were
given expensive medication manufactured at $1500 USD/​dose demonstrated a greater
reduction in motor symptoms than patients told they were given cheaper medication
manufactured at $100 USD/​dose, both of which were placebos (Espay et al. 2015). Clearly
these placebo effects are modulated both by direct and indirect experience and embedded
meanings in those experiences. In a global study of placebo effects in clinical trials for
pain medications, researchers identified an increasing effect in the United States and only
United States (Tuttle et al. 2015). These effects are stronger in longer and larger trials that
tended to occur in the United States, suggesting the strong influence of cultural values and
meaning of pharmacology on eliciting placebo responses.

Neurobiological insights from disease with established biochemical

pathways
A lingering mindset among some skeptics, even with the information above-​mentioned,
is that placebos may alter subjective illness but would never have an impact on the disease
or the biological processes of that disease (Spiro 1986). This has all been controverted by
a growing and impressive set of data outlining changes in human and nonhuman neu-
rophysiology underlying placebo effects that are related to neurological disorders whose
biochemical pathways are well-​characterized (Benedetti 2014). These data also build on,
but should not replace, the body of research exploring the psychosocial dimensions of
placebo therapy.
Placebo responses have been identified in 16–​55% of Parkinson’s disease patients (Goetz
et al. 2008), 30% of migraine patients (Bendtsen et al. 2003), and 50% of depressed patients
(Dworkin et al. 2005). Studies in Parkinson’s disease have demonstrated enhanced endog-
enous release of neurotransmitters such as dopamine (De La Fuente-​Fernandez et  al.
2001; Mercado et al. 2006; Lidstone et al. 2010) as well therapeutically associated changes
in neuronal activity upon placebo administration (Benedetti et al. 2004). In one of the
most compelling studies on placebo neurophysiology, Benedetti and colleagues showed
that aberrant neuronal activity in the subthalamic nucleus associated with Parkinson’s
disease recorded in single neurons was normalized after placebo treatment (Benedetti
et  al. 2004). The physician’s examination corroborated the patient’s reported improve-
ments (Benedetti et al. 2004).
Opiate release (Zubieta et al. 2005; Wager et al. 2007) has also been documented upon
placebo administration, and pharmacological antagonists, such as naloxone (Amanzio
& Benedetti 1999) can inhibit placebo-​induced analgesia in both humans (Amanzio &
24

224 Placebo beyond controls

Benedetti 1999)  and animal models (Nolan et  al. 2012)  indicating that placebos have
specificity with regard to endogenous neurochemistry.
As noted earlier, studies in human patients suggest that placebo effects utilize reward
pathways in the ventral striatum and that these reward pathways are modulated by
expectation. De la Fuente-​Fernandez and colleagues demonstrated in several occasions
through positron emission tomography that placebo can activate the specific nigrostriatal
dopamine system whose degeneration and disruption characterizes Parkinson’s disease,
and greater placebo-​induced dopamine release associated with patient-​reported clinical
improvement (De La Fuente-​Fernandez et al. 2001, 2004). Regardless of whether patients
reported clinical improvement, all participants demonstrated placebo-​induced increases
in dopamine in the ventral striatum, an area typically associated with reward functioning
and expectation of rewards (De La Fuente-​Fernandez et al. 2004; Schultz 2006). These
studies suggest that while expectation plays a key role in facilitating downstream pla-
cebo effects, the degree of recruitment of the specific relevant biochemical pathway can
impact the perceived therapeutic benefit. Critically, intact top-​down cognitive processing
may mediate these placebo effects, as some are lost in patients with Alzheimer’s disease
(Benedetti 2006; Enck et al. 2008).
While many placebo studies have been conducted in pain studies, Parkinson’s disease
allows unique attributes for exploring the biological correlates to the placebo pathway.
For example, with Parkinson’s disease versus pain, treatment responses can be evalu-
ated objectively by the experimenter evaluations of motor performance (Frisaldi et  al.
2014). The second unique advantage is that neurophysiological correlates of placebo
response can be measured at the level of the individual brain cell in awake patients by
using electrodes implanted for deep brain stimulation. In a study building on that by
Benedetti and colleagues (Benedetti et al. 2004), Fisaldi and colleagues examined the pla-
cebo response in Parkinson’s disease through single-​unit recordings throughout the basal
ganglia (Frisaldi et al. 2014). These studies were critical to connect previous studies that
separately indicated changes in downstream neurophysiology in the subthalamic nucleus
(Benedetti et al. 2004) and the facilitation of this effect mediated by changes in expecta-
tion and reward pathways (De La Fuente-​Fernandez et al. 2001). They were able to dem-
onstrate that critical areas affected in Parkinson’s disease, subthalamic nucleus, and the
substantia nigra pars reticulata as well as the ventral anterior thalamus were involved in
the placebo response. Frisaldi and colleagues were also able to compare patterns of activ-
ity between placebo responders and nonresponders (Frisaldi et al. 2014).
In sum, we see the development of an evolving model of placebo (Diederich & Goetz
2008) that suggests that high-​order brain regions (such as the prefrontal and cingulate
cortices) modulate pathways involved in expectation and reward processing (such as the
ventral striatum). In turn, changes in these pathways affect disease-​specific or condition-​
specific pathways—​the dorsal striatum in Parkinson disease, the midbrain in modulation
of opioid release for pain relief, and the amygdala and limbic areas to mimic serotonin
reuptake inhibitors in depression (Mayberg et al. 2002). Enck and colleagues postulate
that placebo is a kind of evolved “endogenous healthcare system” (Enck et al. 2008).
 25

Deception 225

More recent studies have explored possible biomarkers and genetic polymorphisms
such as enzymes that metabolize catecholamines like catechol-​O-​methyl transferase, that
would make one more susceptible to placebo responses, the so-​called placebome (Hall
et  al. 2012, 2015). These studies, along with the notion of placebo effects as a product
of social learning or classical conditioning (even in nonhuman animals), suggest that
placebo responses are biological and evolutionarily conserved (Colloca & Miller 2011a).
Evolutionary psychologist Nicholas Humphrey proposes that typical bodily response to
stressors such as pain or anxiety are counteracted by placebo responses using hope to
counteract pain and anxiety and engaging internal healing mechanisms instead of shut-
ting down (Humphrey 2002). While there is no shortage of future empirical research
needed to further elucidate such mechanisms, this research has moved past its infancy
and warrants more sophisticated integration into practical applications of placebo therapy.

Deception
A seemingly universal tenet of medical ethics is the belief that good practice requires hon-
esty and forbids deceit. The clearest ethical violation of placebo therapy is not necessarily
the use of the placebo itself, but the secreted nature of this use. The use is hidden not just
to the patient, but also from other physicians in the healthcare team.

Deception and physician belief

The AMA’s recommendation against placebos defines placebo as “a substance provided
to a patient that the physician believes has no specific pharmacological effect upon the
condition being treated.” Therefore the troubling act of placebo administration is that
physicians are knowingly using substances that they believe are inert to treat patients.
Given the body of mechanistic evidence of placebo and its effect outlined earlier, one
might argue that to assert that placebos are inert is either willful ignorance or an active
choice to not practice evidence-​based medicine, its own brand of ethical violation. If phy-
sicians believe placebos are not inert, is it still a violation of AMA guidelines? According
to some studies, 96% of physicians who utilize placebo believe that the placebo offers
physiological benefit to patients (Sherman & Hickner 2008; Kermen et al. 2010). This is
also an important counterargument to placebo critics who voice concerns related to the
physicians mal-​intent, that is, physicians are trying to punish patients, relieve their own
frustrations, or trick patients into revealing that their symptoms are not real when using
placebo (Purtilo 1993). Studies suggesting physicians are using placebos because they do
not believe placebos are inert does not eliminate the possibility of mal-​intent. Were pla-
cebo to be adopted openly into routine use, mal-​intent would need to be monitored, but
mal-​intent is likely not to be the primary driving force behind placebo therapy.

Deception and patient autonomy

Protecting patient autonomy is a prominent ethical concern around placebo practice.
To truly empower patients, healthcare practitioners must be sure of what patients want;
26

226 Placebo beyond controls

the answer to this question must be empirically informed. A handful of studies report
actual collected data on patient preferences about placebo treatment. A study of patients
from Sweden revealed that patients were, perhaps surprisingly, stronger (25% of patients)
advocates of deceptive placebo than physicians (7% of physicians) (Lynoe et  al. 1993).
In a more recent study, US respondents reported significant acceptance of placebos with
some respondents supportive of deceptive placebo (Hull et al. 2013). It remains unclear
precisely how patients are conceptualizing placebos. In a study by Bishop and colleagues,
while many patients reported supporting placebo usage, particularly if there were per-
ceived beneficial outcomes, those who had negative views of placebo interpreted the
term “placebo” as synonymous with “ineffective” and requiring deception (Bishop et al.
2014). Similar studies will need to be conducted before generalizing results, but these data
should give us pause before categorically prohibiting placebo usage, deceptive or other-
wise, in the name of protecting patient autonomy.
In a paper advocating for “Paternalism and partial autonomy,” O’Neill argued that
deception associated with placebo does not infringe upon patient autonomy because it
does not infringe upon fundamental aspects of care (O’Neill 1984), and Barnehill has
argued that the “fundamental aspects” of care are the purpose of the treatment and that
the mechanism of action is ancillary (Barnhill 2011). Not unlike Barnehill, I have argued,
the deciding factor of what is ancillary information or not should be based on empirical
investigation of patient’s attitudes about placebo administration (Rommelfanger 2013b),
and at the very least determinations of what counts as fundamental should be strongly
informed by such data. A way forward is for medicine to strive for a scenario in which
patients are informed about the nature of placebo and its potential uses rather than purely
relying on patient intuitions (Blease et al. 2016). However, making decisions, that is, joint
care decisions, about whether deceptive or open-​label placebo is the appropriate way for-
ward should be informed by patient values.

Deception and disclosure

As discussed in “Deception and physician belief,” the AMA Code of Medical Ethics pro-
hibited the deceptive use of placebo as of 2006. However, what if deception could be elim-
inated from the equation and was not required to gain benefit from placebo? In a study
from 2010, researchers found that placebo effects were maintained even when patients
were aware that they are being given placebo (Kaptchuk et al. 2010). Patients with irritable
bowel syndrome experienced relief from their symptoms after being told they would be
given “placebo (inert) pills, which were like sugar pills which [sic] had been shown to
have self-​healing properties.” While not as well known, an earlier study from 1965 dem-
onstrated similar results in patients with somatic symptoms in a non-​blind placebo trial
of a week’s worth of sugar pills (Park & Covi 1965).
Sandler and colleagues used placebo in a conditioned placebo dose reduction paradigm
in 99 children between the ages of 6 and 12 with attention deficit hyperactivity disorder
(Sandler et al. 2010). In this study, children who began on their full optimal stimulant
dose were then given 50% of this dose for 1 month either with or without a placebo. Both
 27

A new way forward? 227

children and their parents were told that they would receive placebo as a dose extender.
Importantly, they were told that the placebo contained no active pharmaceutical ingredi-
ent. The reduced dose plus placebo was not only more effective than the 50% dose alone,
but also was just as effective as the full optimal dose, once again demonstrating that that
placebo can be used without deception to elicit positive therapeutic results. These find-
ings also suggest placebo need not replace existing treatments, but can also be used to
modify existing treatments—​in this case to reduce the dose of medication that is poten-
tially addictive to children.
A common intuition is that once placebo is revealed, it can no longer have its effects.
Schafer and colleagues addressed this topic by first giving participants deceptive topical
cream placebo to elicit the placebo analgesia. Then participants were told explicitly that
the cream was simply petroleum jelly with blue food coloring and participants were even
shown how the placebo cream was prepared (Schafer et al. 2015). Participants continued
to experience placebo-​induced analgesia even after being told about and visually seeing
the inert components of the cream, demonstrating that revealing that an intervention is a
placebo, after experiencing placebo effects during blinded administration, does not nec-
essarily impact the placebo’s future ability to elicit positive effects. Taken together, we see
several models of effective non-​deceptive placebo therapy applications.

A new way forward?

Given the emerging mechanistic information on placebo and that deception is not neces-
sary to elicit a placebo response, at least in some paradigms (Kaptchuk et al. 2010; Schafer
et al. 2015), how might we conceptualize an ethical way forward? How might we refine
our definitions of deception, autonomy, and informed consent to ultimately advance
patient care?
Placebo studies may be used to investigate how to improve general clinical practices.
For example, in one experimental model of pain, participants were divided into three
groups and given a novel or established analgesic—​both placebos: choice, wherein par-
ticipant could choose the analgesic; no-​choice, wherein participants were instructed
which analgesic to use; and a control group who was not given a choice but also not given
expectations of the analgesic’s efficacy (Rose et al. 2012). The choice group had the high-
est placebo effect suggesting that enhanced patient involvement elicited greater placebo
responses and perhaps might even be used to inform patient-​centered medicine (Rose
et al. 2012; Fleurence et al. 2013). Varying role and levels of choice a patient is given might
help to improve placebo responses and perhaps even standard treatment outcomes.
It is also known that open administration of analgesics delivered by a computer-​
controlled infusion pump can result in greater pain relief than concealed administra-
tion. While hidden administration of the analgesic resulted in pain relief and associated
decreased activity in regions of the brain associated with pain processing, pain relief of
open administration of the drug doubled this activation with the recruitment of the pre-
genual anterior cingulate and dorsolateral prefrontal cortex associated with expectation
28

228 Placebo beyond controls

(Benedetti et al. 2011; Bingel et al. 2011). Conversely, describing potential adverse side
effects of interventions can elicit nocebo effects or a higher likelihood of experiencing
those negative side effects (Amanzio et al. 2009). Nocebo has become such a prominent
concern that researchers self-​identified as the “placebo competence team” have argued
for a professional imperative to decrease negative expectations of interventions (Bingel &
Placebo Competence Team 2014). This suggests not just open, but conspicuous adminis-
tration of standard drugs may be helpful in augmenting their effects and possibly reduce
adverse effects of drugs where long-​term use is detrimental to patient health. These results
also suggest a need for changes in the way informed consent is conceptualized and perhaps
even a need to inform of potential nocebo effects as a consequence of over-​informing.
Placebos may become an attractive candidate for personalized therapy and based on pre-
vious studies about expectancy and conditioning. However, it would be imperative to
acknowledge that each patient may have a completely different history and experience
with medication, therapeutic encounters, and series of symbols for understanding their
therapeutic encounters.
To be clear, administration of placebos is not harmless. Deceptive placebos can be
harmful in the case of active or impure substances that are subthreshold doses of medi-
cation. Foddy argues that “placebos are always safe,” and “are sometimes the best treat-
ment” (Foddy 2009). If placebos do have specific physiological effects that could possibly
impact disease pathways then not only are they not inert, but also they could possibly
be contraindicated (Rommelfanger 2013b). If placebo is surreptitiously administered, it
may hamper the rest of the healthcare team’s efforts to address adverse events related to
placebo. Further, as others and I (Freedman 1990; La Vaque and Rossiter 2001; Foddy
2009; Rommelfanger 2013b) have argued, it would be unethical to prescribe placebos in
the place of established successful standards of care or if a better treatment became avail-
able. Placebos need not replace existing successful therapies; they may be able to augment
or supplement existing therapies (Ader et al. 2010; Sandler et al. 2010). Future placebo
research could be directed toward reducing side effects or mitigating addictive potential
of select therapies.
Perhaps one of the greatest potential gains in devoting research to placebo and its
mechanism is to break down silos and move toward perceiving health more holistically.
Current secretive placebo practices can largely be attributed to an entrenched belief in our
medical care system that the mind is somehow separate from the body. Bodily disorders
enjoy the privilege of being legitimate problems and in turn escape the stigma, blamewor-
thiness, and illness invalidation that accompany the stigma of a disorder that is consid-
ered to be psychological (Kendell 2001; Miresco & Kirmayer 2006). Placebo effects have
been similarly dismissed as a phenomenon of the mind, and therefore non-​physiological
or nonspecific in origin and illegitimate (Lichtenberg et al. 2004). The emerging neurosci-
ence data suggest the placebo story is more multifaceted. Therefore, a renewed explora-
tion of placebo with these data in mind offers an opportunity to disrupt this division of
mind versus body and provides an opportunity to redress the resulting confusion.
 29

References 229

It is also critical to note that the rise of biomedicine has been critiqued as creating an
impractical dichotomy between disease seen as objectively measurable, and illness seen
as the patient’s subjective experience (Kleinman 1988), and there certainly is a danger
of using neuroscience of placebo (Miller & Brody 2011)  to reinforce this dichotomy.
Contemporary Western medicine is besotted with biomarkers and biological mechanisms
and some have argued to the detriment of the patient (Kleinman 1988); the patient’s sub-
jective experience of their improvement is confirmation of the measured biological out-
come and not converse.
However, until recently, the perceived improvement or placebo effects reported by
patients were interpreted in the popular imagination as purely subjective and without a
biomarker of their effects, were limited to subjective improvement. The emerging neuro-
physiological correlates to placebo should not be interpreted as neuroscience usurping the
import of social and psychological science, anthropology, or humanities in the conversa-
tion, but should be a reminder that conversations about human health must continue to
be conducted with humility with an openness toward cross-​disciplinary discussion and
design. These data invite a broader conversation about the healthcare context, what we
mean by evidence-​based medicine, and how we, as a society, balance the value of holistic
patient care.
In some ways, to keep abreast of the emerging data on placebo is extremely threatening
in a healthcare model where physicians are pressured to increase the number of patients
and feel pressures to shorten visits—​devaluing the intricacies of the context of the thera-
peutic encounter—​to meet productivity quotas in an assembly line style of healthcare
(Konrad et al. 2010). While these financial concerns are legitimate and pragmatic, there
may be a missed opportunity to utilize placebo therapy to minimize unnecessary expen-
ditures. The clear way forward is that placebos become a therapeutic target and a subject
of empirical research—​rather than psychological contamination—​and a fertile area of
investigation in its own right.

References
Adam, H., Obodaru, O., and Galinsky, A.D. (2015). Who you are is where you are: antecedents and
consequences of locating the self in the brain or the heart. Organizational Behavior and Human
Decision Processes, 128, 74–​83.
Ader, R., Mercurio, M.G., Walton, J., et al. (2010). Conditioned pharmacotherapeutic effects: a
preliminary study. Psychosomatic Medicine, 72, 192–​197.
Amanzio, M. and Benedetti, F. (1999). Neuropharmacological dissection of placebo
analgesia: expectation-​activated opioid systems versus conditioning-​activated specific subsystems.
Journal of Neuroscience, 19, 484–​494.
Amanzio, M., Corazzini, L.L., Vase, L., and Benedetti, F. (2009). A systematic review of adverse events
in placebo groups of anti-​migraine clinical trials. Pain, 146, 261–​269.
American Medical Association (2007). Opinion 8.083: Placebo Use in Clinical Practice. American
Medical Association. Available from: http://​www.ama-​assn.org/​ama/​pub/​physician-​resources/​
medical-​ethics/​code-​medical-​ethics/​opinion8083.page? [accessed April 25, 2016].
230

230 Placebo beyond controls

Barnhill, A. (2011). What it takes to defend deceptive placebo use. Kennedy Institute of Ethics Journal,
21, 219–​250.
Beauchamp, T.L. and Childress, J.F. (2009). Principles of Biomedical Ethics. New York: Oxford
University Press.
Bendtsen, L., Mattsson, P., Zwart, J.A., and Lipton, R.B. (2003). Placebo response in clinical
randomized trials of analgesics in migraine. Cephalalgia, 23, 487–​490.
Benedetti, F. (2006). Placebo analgesia. Neurological Sciences, 27(Suppl. 2), S100–​S102.
Benedetti, F. (2014). Placebo effects: from the neurobiological paradigm to translational implications.
Neuron, 84, 623–​637.
Benedetti, F., Pollo, A., Lopiano, L., et al. (2003). Conscious expectation and unconscious conditioning
in analgesic, motor, and hormonal placebo/​nocebo responses. Journal of Neuroscience, 23, 4315–​423.
Benedetti, F., Colloca, L., Torre, E., et al. (2004). Placebo-​responsive Parkinson patients show decreased
activity in single neurons of subthalamic nucleus. Nature Neuroscience, 7, 587–​588.
Benedetti, F., Carlino, E., and Pollo, A. (2011). Hidden administration of drugs. Clinical Pharmacology &
Therapeutics, 90, 651–​661.
Bingel, U. and Placebo Competence Team (2014). Avoiding nocebo effects to optimize treatment
outcome. JAMA, 312, 693–​694.
Bingel, U., Wanigasekera, V., Wiech, K., et al. (2011). The effect of treatment expectation on drug
efficacy: imaging the analgesic benefit of the opioid remifentanil. Science Translational Medicine, 3,
70ra14.
Bishop, F.L., Aizlewood, L., and Adams, A.E. (2014). When and why placebo-​prescribing is acceptable
and unacceptable: a focus group study of patients’ views. PLoS One, 9, e101822.
Blease, C. (2012). The principle of parity: the “placebo effect” and physician communication. Journal of
Medical Ethics, 38, 199–​203.
Blease, C., Colloca, L., and Kaptchuk, T.J. (2016). Are open-​label placebos ethical? informed consent
and ethical equivocations. Bioethics, 30(6), 407–​414.
Bostick, N.A., Sade, R., Levine, M.A., and Stewart, D.M., Jr. (2008). Placebo use in clinical
practice: report of the American Medical Association Council on Ethical and Judicial Affairs.
Journal of Clinical Ethics, 19, 58–​61.
Brody, H. (1982). The lie that heals: the ethics of giving placebos. Annals of Internal Medicine, 97,
112–​118.
Brody, H., Colloca, L., and Miller, F.G. (2012). The placebo phenomenon: implications for the ethics of
shared decision-​making. Journal of General Internal Medicine, 27, 739–​742.
Burton, R. (1621). The Anatomy of Melancholy. [Reprinted in 2001 by The New York Review of Books,
New York.]
Colloca, L. and Benedetti, F. (2005). Placebos and painkillers: is mind as real as matter? Nature Reviews
Neuroscience, 6, 545–​552.
Colloca, L. and Benedetti, F. (2006). How prior experience shapes placebo analgesia. Pain, 124, 126–​133.
Colloca, L. and Benedetti, F. (2009). Placebo analgesia induced by social observational learning. Pain,
144, 28–​34.
Colloca, L. and Miller, F.G. (2011a). Harnessing the placebo effect: the need for translational research.
Philosophical Transactions of the Royal Society B: Biological Sciences, 366, 1922–​1930.
Colloca, L. and Miller, F.G. (2011b). How placebo responses are formed: a learning perspective.
Philosophical Transactions of the Royal Society B: Biological Sciences, 366, 1859–​1869.
De La Fuente-​Fernandez, R., Ruth, T.J., Sossi, V., et al. (2001). Expectation and dopamine
release: mechanism of the placebo effect in Parkinson’s disease. Science, 293, 1164–​1166.
 231

References 231

De La Fuente-​Fernandez, R., Schulzer, M., and Stoessl, A.J. (2004). Placebo mechanisms and reward
circuitry: clues from Parkinson’s disease. Biological Psychiatry, 56, 67–​71.
Di Blasi, Z., Harkness, E., Ernst, E., Georgiou, A., and Kleijnen, J. (2001). Influence of context effects
on health outcomes: a systematic review. The Lancet, 357, 757–​762.
Diederich, N.J. and Goetz, C.G. (2008). The placebo treatments in neurosciences: new insights from
clinical and neuroimaging studies. Neurology, 71, 677–​684.
Dworkin, R.H., Katz, J., and Gitlin, M.J. (2005). Placebo response in clinical trials of depression and its
implications for research on chronic neuropathic pain. Neurology, 65, S7–​19.
Enck, P., Benedetti, F., and Schedlowski, M. (2008). New insights into the placebo and nocebo
responses. Neuron, 59, 195–​206.
Espay, A.J., Norris, M.M., Eliassen, J.C., et al. (2015). Placebo effect of medication cost in Parkinson
disease: a randomized double-​blind study. Neurology, 84, 794–​802.
Evers, K. (2007). Towards a philosophy for neuroethics. An informed materialist view of the brain
might help to develop theoretical frameworks for applied neuroethics. EMBO Reports, 8(Spec No.),
S48–​51.
Fassler, M., Gnadinger, M., Rosemann, T., and Biller-​Andorno, N. (2011). Placebo interventions in
practice: a questionnaire survey on the attitudes of patients and physicians. British Journal of General
Practice, 61, 101–​107.
Fassler, M., Meissner, K., Schneider, A., and Linde, K. (2010). Frequency and circumstances of placebo
use in clinical practice –​a systematic review of empirical studies. BMC Medicine, 8, 15.
Fent, R., Rosemann, T., Fassler, M., Senn, O., and Huber, C.A. (2011). The use of pure and impure
placebo interventions in primary care—​a qualitative approach. BMC Family Practice, 12, 11.
Finniss, D.G., Kaptchuk, T.J., Miller, F., and Benedetti, F. (2010). Biological, clinical, and ethical
advances of placebo effects. The Lancet, 375, 686–​695.
Fleurence, R., Selby, J.V., Odom-​Walker, K., et al. (2013). How the Patient-​Centered Outcomes
Research Institute is engaging patients and others in shaping its research agenda. Health Affairs
(Millwood), 32, 393–​400.
Foddy, B. (2009). A duty to deceive: placebos in clinical practice. American Journal of Bioethics, 9, 4–​12.
Ford, P.L. (1898). The Writings of Thomas Jefferson. New York: Putnam.
Freedman, B. (1990). Placebo-​controlled trials and the logic of clinical purpose. IRB, 12, 1–​6.
Frisaldi, E., Carlino, E., Lanotte, M., Lopiano, L., and Benedetti, F. (2014). Characterization of the
thalamic-​subthalamic circuit involved in the placebo response through single-​neuron recording in
Parkinson patients. Cortex, 60, 3–​9.
Goebel, M.U., Trebst, A. E., Steiner, J., et al. (2002). Behavioral conditioning of immunosuppression is
possible in humans. FASEB Journal, 16, 1869–​1873.
Goebel, M.U., Hubell, D., Kou, W., et al. (2005). Behavioral conditioning with interferon beta-​1a in
humans. Physiology & Behavior, 84, 807–​814.
Goetz, C.G., Wuu, J., McDermott, M.P., et al. (2008). Placebo response in Parkinson’s
disease: comparisons among 11 trials covering medical and surgical interventions. Movement
Disorders, 23, 690–​699.
Guo, J.Y., Wang, J.Y., and Luo, F. (2010). Dissection of placebo analgesia in mice: the conditions for
activation of opioid and non-​opioid systems. Journal of Psychopharmacology, 24, 1561–​1567.
Guo, J.Y., Yuan, X.Y., Sui, F., et al. (2011). Placebo analgesia affects the behavioral despair tests and
hormonal secretions in mice. Psychopharmacology (Berlin), 217, 83–​90.
Hall, K.T., Lembo, A.J., Kirsch, I., et al. (2012). Catechol-​O-​methyltransferase val158met
polymorphism predicts placebo effect in irritable bowel syndrome. PLoS One, 7, e48135.
23

232 Placebo beyond controls

Hall, K.T., Loscalzo, J., and Kaptchuk, T.J. (2015). Genetics and the placebo effect: the placebome.
Trends in Molecular Medicine, 21, 285–​294.
Howick, J., Bishop, F.L., Heneghan, C., et al. (2013). Placebo use in the United Kingdom: results from a
national survey of primary care practitioners. PLoS One, 8, e58247.
Hrobjartsson, A. and Norup, M. (2003). The use of placebo interventions in medical practice –​a
national questionnaire survey of Danish clinicians. Evaluation & the Health Professions, 26, 153–​165.
Hull, S.C., Colloca, L., Avins, A., et al. (2013). Patients’ attitudes about the use of placebo
treatments: telephone survey. BMJ, 347, f3757.
Humphrey, N. (2002). Great Expectations: The Evolutionary Psychology of Faith Healing and Placebo
Effect. Oxford: Oxford University Press.
Kam-​Hansen, S., Jakubowski, M., Kelley, J.M., et al. (2014). Altered placebo and drug labeling changes
the outcome of episodic migraine attacks. Science Translational Medicine, 6, 218ra5.
Kaptchuk, T.J., Kelley, J.M., Conboy, L.A., et al. (2008). Components of placebo effect: randomised
controlled trial in patients with irritable bowel syndrome. BMJ, 336, 999–​1003.
Kaptchuk, T.J., Friedlander, E., Kelley, J.M., et al. (2010). Placebos without deception: a randomized
controlled trial in irritable bowel syndrome. PLoS One, 5, e15591.
Kendell, R.E. (2001). The distinction between mental and physical illness. British Journal of Psychiatry,
178, 490–​493.
Kermen, R., Hickner, J., Brody, H., and Hasham, I. (2010). Family physicians believe the placebo effect
is therapeutic but often use real drugs as placebos. Family Medicine, 42, 636–​642.
Kirsch, I. (2004). Conditioning, expectancy, and the placebo effect: comment on Stewart-​Williams and
Podd (2004). Psychological Bulletin, 130, 341–​343.
Kleinman, A. (1988). The Illness Narratives: Suffering, healing and the Human Condition.
New York: Basic Books.
Konrad, T.R., Link, C.L., Shackelton, R.J., et al. (2010). It’s about time: physicians’ perceptions of time
constraints in primary care medical practice in three national healthcare systems. Medical Care, 48,
95–​100.
La Vaque, T.J. and Rossiter, T. (2001). The ethical use of placebo controls in clinical research: the
Declaration of Helsinki. Applied Psychophysiology and Biofeedback, 26, 23–​37.
Lee, I.S., Lee, B., Park, H.J., et al. (2015). A new animal model of placebo analgesia: involvement of the
dopaminergic system in reward learning. Scientific Reports, 5, 17140.
Lichtenberg, P., Heresco-​Levy, U., and Nitzan, U. (2004). The ethics of the placebo in clinical practice.
Journal of Medical Ethics, 30, 551–​554.
Lidstone, S.C., Schulzer, M., Dinelle, K., et al. (2010). Effects of expectation on placebo-​induced
dopamine release in Parkinson disease. Archives of General Psychiatry, 67, 857–​865.
Lou, J.S., Dimitrova, D.M., Hammerschlag, R., et al. (2013). Effect of expectancy and personality on
cortical excitability in Parkinson’s disease. Movement Disorders, 28, 1257–​1262.
Lui, F., Colloca, L., Duzzi, D., et al. (2010). Neural bases of conditioned placebo analgesia. Pain, 151,
816–​824.
Luparello, T., Lyons, H.A., Bleecker, E.R., and Mcfadden, E.R., Jr. (1968). Influences of suggestion on
airway reactivity in asthmatic subjects. Psychosomatic Medicine, 30, 819–​825.
Luparello, T.J., Leist, N., Lourie, C.H., and Sweet, P. (1970). The interaction of psychologic stimuli
and pharmacologic agents on airway reactivity in asthmatic subjects. Psychosomatic Medicine, 32,
509–​513.
Lynoe, N., Mattsson, B., and Sandlund, M. (1993). The attitudes of patients and physicians towards
placebo treatment –​a comparative study. Social Science & Medicine, 36, 767–​774.
 23

References 233

Mayberg, H.S., Silva, J.A., Brannan, S.K., et al. (2002). The functional neuroanatomy of the placebo
effect. American Journal of Psychiatry, 159, 728–​737.
Meissner, K., Hofner, L., Fassler, M., and Linde, K. (2012). Widespread use of pure and impure placebo
interventions by GPs in Germany. Family Practice, 29, 79–​85.
Mercado, R., Constantoyannis, C., Mandat, T., et al. (2006). Expectation and the placebo effect in
Parkinson’s disease patients with subthalamic nucleus deep brain stimulation. Movement Disorders,
21, 1457–​1461.
Miller, F.G. and Brody, H. (2011). Understanding and harnessing placebo effects: clearing away the
underbrush. Journal of Medicine and Philosophy, 36, 69–​78.
Miller, F.G. and Kaptchuk, T.J. (2008). The power of context: reconceptualizing the placebo effect.
Journal of the Royal Society of Medicine, 101, 222–​225.
Miller, F.G., Colloca, L., and Kaptchuk, T.J. (2009). The placebo effect: illness and interpersonal healing.
Perspectives in Biology and Medicine, 52, 518–​539.
Miresco, M.J. and Kirmayer, L.J. (2006). The persistence of mind-​brain dualism in psychiatric
reasoning about clinical scenarios. American Journal of Psychiatry, 163, 913–​918.
Moerman, D.E. (2002). The meaning response and the ethics of avoiding placebos. Evaluation & the
Health Professions, 25, 399–​409.
Moerman, D.E. and Jonas, W.B. (2002). Deconstructing the placebo effect and finding the meaning
response. Annals of Internal Medicine, 136, 471–​476.
Montgomery, G.H. and Kirsch, I. (1997). Classical conditioning and the placebo effect. Pain, 72,
107–​113.
Nolan, T.A., Price, D.D., Caudle, R.M., Murphy, N.P., and Neubert, J.K. (2012). Placebo-​induced
analgesia in an operant pain model in rats. Pain, 153, 2009–​2016.
O’Neill, O. (1984). Paternalism and partial autonomy. Journal of Medical Ethics, 10, 173–​178.
Park, L.C. and Covi, L. (1965). Nonblind placebo trial: an exploration of neurotic patients’ responses
to placebo when its inert content is disclosed. Archives of General Psychiatry, 12, 36–​45.
Pavlov, I.P. (1927). Conditioned Reflexes: An Investigation of the Physiological Activity of the Cerebral
Cortex. London: Oxford University Press.
Petrovic, P., Dietrich, T., Fransson, P., et al. (2005). Placebo in emotional processing –​induced
expectations of anxiety relief activate a generalized modulatory network. Neuron, 46, 957–​969.
Pollo, A., Amanzio, M., Arslanian, A., et al. (2001). Response expectancies in placebo analgesia and
their clinical relevance. Pain, 93, 77–​84.
Pugh, J. (2015). Ravines and sugar pills: defending deceptive placebo use. Journal of Medicine and
Philosophy, 40, 83–​101.
Pugh, J., Kahane, G., Maslen, H., and Savulescu, J. (2016). Lay attitudes toward deception in
medicine: theoretical considerations and empirical evidence. AJOB Empirical Bioethics, 7, 31–​38.
Purtilo, R. (1993). Ethical Dimensions in the Health Care Professions. Philadelphia, PA: WB Saunders.
Racine, E., Waldman, S., Rosenberg, J., and Illes, J. (2010). Contemporary neuroscience in the media.
Social Science & Medicine, 71, 725–​733.
Rommelfanger, K.S. (2013a). Attitudes on mind over matter: physician views on the role of placebo in
psychogenic disorders. American Journal of Bioethics Neuroscience, 4, 9–​15.
Rommelfanger, K.S. (2013b). Opinion: a role for placebo therapy in psychogenic movement disorders.
Nature Reviews Neurology, 9, 351–​356.
Rose, J.P., Geers, A.L., Rasinski, H.M., and Fowler, S.L. (2012). Choice and placebo expectation effects
in the context of pain analgesia. Journal of Behavioral Medicine, 35, 462–​470.
Rosenberg, C.E. (2002). The tyranny of diagnosis: specific entities and individual experience. Milbank
Quarterly, 80, 237–​260.
234

234 Placebo beyond controls

Roskies, A.L. (2007). Neuroethics beyond genethics. Despite the overlap between the ethics of
neuroscience and genetics, there are important areas where the two diverge. EMBO Reports, 8(Spec
No.), S52–​56.
Sandler, A.D., Glesne, C.E., and Bodfish, J.W. (2010). Conditioned placebo dose reduction: a new
treatment in attention-​deficit hyperactivity disorder? Journal of Developmental and Behavioral
Pediatrics, 31, 369–​375.
Schafer, S.M., Colloca, L., and Wager, T.D. (2015). Conditioned placebo analgesia persists when
subjects know they are receiving a placebo. Journal of Pain, 16, 412–​420.
Schultz, W. (2006). Behavioral theories and the neurophysiology of reward. Annual Review of
Psychology, 57, 87–​115.
Scott, D.J., Stohler, C.S., Egnatuk, C.M., et al. (2008). Placebo and nocebo effects are defined by
opposite opioid and dopaminergic responses. Archives of General Psychiatry, 65, 220–​231.
Shanks, D.R. (2010). Learning: from association to cognition. Annual Review of Psychology, 61,
273–​301.
Sherman, R. and Hickner, J. (2008). Academic physicians use placebos in clinical practice and believe
in the mind-​body connection. Journal of General Internal Medicine, 23, 7–​10.
Spiro, H.M. (1986). Doctors, Patients, and Placebos. London: Yale University Press.
Stewart-​Williams, S. and Podd, J. (2004). The placebo effect: dissolving the expectancy versus
conditioning debate. Psychological Bulletin, 130, 324–​340.
Tilburt, J.C., Emanuel, E.J., Kaptchuk, T.J., Curlin, F.A., and Miller, F.G. (2008). Prescribing
“placebo treatments”: results of national survey of US internists and rheumatologists. BMJ,
337, a1938.
Tuttle, A.H., Tohyama, S., Ramsay, T., et al. (2015). Increasing placebo responses over time in
U.S. clinical trials of neuropathic pain. Pain, 156, 2616–​2626.
Van Laarhoven, A.I., Vogelaar, M.L., Wilder-​Smith, O.H., et al. (2011). Induction of nocebo and
placebo effects on itch and pain by verbal suggestions. Pain, 152, 1486–​1494.
Wager, T.D., Scott, D.J., and Zubieta, J.K. (2007). Placebo effects on human mu-​opioid activity
during pain. Proceedings of the National Academy of Sciences of the United States of America, 104,
11056–​11061.
Yang, Q. and Miller, G. (2015). East-​West differences in perception of brain death. Review of history,
current understandings, and directions for future research. Journal of Bioethical Inquiry, 12,
211–​225.
Zhang, R.R., Zhang, W.C., Wang, J.Y., and Guo, J.Y. (2013). The opioid placebo analgesia is mediated
exclusively through mu-​opioid receptor in rat. International Journal of Neuropsychopharmacology,
16, 849–​856.
Zubieta, J.K., Bueller, J.A., Jackson, L.R., et al. (2005). Placebo effects mediated by endogenous opioid
activity on mu-​opioid receptors. Journal of Neuroscience, 25, 7754–​7762.
 235

Chapter 13

Ethical challenges of modern

psychiatric neurosurgery
Sabine Müller

Introduction
Until the 1970s, rather crude forms of psychosurgery had been used in hundreds of
thousands of mentally ill patients (Valenstein 1986; Diering & Bell 1991; Chodakiewitz
et al. 2015). The abuse of psychosurgery was brought to the public consciousness by Ken
Kesey’s famous novel One Flew Over the Cuckoo’s Nest (Kesey 1964). Due to public criti-
cism and, coincidentally, the development of antipsychotic drugs, psychosurgery was
nearly completely abandoned and forbidden in many countries. Since 1999, after a nearly
30-​year hiatus, there is a renaissance of psychiatric neurosurgery in a much more refined
and safer form. Today it is developing quickly as an experimental therapy for medically
refractory psychiatric disorders (Lévèque et al. 2013; Luigjes et al. 2013; Lévèque 2014;
Sun & De Salles 2015) that are not caused directly by identified brain anatomical or func-
tional pathologies, such as brain tumors or epileptogenic tissue, and for which biologi-
cal underpinnings are unknown. Nonetheless, psychiatric neurosurgery is based on the
assumption that certain dysfunctional brain areas or structures play a crucial role in psy-
chiatric disorders, and that lesioning or deactivating them can alleviate psychiatric symp-
toms. For example, the cortico-​striato-​thalamo-​cortical loop is strongly implicated in the
pathogenesis of obsessive–​compulsive disorder (OCD). Decreased frontal-​striatal control
of limbic structures such as the amygdala might account for the inadequate fear response
seen in OCD patients with fear of contamination (Na et al. 2015). Thus, knowledge of
the interconnected neural circuits underlies hypothesis-​driven rationales for choosing
particular targets of neurosurgical intervention (Na et al. 2015).
Many researchers and clinicians expect that modern psychiatric neurosurgery has the
potential to become a safe and effective treatment option for severe, therapy-​refractory
psychiatric disorders. According to a recent survey, about 90% of functional neurosur-
geons feel optimistic about the future of psychiatric neurosurgery (Lipsman et al. 2011;
Mendelsohn et al. 2013).
Currently, such psychiatric neurosurgical procedures include deep brain stimulation
(DBS) and ablative neurosurgical procedures. Because DBS is an established therapy for
treatment-​refractory Parkinson’s disease, essential tremor and dystonia, and because it is
considered reversible, its experimental use for treating psychiatric disorders was seen as
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236 Ethical challenges of modern psychiatric neurosurgery

justifiable by most commentators. Indeed, high-​frequency DBS creates temporary lesions

by deactivating the targeted brain areas through chronic electrical current. Thus, areas
that are assumed to be hyperactive in people with psychiatric disorders can be inhibited
as long as the stimulation is activated. Since its effect can be adjusted through fine-​tuning
the stimulation parameters, DBS is considered also to be a neuromodulatory technique.
In the wake of psychiatric DBS, ablative neurosurgical procedures are seeing a revival.
The ablative neurosurgical procedures currently in use comprise thermocoagulation or
radiofrequency ablation procedures, and Gamma Knife® radiosurgery. The latter is a non-
invasive and very precise method for creating confined brain lesions. Moreover, a new
technique has recently been introduced into the field: magnetic resonance-​guided focused
ultrasound (MRgFUS), which has been tested in the first four psychiatric patients (Na
et al. 2015). Most recent developments aim at controlling the brain situation-​specifically.
Such developments comprise closed-​loop DBS (Tass 2003; Rosin et al. 2011), DBS com-
bined with optogenetics (Deisseroth 2012; Walter and Müller S. 2013), as well as implant-
able devices that measure continuously the brain activity and initiate counter-​measures
(e.g., warning signals or painful stimuli) as soon as suspicious arousal is detected (Cook
et al. 2013; Gilbert 2015). Since modern psychiatric neurosurgery procedures are much
safer and more effective than their historical predecessors, it would not be justified to
condemn them generally. Rather, a careful re-​evaluation of these techniques is neces-
sary. Characterizing modern ablative procedures as successors of historical psychosur-
gery while considering DBS as something quite different is unwarranted. In reality, both
psychiatric DBS as well as modern ablative psychiatric neurosurgery are significantly
improved successors of the historical psychosurgery.
From a medical perspective, each of these types of procedures has different profiles of
advantages and disadvantages such that none can be considered absolutely superior over
another. Specifically, DBS advantages include adjustability and a high degree of reversibil-
ity, whereas microsurgical ablative procedures have a rapid onset of action, and radiosur-
gery and MRgFUS are noninvasive and have low rates of adverse effects.
The use of all methods of psychiatric neurosurgery raises difficult ethical and legal
issues. A fundamental issue is whether it is justified to intervene directly in the brain of
mentally ill patients with the risk or even with the aim to change personality and behavior.
Even if this question is answered in the affirmative, many ethical issues remain:
◆ What is the risk:benefit ratio of the different methods?
◆ Who shall decide how the patient’s mood and personality are to be changed and
according to which criteria?
◆ Can the autonomy of patients be respected, in particular if their capacity for autono-
mous decision-​making is affected by their psychiatric disorder or as a consequence of
the intervention?
◆ For which kind of disorders is psychiatric neurosurgery justified?
◆ Can these procedures be justified in cases of self-​inflicted disorders such as drug addic-
tion or anorexia nervosa?
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Overview of the different techniques of psychiatric neurosurgery 237

◆ How should researchers and physicians deal with conflicts of interest, for example,
conflicts between research interests and benefits to patients?
◆ Should psychiatric neurosurgery be applied in forensic contexts, for example, to reduce
the risk of re-​offense of pedophilic child offenders or violent psychopaths?
Whereas medical ethicists have discussed such questions intensively for DBS, they have
neglected ablative psychiatric neurosurgery. This blind spot is astonishing. Rather than
ignoring the widespread practice of ablative psychiatric neurosurgery, a comprehensive
and differentiated ethical analysis of the pros and cons of the distinct approaches is nec-
essary, which is based on rational evidence, not on fear or hopes or outdated prejudices.
In response, in the rest of this chapter, I provide a continuing overview of the different
techniques of psychiatric neurosurgery and explain their various underlying paradigms
and follow with an overview and comparison of the efficacy and the adverse effects of
the different techniques. Next, I  summarize the ethical debate about DBS, and discuss
the neglect in ethics with regard to ablative psychiatric neurosurgery, and conclude with
some preliminary recommendations for the future.

Overview of the different techniques of psychiatric

neurosurgery
Modern psychiatric neurosurgery differs with regards to the paradigm used. Deep brain
stimulation is based on the adjustability paradigm, because it allows for optimizing the
treatment outcome individually. Microsurgical ablative procedures are based on a quick-​
fix paradigm aimed at a very rapid onset of action. In comparison, Gamma Knife® radio-
surgery and MRgFUS are grounded in the paradigm of minimal invasiveness as they do
not require a craniotomy, and their side effects are very limited (Müller S. et al. 2015a).

Deep brain stimulation

Deep brain stimulation has been investigated in several clinical studies for treating vari-
ous severe psychiatric disorders, including major depression (Morishita et al. 2014), OCD
(Kohl et al. 2014), anorexia nervosa (Müller S. et al. 2015b), schizophrenia (Corripio et al.
2016; Salgado-​López et al. 2016), aggressive disorder (Franzini et al. 2013; Torres et al.
2013), drug addiction (Müller U.J. et al. 2013), Tourette syndrome (Andrade & Visser-​
Vandewalle 2016), dementia (Mirzadeh et  al. 2016), and severe obesity (Dupré et  al.
2015). The procedure requires drilling small burr holes in the skull to insert usually two
electrodes deep into the brain. These electrodes are connected with a stimulator that con-
tinuously delivers electrical current to the targeted brain area in order to activate or deac-
tivate these areas. The result is also known as a reversible lesion. Indeed, high-​frequency
DBS has a similar effect to lesions in that the activity of brain areas that are believed to
be hyperactive in psychiatric disorders is inhibited. However, the precise mechanism of
action is still the subject of ongoing debate. Several hypotheses are discussed to explain
the blocking effect of stimulation (Lévèque 2014).
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238 Ethical challenges of modern psychiatric neurosurgery

When subcortical motor areas of the basal ganglia and the thalamus are targeted for
treating movement disorders, the chief benefit of DBS over ablative procedures is that
DBS has a lower risk of side effects on speech, swallowing, cognition, and balance (Pepper
et  al. 2015). However, the rationale for DBS is less compelling when non-​motor areas
are targeted such as for treating psychiatric disorders (Pepper et al. 2015). There is not
much more in favor of DBS “other than it is perceived as nonablative and assumed to be
reversible and more forgiving than lesions, and therefore more acceptable” (Pepper et al.
2015, p.1029). However, many experts doubt that DBS is always reversible and, thus, the
case for DBS is attenuated. In an expert survey conducted by Markus Christen and me,
results showed that about 40% of the participating DBS experts (strongly) disagree with
the statement that DBS is a completely reversible procedure, whereas 43% (strongly) agree
(Christen et al. 2014). The reversibility is questionable because, first, the insertion of the
electrodes might cause irreversible lesions, even with the consequence of death or of per-
manent neurological damage; and second, because the brain will adapt to the stimulation.
Therefore, arguably, the main advantage of DBS is not its reversibility after all, but its
adjustability, that is, that the stimulation parameters like voltage, pulse width, and fre-
quency can be fine-​tuned individually to optimize the effect on the target symptoms with
respect to the disease progression over time. Consequently, DBS requires extensive follow-​
up for programming and adjusting stimulation parameters, which can only be done by
specialists. Furthermore, the implantable pulse generator (including the battery) has to
be replaced every 3–​5 years requiring regular surgeries with full anesthesia. The cost of
DBS device implantation is estimated at $50,000–​$120,000 USD. Each battery replace-
ment costs between $10,000 and $25,000 USD (Chodakiewitz et al. 2015). Therefore, the
treatment is both time-​consuming and, also in the long-​run, very expensive.

Ablative microsurgical procedures

Ablative microsurgical procedures require a craniotomy. The tiny ablations are performed
after neuroimaging (computer tomography, magnetic resonance imaging (MRI), and dif-
fusion tensor imaging) and can be performed by either thermocoagulation or radiofre-
quency heating.
The purpose of ablative microsurgical procedures is to enhance brain function and
reduce psychiatric symptoms by disconnecting limbic system circuits related to differ-
ent psychiatric disorders (Martínez-​Álvarez 2015). The effects occur rapidly, often within
days. If the effect is not sufficient, a second intervention can be performed in order to
enlarge the lesion or create an additional lesion in another target. However, if the lesions
are too large or misplaced, it is not possible to correct them.
Although today the field has advanced substantially, these procedures have a long tradi-
tion. In 1949, Talairach introduced anterior capsulotomy in France. In parallel, anterior
cingulotomy was introduced in the United States (Pepper et al. 2015). The main targets
for treating OCD are the anterior cingulate gyrus (cingulotomy) and the anterior limb
of the internal capsule (anterior capsulotomy) (Na et al. 2015). Further indications for
 239

Overview of the different techniques of psychiatric neurosurgery 239

contemporary ablative microsurgical procedures comprise anxiety disorder, major

depression, anorexia nervosa, drug addiction, hyperaggressivity, and schizophrenia.

Gamma Knife® radiosurgery

In 1968, Leksell and Larsson developed the first Gamma Knife® unit in Sweden (De Salles
& Gorgulho 2015). Gamma Knife® radiosurgery is a noninvasive procedure which does
not actually involve surgery with a knife; instead, external photon beam radiation is
used to concentrate a radiation dose to a pathological area while peripheral structures
are spared. The Gamma Knife® focuses about 200 beams of gamma radiation emitted by
cobalt-​60 sources in the target to be treated. The radiation dose of each single beam is
low, but focusing beams with high precision for several hours results in doses of 120 Gy
or more and produces a lesion at the target, while the adjacent radiation exposure is low
(Martínez-​Álvarez 2015). Radiosurgery can also be performed with a CyberKnife® or a
linear accelerator (e.g., LINAC®), but only the Gamma Knife® and the CyberKnife® have
been used so far for treating psychiatric disorders.
The main indications of Gamma Knife® radiosurgery are tumors and arteriovenous
malformations of the brain. However, the Gamma Knife® is also used for treating func-
tional disorders of the brain, particularly Parkinson’s disease, essential tremor, trigeminal
neuralgia, intractable tumor pain, some forms of epilepsy, and psychiatric illness (Friehs
et al. 2007). In 1988, the Karolinska Institute in Stockholm started to treat OCD patients
with bilateral radiosurgical anterior capsulotomy (Friehs et al. 2007). Today, capsuloto-
mies and cingulotomies are performed with the Gamma Knife® in specialized centers in
the United States, Spain, Brazil, and Asia.
The main advantage of radiosurgery compared to DBS or ablative microsurgery is
its minimal invasiveness. Gamma Knife® radiosurgery does not require a craniotomy.
Normally, it is conducted as an ambulant treatment. Hair is not shaved. Patients stay fully
awake during the whole treatment and can listen to music during the procedure. It is suit-
able even for patients with advanced age, with medical conditions that preclude surgery,
or who receive anticoagulation therapy (Friehs et al. 2007).
Alongside these benefits, limitations are known:  neurophysiological confirmation of
the target area is not possible and targeting relies completely on neuroimaging; lesion
sizes may vary; and, it might be difficult or impossible to shield adjacent structures against
the radiation (Friehs et al. 2007).
Radiosurgery is generally categorized as an ablative treatment. MRI studies have veri-
fied formation of small lesions after radiosurgical treatments, with necrosis volume of
100 mm3 or less when doses of 120–​180 Gy were used (Friehs et al. 2007). Recent neuro-
physiological, radiological, and histological research, however, calls into question whether
all Gamma Knife® radiosurgery procedures should indeed be considered ablative (Régis
2013). Whether it is ablative or not appears to depend on the dose used. Radiosurgical
protocols for functional disorders are assumed to have differential effects on various neu-
ronal populations and the glial environment, some of which may play a modulatory role
on neuronal function while preserving basic processing. Thus, depending on the context,
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240 Ethical challenges of modern psychiatric neurosurgery

the paradigm used in modern functional radiosurgery might be more appropriately cat-
egorized as neuromodulatory rather than ablative (Régis 2013).

Magnetic resonance-​guided focused ultrasound

Magnetic resonance-​guided focused ultrasound (MRgFUS) is a novel thermal ablation
method that is performed without craniotomy. It is a non-​ionized MR-​guided procedure
with real-​time MRI and intraoperative feedback on the temperature at the target (Na et al.
2015). The patients remain fully awake during the treatment. The first tests of MRgFUS
for a psychiatric indication have been conducted in South Korea (Na et al. 2015).
A beam of ultrasound is used in MRgFUS that is concentrated with its focal point on the
target area. The MRgFUS system combines a focused ultrasound delivery system with a
1.5 or 3 Tesla MRI scanner. This system provides a real-​time therapy planning algorithm,
thermal dosimetry, and closed-​loop therapy control. During the treatment, a specific MR
scan, which can be processed to identify changes in tissue temperature, provides a ther-
mal map of the treatment volume. With this map, the treatment in progress is monitored
in order to confirm that the ablation is proceeding according to plan (Na et al. 2015).
The method promises several advantages: like Gamma Knife® radiosurgery, MRgFUS
is noninvasive and does not require scalp incision, holes, and electrodes penetrating the
brain, thus reducing the risk of hemorrhagic complications and of infectious complica-
tions (Na et al. 2015). Unlike Gamma Knife® radiosurgery, MRgFUS does not use ion-
izing radiation, which precludes the risk of radiation-​induced tumorigenesis. However,
MRgFUS is a novel procedure, with very limited data available regarding its efficacy and
side effects.

Efficacy
Reliable estimation and comparison of the efficacy of the different psychiatric neurosur-
gery procedures remains elusive due to a number of reasons such as publication bias,
methodological heterogeneity, and use of weak methodology of the studies (Müller
S. et al. 2015a).

Publication bias
Due to a strong publication bias in the DBS literature (Schläpfer & Fins 2010), the efficacy
of psychiatric neurosurgery procedures is certainly overestimated. Most reviews consider
only cases published in Anglophone medical journals, and cases with an unfavorable out-
come are often not reported (Schläpfer & Fins 2010). The presumed efficacy of psychiat-
ric neurosurgery procedures is thus very likely an overestimation. The publication bias
might be the explanation for another astonishing phenomenon. A recent review, compris-
ing 22 papers with data from 188 patients and 6 stimulation targets reported responder
rates ranging from 29% to 92%, thus suggesting that DBS is efficacious in ameliorating
treatment-​refractory major depression (Morishita et al. 2014). In contrast, however, these
positive results could not be verified in the first two studies that fulfilled scientific quality
 241

Efficacy 241

criteria such as randomization, double blinding, and placebo control. Indeed, two ran-
domized, controlled, prospective multicenter studies were discontinued because of inef-
ficacy. These studies had two different targets:  (1)  the ventral capsule/​ventral striatum
(Dougherty et al. 2015) and (2) the subgenual cingulate cortex. Only a short report exists
about DBS in the subgenual cingulate cortex (Cavuoto 2013).
As concerns ablative procedures, there is probably an even stronger publication bias.
Most data on ablative neurosurgery are not published at all, since the procedure is pre-
dominantly applied in clinical practice and not in research. Public websites of private clin-
ics in Asia reveal that ablative neurosurgery for psychiatric disorders is offered there as a
part of clinical routine rather than clinical trials. Recently, Sun and De Salles published a
book with more than 100 previously unpublished ablative psychiatric neurosurgery case
reports from around the world (Sun & De Salles 2015). However, most data in this book
do not contain sufficient detail for consideration in systematic reviews.
Publication bias in psychiatric neurosurgery literature is a fundamental problem that
compromises the systematic evaluation and comparison of the different procedures
(Müller S. et al. 2015a). It also undermines the ethical evaluation, which critically depends
on adequate and objective information of evidence-​based risk:benefit ratios.

Methodological and study heterogeneity

Deep brain stimulation targets for major depression include a variety of brain regions,
including the VC/​VS, the nucleus accumbens (NAcc), the Brodmann area 25 (Cg25) in
the subgenual cingulate cortex (SCC), the superolateral medial forebrain bundle (slMFB),
the lateral habenula, the inferior thalamic peduncle (ITP), and the anterior limb of the
internal capsule (ALIC) (Morishita et  al. 2014; Bergfeld et  al. 2016). Similarly, brain
regions targeted for OCD include the ALIC, the NAcc, VC/​VS, ITP, and the nucleus sub-
thalamicus (STN) (Kohl et al. 2014). Several of these regions are also targets for treating
other psychiatric disorders such as drug addiction or anorexia nervosa. Thus, whereas
many targets are tested for the same disorder, the same targets are tested for different
disorders. Additional methodological and study heterogeneity results from continuous
development and refinement of psychiatric neurosurgical methods. In radiosurgery, for
example, radiation doses have been reduced significantly over the years. Diversity in tar-
geted brain regions for various psychological disorders as well as rapid methodological
progress both contribute to pragmatic challenges in comparing efficacy of different psy-
chiatric neurosurgery approaches.

Methodological weaknesses
Studies published thus far in English-​language journals have very small patient num-
bers, most with fewer than ten patients, and so lack of statistical power is thus a major
concern in these studies. Furthermore, most studies are neither placebo-​controlled nor
double-​blinded, and notably, none of the psychiatric neurosurgery approaches is strictly
evidence-​based (Pepper et  al. 2015). Observer bias in reporting results also presents
a methodological concern as the evaluation of treatment outcomes have not yet been
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242 Ethical challenges of modern psychiatric neurosurgery

conducted by independent parties who were not involved in patient selection, surgery, or
follow-​up (Pepper et al. 2015).
Despite the positive results of DBS studies in open-​label trials, the above-​mentioned
failure of two high-​quality studies may indicate the typical overestimation of efficacy that
is associated with open-​label trials with missing placebo control, and biases due to lack of
blinding and randomization (Morishita et al. 2014). The failure of these studies, however,
does not prove that DBS is in general ineffective for treatment-​refractory major depres-
sion. The study of Dougherty and colleagues (Dougherty et al. 2015), for example, had
severe deficits such as a short treatment period (4 months) and unsatisfactory adjustment
of stimulation parameters (Schläpfer 2015). A current study is investigating the slMFB
(Schläpfer et al. 2013) as a DBS target for major depression in a randomized, controlled,
prospective study; the outcome of this study may shed light on the efficacy of DBS for
major depression. For Gamma Knife® radiosurgery, several very small double-​blind, ran-
domized controlled trials have been performed thus far (Lévèque et al. 2013).
Rigorous evidence-​based comparison of the efficacy of the different psychiatric neu-
rosurgery approaches is not yet possible due to methodological hurdles and publication
bias. Despite these limitations, however, attempts to review efficacy of procedures have
utilized pertinent data, reviews, and a book (Sun & De Salles 2015).

Efficacy of the different techniques

Deep brain stimulation
Two reviews have been recently published on the efficacy of DBS for OCD. Kohl and col-
leagues analyzed 25 papers comprising 109 DBS patients and 5 targets (NAcc, VC/​VS,
ITP, STN, and ALIC) and found response rates ranging from 45.5% to 100% (Kohl et al.
2014). Pepper and colleagues compared DBS and ablative neurosurgery that included
more or less homogeneous anatomical areas to ensure a fair comparison (Pepper et al.
2015). Thus, they included DBS studies with the targets of VC/​VS and NAcc, and only
anterior capsulotomy (but not cingulotomy, subcaudate tractotomy, or limbic leucotomy).
Their analysis included 10 studies with a total of 108 patients, who were treated with
anterior capsulotomy, and 10 studies with a total of 62 patients, who underwent DBS.
The response rate of DBS patients was 52%, and of the anterior cingulotomy patients 62%
(response = improvement of Yale–​Brown Obsessive Compulsive Scale (Y-​BOCS) score ≥
35%) (Pepper et al. 2015).
For treatment-​refractory major depression, Morishita and colleagues reviewed data
from 22 papers comprising 188 DBS patients and 6 targets (NAcc, VC/​VS, SCC, lateral
habenula, ITP, and slMFB) (Morishita et  al. 2014). Very recently, an additional target,
namely the ALIC, has been tested in 25 patients (Bergfeld et  al. 2016). The reported
response rates ranged from 29% to 92%. However, as mentioned earlier, the failure of two
multicenter, randomized, controlled, prospective studies evaluating the efficacy of VC/​
VS DBS and SCC DBS (Cavuoto 2013; Dougherty et al. 2015) raises questions about the
efficacy of DBS for depression.
 243

Efficacy 243

For anorexia nervosa, we have reviewed 6 papers comprising 18 patients and three tar-
gets (NAcc, SCC, and VC/​VS) (Müller S. et al. 2015b). Remission in terms of normalized
body mass index occurred in 61% of patients, and psychiatric comorbidities improved in
88.9% of the patients as well. However, Sun and colleagues have recently published less
favorable results in which only 20% (3/​15) of their patients treated with NAcc DBS showed
improvements in symptoms. The other 80% underwent anterior capsulotomy, which
improved eating behavior and psychiatric symptoms in all patients (Sun et al. 2015).

Microsurgical ablative procedures

A review by Greenberg and colleagues reported that 45–​65% of patients with intrac-
table OCD benefitted from ablative procedures (Greenberg et  al. 2003). According to
Martínez-​Álvarez (2015), response rates between 36% and 89% have been published for
ablative neurosurgery for OCD. Martínez-​Álvarez (2015) reports data of 100 of their own
OCD patients of whom 71% responded. According to the review of Pepper et al. (2015),
62% of the patients treated with anterior capsulotomy (micro-​or radiosurgery) showed a
clinically significant improvement (Y-​BOCS score ≥ 35%).
For treatment-​refractory depression, 40–​60% of patients responded to bilateral capsu-
lotomy or cingulotomy (Eljamel 2015). Response was defined as at least 50% improve-
ment on depression scoring system such as Hamilton Rating Scale for Depression, or the
Montgomery-​Asberg Depression Rating Scale.
For anorexia nervosa, three papers with a total of nine patients reported a remission
rate of 100% with regard to both weight normalization and psychiatric comorbidities.
Different targets were used (dorsomedial thalamus, anterior capsula, and NAcc) (Müller
S. et al. 2015b). Sun and colleagues report 150 patients treated with capsulotomy, of which
85% experienced an improvement in symptoms (Sun et al. 2015).

Gamma Knife® radiosurgery

Martínez-​Álvarez (2015) reported a response rate of 100% in five OCD patients treated
with Gamma Knife® radiosurgery. Friehs and his coauthors reported long-​term and sig-
nificant reduction of OCD symptoms in roughly two-​thirds of their patients who were
treated in a currently ongoing open-​label study (Friehs et al. 2015). A review by Lévèque
et al. (2013) found that at least 55% of OCD patients responded to Gamma Knife® capsu-
lotomy. The review by Pepper and colleagues found that 62% of patients responded (Y-​
BOCS score ≥ 35%) when treated with anterior capsulotomy using either microsurgery or
radiosurgery for OCD (Pepper et al. 2015).

Magnetic resonance-​guided focused ultrasound

Presently, data from only four OCD patients who have been treated with MRgFUS is
available (Na et  al. 2015), and in all patients, the Y-​BOCS score improved. The mean
improvement in Y-​BOCS was 33%, whereby the range was 24–​47%. Two of the four
patients achieved a full response (Y-​BOCS ≥ 35%) during the 6 months of follow-​up (Na
et al. 2015). The Y-​BOCS of all patients was still falling at the end of the study. Perhaps,
it takes more than 6 months until the full treatment effect can be seen (Na et al. 2015).
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244 Ethical challenges of modern psychiatric neurosurgery

Another interesting result is the strong reduction of anxiety and depression after
MRgFUS. The mean Hamilton Rating Scale for Depression score improved about 61% at
6 months after treatment, and the mean Hamilton Rating Scale for Anxiety score about
69%. Anxiety and depression improved significantly within 1 week after MRgFUS, and
this improvement was maintained throughout the 6 months (Na et al. 2015).

Comparative efficacy
Pepper and colleagues found greater response rates for OCD patients who underwent
anterior capsulotomy (micro-​or radiosurgery) than for patients treated with DBS (62%
versus 52% (response  =  improvement on Y-​BOCS score ≥ 35%) (Pepper et  al. 2015).
Additionally, patients who underwent anterior capsulotomy were more likely to go into
remission than DBS patients. This difference in efficacy cannot be explained by group
differences in patient age, symptom severity, or disease duration (Pepper et  al. 2015).
A possible explanation is the differential surgical experience. Surgeons have greater expe-
rience with ablation and anterior capsulotomy is more standardized, whereas there is still
a learning curve in the practice of DBS for OCD (Pepper et al. 2015).

Adverse effects
Deep brain stimulation
Adverse effects of DBS are usually differentiated into surgery-​related, device-​related, and
stimulation-​related effects. Because the implantable pulse generator has to be replaced
every 3–​5  years, risks of surgery and infection are not limited to the implantation of
the DBS system. Furthermore, infections near the implanted device can always occur.
Furthermore, DBS devices are sensitive to high-​energy electrical fields, which can switch
them off or even cause a reset of the device (Na et al. 2015). The adverse effects depend
less on the indication for the intervention; therefore, I recapitulate them in the following
collectively.
Serious adverse events during or shortly after surgery occurred in a few reported cases.
These include intracerebral hemorrhages, which in one case, resulted in a temporary
hemiparesis (Kohl et al. 2014; Morishita et al. 2014; Pepper et al. 2015); intraoperative
seizure; intraoperative panic attack; and cardiac air embolus (Lipsman et  al. 2013a).
In several cases, wound infections or inflammation occurred (Kohl et al. 2014; Pepper
et al. 2015).
Several device-​related adverse effects have been reported, namely breaks of electrodes,
stimulating leads or extension wires requiring replacement (Kohl et al. 2014; Pepper et al.
2015). Further device-​related side effects are dysesthesia in the subclavicular region, feel-
ings of the leads or stimulators (Kohl et al. 2014), or allergy to the pulse generator (Pepper
et al. 2015).
Some patients suffered temporarily from vertigo, olfactory hallucinations, insomnia,
headache, micturition problems, weight loss or gain, long-​lasting fatigue, and visual dis-
turbances (Kohl et al. 2014; Pepper et al. 2015). Patients suffering from anorexia nervosa
 245

Adverse effects 245

had a particularly high rate of severe complications, namely an epileptic seizure during
electrode programming, further weight loss, pancreatitis, hypophosphataemia, hypo-
kalaemia, a refeeding delirium, cardiological disturbances, and worsening of mood
(Lipsman et al. 2013a).
Several patients had cognitive problems following DBS, particularly forgetfulness and
word-​finding difficulties (Pepper et al. 2015). Many patients suffered from stimulation-​
induced adverse effects, particularly from depression, anxiety, worsening of OCD, sui-
cidality, panic attacks, fatigue, hypomania, increased libido, and problems at home. In
some cases, these adverse effects were caused either by a change of stimulation parameters
or by battery depletion, and were reversible by respective adjustments (Kohl et al. 2014;
Morishita et al. 2014). Some DBS patients reported feelings of self-​estrangement (Gilbert
2013a). A great problem after DBS is the high number of suicides and suicide attempts
(Kohl et al. 2014; Morishita et al. 2014; Pepper et al. 2015).

Microsurgical ablative procedures

Ablative procedures bear the risk of surgical complications such as intracerebral hemor-
rhage, epilepsy, and hydrocephalus (Na et al. 2015). Adverse side effects of microsurgi-
cal ablative surgery for major depression comprised epilepsy (up to 10%), weight gain,
transient confusion, transient mania, and transient incontinence. Further side effects
reported by only one or two studies are personality change, lethargy, hemiplegia, and
suicide (Eljamel 2015). Following microsurgical ablative surgery for treating OCD, the
following transient adverse effects have been observed: mood disturbances, somnolence,
lethargy, frontal syndrome, headaches, hallucinations, urinary incontinence, pneumonia,
impaired cognitive function, confusion, and epileptic seizures (Martínez-​Álvarez 2015;
Pepper et al. 2015). The following adverse long-​term effects have been reported: weight
gain, incontinence, long-​term hemiplegia, cognitive deficits, sexual disinhibition, apathy,
memory problems, seizures, and personality or behavior change (Pepper et al. 2015). In
the case of anorexia nervosa, the published journal papers reported only transient adverse
effects:  bradycardia, mild disorientation, moderate somnolence, loss of concentration,
apathy, emotional emptiness and mild loss of decorum, headaches, and centric fever
(Müller S. et al. 2015b). However, Sun and colleagues reported intracranial hematomas in
1.9% of their patients (4/​216); one patient died thereof (0.5%) (Sun et al. 2015).

Gamma Knife® radiosurgery

According to Lévèque (2014), adverse effects such as fatigue, weight gain, or apathy did
not occur in newer studies with radiation doses of not more than 180 Gy. The dose effect
is also supported by the review of Pepper and colleagues (Pepper et al. 2015). In stud-
ies in which radiation doses of maximum 160 Gy were applied, no relevant side effects
occurred, whereas in studies with 180–​200 Gy, a few patients suffered from adverse long-​
term effects such as worsening scores on tests of executive function (without negative
impact on life), weight gain, tinnitus, facial paresthesia, sexual disinhibition (Rück et al.
2008), or urinary incontinence.
246

246 Ethical challenges of modern psychiatric neurosurgery

Magnetic resonance-​guided focused ultrasound

There is a potential risk that the scalp, the dura, the arachnoid, and brain tissues adja-
cent to the target can become heated to the point where tissue damage or a burn might
occur. Furthermore, there is a risk that the blood–​brain barrier is disrupted, and that
edema, swelling, and hemorrhage outside and remote from the targeted area occur (Na
et al. 2015).
There is a long list of contraindications of MRgFUS:  standard contraindications for
MRI , dialysis treatment, unstable cardiac status, severe hypertension, a history of abnor-
mal bleeding or coagulopathy, risk factors for intra-​or postoperative bleeding, a cere-
brovascular disease, a history of intracranial bleeding, increased intracranial pressure,
neurodegenerative diseases, brain tumors, history of aneurysms, an acute or chronic
uncontrolled infection or known life-​threatening systemic disease, history of immuno-
compromise (including HIV-​positive status), seizures within the past year, remarkable
atrophy and poor healing capacity of the scalp, ethanol or drug abuse, pregnancy or lacta-
tion, prior treatment with DBS, or stereotactic ablation of the anterior cingulated gyrus
(Na et al. 2015).
A frequent adverse effect is vertigo that is induced by high-​field (≥2 Tesla) MRI scan-
ners. Symptoms include nausea, vomiting, and dizziness. About half of the patients (5 of
11 patients) who have been treated with MRgFUS for essential tremor suffered from MR-​
induced vertigo (Na et al. 2015).
In the four patients treated so far with MRgFUS for OCD, no significant and/​or perma-
nent complications including physical, neurological, and psychological changes occurred
(Na et al. 2015).

Comparison of the different techniques of psychiatric

neurosurgery
Table 13.1 summarizes the results of the comparison between DBS, ablative neurosurgery,
and radiosurgery (Müller S. et al. 2015a; slightly modified and column “MRgFUS” added).
What Pepper and colleagues have stated with regard to OCD (Pepper et al. 2015) can
be generalized to several further psychiatric disorders such as depression and anorexia
nervosa. The superiority of DBS cannot be the reason for contemporary enthusiasm for
DBS, neither in terms of efficacy nor with regard to side effects and complications. Rather,
the enthusiasm for DBS might be grounded in the opportunity to study brain circuitry
and individual optimization of outcomes. An absolute superiority of one of the different
methods cannot be established, therefore. Each method has its own profile of advantages
and disadvantages. The significant differences between neurosurgical approaches clearly
suggest that they should be investigated differentially from an ethical, legal, and societal
perspective. In particular, arguments developed with regard to DBS cannot just be trans-
ferred to ablative neurosurgery and radiosurgery.
 247

Comparison of the different techniques of psychiatric neurosurgery 247

Table 13.1  Comparison of the different approaches of psychiatric neurosurgery

DBS Microsurgery Radiosurgery MRgFUS

Paradigm Adjustability Quick fix Minimal Minimal
invasiveness invasiveness

Adjustability Very high Low (second interven- Low (second inter- Low (second
tion to create another vention to create intervention to
lesion or enlarge the another lesion) to create another
lesion) medium (through lesion) to
a step-​by-​step medium (through
approach) a step-​by-​step
approach)
Multiple targets No Yes Yes Not yet done
in a single
session
Reversibility High (exception: No No No
permanent adverse
effects due to
lesions, infections,
bleeding)
Invasive Yes Yes No No
craniotomy
Onset of action Hours to 12 months Days or weeks 6–​12 months 1–​6 months
Appropriateness No Patients who would Patients: Patients:
for patients with not comply with ◆ who would ◆ who would
special needs long-​term follow-​up not comply not com-
with long-​term ply with
follow-​up long-​term
◆ for whom follow-​up
open surgery is ◆ for whom
precluded open surgery
◆ with higher is precluded
risks of ◆ with higher
anesthesia risks of
◆ with higher anesthesia
infection risks
◆ who must
receive anti-
coagulation
therapy
Time and effort High (single surgery; Medium (single sur- Low (ambulatory Medium (single
of the procedure several days in gery; several days in treatment, single surgery; several
hospital; parameter hospital) session) days in hospital)
adaption)
Long-​term Frequent consulta- Not necessary Not necessary Not necessary
treatment tion of specialists
required (parameter
adjustment, regular
device exchange)
(continued)
248

248 Ethical challenges of modern psychiatric neurosurgery

Table 13.1

DBS Microsurgery Radiosurgery MRgFUS

Costs Very high direct and Medium Low (in Probably medium
life-​long costs Germany: about
(first implanta- €4500)
tion: $50,000–​
$120,000 USD,
each battery
exchange: $10,000–​
$25,000 USD)
Mortality risk Yes Yes No Probably no
Short-​term risks ◆ Anesthesia ◆ Anesthesia ◆ Development ◆ Damage to
◆ Infection ◆ Infection of cysts the scalp,
◆ Intracerebral ◆ Hemorrhage ◆ Edemas the dura, the
hemorrhage arachnoid, or
◆ Hardware brain tissue
complications adjacent to
the target
◆ MR-​induced
vertigo
Possible adverse ◆ Suicidality ◆ Suicidality ◆ Transient Not known
effects ◆ Neurological ◆ Neurological cognitive
disorders, e.g., disorders, e.g., impairment
hemiparesis hemiplegia ◆ Transient apa-
◆ Mood ◆ Headaches thy
disturbance ◆ Seizures ◆ Radiation
◆ Anxiety ◆ Drowsiness dose >180
◆ Panic attacks ◆ Urinary Gy: fatigue,
◆ Hypomania incontinence weight gain,
◆ Increased libido ◆ Cognitive apathy, tin-
◆ Weight loss impairment nitus, facial
or gain ◆ Personality change paresthesia,
◆ Long-​lasting ◆ Weight gain sexual disinhi-
fatigue ◆ Sexual disinhibition bition, urinary
◆ Headaches incontinence
◆ Visual
disturbances
◆ Cognitive
problems
Risks of long-​ Yes: No No No
term treatment ◆ Infection risks
(due to biofilms
and battery
exchange every
few years)
◆ Hardware
complications
(continued)
 249

Ethical discussion 249

Table 13.1  Continued

DBS Microsurgery Radiosurgery MRgFUS

Disadvantages Yes: No No No
in daily life ◆ device-​related
problems in daily
life (e.g., at air-
port controls)
Disadvantages Yes: No No No
for further ◆ Special MRI
medical required
treatment
Possible Possible; self-​ Possible; burden of Improbable Improbable
problems of estrangement, normality syndrome
psychosocial feeling of being
adaptation manipulated;
burden of normality
syndrome

Ethical discussion
Ethical, legal, and social context
The clinical, ethical, legal, and societal issues of psychiatric neurosurgery are strongly
intermingled. The desperate situation of many people with mental disorders, who suf-
fer not only from their disabling condition, but also from stigma, social exclusion, com-
pulsory treatment, and frequently from incarceration, needs to be taken into account.
Thus, development and use of psychiatric neurosurgery has to be considered in a broader
social context, which will undoubtedly impact the development and acceptance of these
new treatment options. Moreover, the context for evaluating neurosurgical developments
also comprises the societal burden of chronic mentally ill patients, the trend of dehospi-
talization, as well as financial and research interests of device producers, hospitals, and
physicians.
Framed within the legal context, national legislation and international law limit the
field of psychiatric neurosurgery. In some countries, for example, ablative neurosurgery
is forbidden. Important legal issues include the admissibility of offering ablative psychi-
atric neurosurgery in general; the admissibility of offering psychiatric neurosurgery to
criminal offenders in jail or forensic psychiatry, particularly, if combined with the offer
of reducing the duration of imprisonment; and the admissibility of treating minors with
psychiatric neurosurgery, particularly, if performed in children with cognitive disabilities
or against the will of a minor (e.g., in cases of anorexia nervosa).
Media reports play a crucial role for the public acceptance or refusal of psychiatric
neurosurgery. The media also influences legal theorists and politicians who are tasked
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250 Ethical challenges of modern psychiatric neurosurgery

with deciding the admissibility of these procedures. The media in turn are influenced by
success stories from researchers and clinicians, and by diverging statements from bio-
ethicists. Social media disseminate information and opinions rapidly to the traditional
media in addition to the general public. For example, a critical article about psychosur-
gery in China in The Wall Street Journal was published in November 2007. It reported that
thousands of patients had been treated with ablative brain surgery, and in many cases,
in an unethical way. The article reports that this was not done with political intention to
suppress dissenters, but mainly because of profit-​interests of physicians. In April 2008,
the Ministry of Health of China issued a strict regulation on neurosurgery for psychiat-
ric disorders that forbids neurosurgical treatments of schizophrenia (Wu et al. 2012). By
contrast, DBS seems to be portrayed over-​optimistically in the media, and ethical issues
are largely ignored (Racine et al. 2007; Gilbert & Ovadia 2011). Many DBS researchers are
very aware of the importance of the image of DBS in the media where negative reports on
psychiatric neurosurgery pose a genuine threat to this field.

Bioethics principles in discussion of deep brain stimulation

Many ethics papers on (psychiatric) DBS are based on the bioethics principles (Beauchamp
& Childress 2013)  and generally focus on issues of autonomy, beneficence, nonmalefi-
cence, and justice.
An important issue of the autonomy-​related debate is informed consent, particularly in
patients with psychiatric diseases (Skuban et al. 2011). The usual methods to determine
the capacity for informed consent are insufficient for psychiatric patients, who often do
not have cognitive, but emotional and value-​related difficulties of decision-​making (Tan
et al. 2006; Breden & Vollmann 2006). Physicians cannot communicate risks and expec-
tations to patients in an objective and comprehensive manner due to the severe publica-
tion bias (Müller S. et al. 2015b). Another factor that confounds acquisition of informed
consent in DBS studies is therapeutic misconception (Fisher et al. 2012), that is, that the
subjects of a clinical study fail to recognize adequately the key differences between treat-
ment and clinical research (Lidz et al. 2004). Furthermore, many patients are influenced
by overoptimistic media reports about DBS which makes counseling very difficult, ulti-
mately challenging the validity of informed consent in these cases.
From the very beginning, ethicists have commented on the development of DBS for
psychiatric disorders. Many ethicists are either directly involved in DBS research projects
or participate in committees that publish guidelines and recommendations. Some ethicists
have demanded an investigation of the publication bias in the DBS literature (Schläpfer &
Fins 2010; Gilbert & Dodds 2013) as well as better regulations for the disclosure of con-
flicts of interests (Schermer 2011). In addition, the enrollment criteria (Bell et al. 2009) as
well as the adequate selection of outcome endpoints (Woopen et al. 2012) for clinical tri-
als in psychiatric DBS have been critically discussed. Furthermore, several authors have
discussed the need to assess equitable distribution of treatment options (Goldberg 2012),
and the influence of economic interests that drive the development of DBS (Christen &
Müller S. 2012; Erickson-​Davis 2012; Christen et al. 2014).
 251

Ethical discussion 251

Personality change and legal responsibility following

deep brain stimulation
The standard interpretation of Beauchamp and Childress’ ethics principles does not suf-
fice to deal with specific ethical problems of interventions that can alter the personality
or the capacity for autonomy (or both of these), or make the patients more dangerous
for third persons. Beauchamp and Childress’ concept of autonomy is too narrow for an
adequate ethical evaluation of such issues, because they do not consider sufficiently the
dependence of the capacity for autonomy from neurological prerequisites (Müller S. &
Walter 2010; Müller S. 2014, pp.91–​106). Furthermore, the ethical evaluation of personal-
ities and personality changes outreaches any ethics of mid-​level moral principles; but such
an evaluation is required for ethically evaluating personality-​changing interventions into
the brain (Müller S. 2014, pp.129–​137). Difficult questions of autonomy are posed with
regard to the question of who should determine the stimulation parameters (Mackenzie
2011a), in particular concerning patients with addiction risk (Glannon 2014a), or patients
whom DBS could make more dangerous to third persons (Müller S. et al. 2014).
Further ethical questions arise from technological advancements such as optogenetics
and closed-​loop DBS, which aim at continuously measuring brain activity in order to pro-
vide patients with feedback about their brain states or to alter these brain states directly.
Such automatic regulation prevents the patients from becoming aware of the automatic
processes controlling their emotions, and thus influencing their behavior. This raises new
dimensions to questions regarding patient autonomy given that their emotions, mood,
decision-​making, and behavior may be influenced automatically according to parameters
set by physicians.
Moreover, these issues lead to questions about the moral and legal responsibility of peo-
ple acting under DBS (Klaming and Haselager 2013) or of people who have been treated
with ablative psychiatric neurosurgery. Although factual litigable cases are very rare, they
occur. For example, a patient, who had undergone capsulotomy, became severely sexu-
ally disinhibited immediately after surgery, and was convicted of rape 5 months post-
operatively (Rück et al. 2008). Perhaps one of the most controversial issues, both from
an ethical and a legal perspective, is psychiatric neurosurgery for the purposes of law
enforcement and social control. Is it ethically justified to offer psychiatric neurosurgery to
forensic patients or offenders with pedophilia, psychopathy, or impulsive aggressiveness,
particularly with the offer of earlier release? Voluntariness, capacity for informed consent,
and responsibility for reoffending in spite of the device implantation or ablative surgery
are critical issues to consider in this context (Merkel et al. 2007; Gilbert et al. 2013b;
Giordano et al. 2014; Glannon 2014b; Vincent 2014).
Furthermore, much of the bioethical debate on DBS concerned with personality
changes are differently conceptualized, for example, in terms of threats to the personal
identity, self-​alienation, or inauthenticity (Northoff 2004; Merkel et al. 2007; Focquaert &
DeRidder 2009; Schechtman 2009; Mackenzie 2011b; Baylis 2013; Kraemer 2013;
Lipsman & Glannon 2013b; Witt et  al. 2013). I  think that the transfer of the concept
of personal identity from analytic philosophy to neurosurgical patients is problematic
25

252 Ethical challenges of modern psychiatric neurosurgery

for two reasons: first, because this debate does not adequately capture the clinical reality
and, second, because it might have negative effects on the patients. If legal theorists take
metaphysical theories about personal identity changes through DBS seriously, then psy-
chiatric advance directives of DBS patients would become invalid. I raised a plea for using
more realistic descriptions in order to capture the different kinds of mental or behavioral
changes following neurosurgery instead of speculating about the metaphysical concept of
personal identity (Müller S. 2014, pp.106–​129).

Neglect of modern ablative psychiatric neurosurgery

Although ethicists have extensively investigated DBS, there is a neglect in ethics with
regard to ablative psychiatric neurosurgery comprising thermocoagulation or radiofre-
quency ablation procedures, and Gamma Knife® radiosurgery. Whereas ethical issues of
DBS are well analyzed, there is nearly no ethical work on modern psychiatric neurosur-
gery other than DBS. Our recent literature research on ethical papers on psychiatric neu-
rosurgery delivered more than 200 papers on ethical issues of DBS, but not a single paper
from ethicists about modern ablative neurosurgery and radiosurgery (apart from our own
papers: Müller S. et al. 2015a, 2015b).
I assume that this neglect in ethics is due to most ethicists having adopted the pre-
vailing position of DBS researchers that all other methods of psychiatric neurosurgery
are forms of psychosurgery, and therefore outdated and ethically obsolete, whereas DBS
is significantly different. Another explanation would be that bioethicists have failed to
see the crucial differences between different psychiatric neurosurgery approaches and
that these differences matter ethically. With regard to the principles of beneficence and
nonmaleficence, for example, evidence-​based risk:benefit ratios are decisive and, as has
been pointed out earlier in this chapter, these ratios may differ dramatically for the vari-
ous distinct neurosurgical procedures. A  last explanation might be that most bioethi-
cists wrongly presuppose that ablative neurosurgery is not in use anymore in Western
countries. This last opinion, however, is challenged both empirically and normatively in
a number of ways:
1. The fraction of ablative procedures in psychiatric neurosurgery is large. In North
America, 50% of psychiatric neurosurgeons use lesioning exclusively or combined
with DBS (Lipsman et al. 2011), and outside of North America the number is even
higher at 54.9% (Mendelsohn et al. 2013). For OCD, the number of patients treated
with Gamma Knife® is more than twice the number of published DBS cases (250
Gamma Knife®1 patients versus 109 DBS patients (Kohl et al. 2014)).
2. The claim that DBS is clearly ethically superior is questionable. Although DBS has
the advantages of adjustability and high reversibility, it is inferior with regard to
adverse effects, contraindications, and the required time and effort. Accordingly, two
expert panels have affirmed stereotactic ablative procedures as important alternatives
for appropriately selected patients (for Parkinson’s disease: Bronstein et al. 2011; for
psychiatric disorders: Nuttin et al. 2014). A clear superiority of any procedure in all
 253

Ethical discussion 253

relevant aspects cannot be established (Müller S. et al. 2015a). The authors of a recent
comparative review of DBS and anterior capsulotomy conclude “that the current pop-
ularity of DBS over ablative surgery for OCD is not due to clinical superiority over AC
[anterior capsulotomy], but rather that clinicians and patients find DBS to be more
acceptable” (Pepper et al. 2015, p.1035).
3. The much higher long-​term costs of DBS, particularly for long-​term treatment, exclude
this option for the majority of patients worldwide.
4. Ablative neurosurgery and Gamma Knife® radiosurgery might avoid several difficult
ethical issues of DBS, which are raised because DBS allows for fine-​tuning the mood
and certain personality aspects of patients. If such a fine-​tuning is not possible, severe
ethical issues referring to the authority over the stimulation parameters, and to con-
flicts between the patients’ will and the physicians’ attitudes with regard to parameters
that might cause hypomania or addiction are not raised. In particular, Gamma Knife®
radiosurgery does not raise the challenging ethical problem of “inauthenticity” and
the so-​called burden of normality syndrome (Wilson et al. 2001; Gilbert 2012), just
because the onset of its effect is delayed for several months (Lindquist et al. 1991; De
Salles and Gorgulho 2015).

Advantages of the different methods

In the following section, I will analyze the main advantages for DBS as well as for the abla-
tive neurosurgical procedures from an ethics point of view.

Reversibility
The reversibility that has been proclaimed for DBS is presumably the most important
argument that has prevented it from general moral condemnation. Only a few com-
mentators consider psychiatric DBS as a continuation of the discredited historical psy-
chosurgery, whereas the majority highlight the important differences between previous
psychosurgery and DBS with regard to reversibility, invasiveness, adjustability, and ethical
orientation (Müller S. 2014, p.5). The reversibility is the main argument in many state-
ments. For example, in Germany, the working team of ethical review committees has writ-
ten in its recommendation for the appraisal of clinical studies that DBS research projects
are only ethically justifiable if the reversibility of the intervention is guaranteed (Raspe
et al. 2012). The German Association for Psychiatry, Psychotherapy and Psychosomatics
(DGPPN) states in its recently published guidelines for the treatment of OCD that neu-
rolesional or ablative methods have a very controversial history, and should be considered
very critically because of their irreversibility. The authors recommend not using capsu-
lotomy by thermocoagulation or gamma radiation because the risk:benefit ratios were
too negative in comparison with DBS, and because of the sometimes severe, irreversible
side effects (Hohagen et al. 2015). However, this recommendation is based on only one
follow-​up study of 25 patients treated with capsulotomy between 1988 and 2000, in which
two patients became sexually disinhibited resulting in one case in a conviction of rape
and in the other case in job loss (Rück et al. 2008). Furthermore, the technique has been
254

254 Ethical challenges of modern psychiatric neurosurgery

significantly refined since then, and the high radiation doses used by Rück and colleagues
(e.g., three bilateral doses of 200 Gy) are not used anymore.
In spite of the broad acceptance of the reversibility argument in favor of DBS, it can be
questioned whether the reversibility of psychiatric neurosurgery is ethically demanded at
all, since generally, a permanent effect of a medical treatment is strongly preferred over
a reversible effect, which requires continuous treatment to maintain the effect. Even in
comparable areas of stereotactic neurosurgery (e.g., for epilepsy or Parkinson’s disease),
reversibility is never demanded, although these interventions often change the patients’
personalities significantly. For these indications, the aim is a permanent cure or relief
and the reversibility of possible adverse effects and personality changes has never been
demanded by ethicists.
I suppose that there are at least three reasons why there is such a strong demand for
reversibility in the case of psychiatric neurosurgery: first, the experimental character of
all procedures and the insecurity about the optimal targets; second, the fear of perma-
nent undesirable personality changes; and third, that some stakeholders consider severe,
therapy-​refractory psychiatric disorders as part of the personality or personal identity
instead of considering them as diseases that compromise the personality.

Adjustability
The other main argument that is brought forward for the ethical superiority of DBS
over ablative psychiatric neurosurgery is its adjustability. However, adjustability, in fact,
leads to one of the most challenging ethical problems of DBS, namely that it allows for
fine-​tuning the mood and personality properties of patients. This raises difficult ques-
tions, such as the following: Who shall decide about the patients’ mood and personality
traits and according to which criteria? How can the patients’ autonomy be respected
optimally: by giving the patients full power about their stimulation parameters, or by
limiting their power in order to prevent addiction to the stimulation? These difficult
problems, which can cause severe conflicts between patients and physicians, do not
occur after ablative neurosurgery and radiosurgery, just because they do not allow for
fine-​tuning.

Quick onset of effect

Compared to Gamma Knife® radiosurgery, ablative microsurgery and DBS (at least DBS
in the slMFB) have a quick onset of effect. This is advantageous for patients, who need
a rapid symptom reduction, for example, for a mother with OCD, who is forced by her
obsession to disinfect her baby before she can touch him. However, for other patients a
slow, gradual onset of action is preferable, for example, for a patient, who has integrated
his Tourette syndrome into his self-​concept and is afraid of radical changes in his per-
sonality. Thus, for a subgroup of patients, a gradual development of effects might in fact
be advantageous, because it alleviates the psychological adjustment to the new situation
(Lindquist et al. 1991; De Salles and Gorgulho 2015). The delayed onset of action might
 25

Recommendations 255

protect against feelings of being manipulated, self-​estrangement, and the burden of nor-
mality syndrome (Müller S. et al. 2015a).
The conclusion must therefore be that an absolute superiority of one of the different
methods cannot be established. Each method has a different profile of advantages and dis-
advantages. Furthermore, what counts as an advantage or disadvantage may differ from
patient to patient, and depends on his or her individual situation and condition (Müller
S. et al. 2015a).

Minimal invasiveness
Minimal invasiveness is proclaimed particularly for Gamma Knife® radiosurgery and
for MRgFUS; although even these methods bear some risks for damaging the brain,
these risks are much less than for DBS and microsurgery. With regard to the nonmalefi-
cence principle, the minimal invasiveness speaks in favor of these two methods.
Since the claimed advantages are not advantages in each respect, it would be unjus-
tified to identify any one of the different methods as superior. Therefore, individual
factors should be crucial in decision-​making. Which approach is optimal, depends sig-
nificantly on individual medical and nonmedical factors, particularly on the patient’s
general health status, social situation, individual preferences, and individual attitudes
(Müller S. et al. 2015a).

Recommendations
Further research in psychiatric neurosurgery is warranted given the need for effective
therapies for treatment-​refractory psychiatric disorders and because of the preliminary
evidence for its efficacy. However, neither the high mortality rates of severe psychiatric
disorders nor their socioeconomic burden can justify therapeutic adventurism. Since
psychiatric neurosurgery has both the goal and the potential to change core features
of the patients’ personalities, these interventions have to fulfill the highest ethical and
scientific standards. The current research practice in this area does not fulfill these stan-
dards in all cases. Therefore, I suggest several protective measures to ensure that psy-
chiatric neurosurgery research proceeds in accord with the ethical demands (Müller S.
2014; Müller S. et al. 2015a, 2015b).
1. Hypothesis-​driven interventions
Testable hypotheses on dysfunctional circuits in the different psychiatric disorders should
be rigorously developed and tested (Müller S. et al. 2015b).
2. Cooperation and competition of different approaches
In spite of the competition of the different approaches of psychiatric neurosurgery, they
do also enrich each other mutually. Most of the DBS targets are known from previous
ablative procedures, whereas successful DBS targets could in turn be used to inform abla-
tive procedures. In the long-​run, DBS could become the preferable method for exploring
new targets, just because it is largely reversible, whereas well-​established targets could
256

256 Ethical challenges of modern psychiatric neurosurgery

become candidates for ablative microsurgery, Gamma Knife® radiosurgery, or MRgFUS

(Müller S. et al. 2015a).
3. Case registries
Independent case registries should become obligatory. These should contain all clinical
studies and all individual treatment attempts, in order to avoid a publication bias and
the negative consequences thereof, namely faulty evaluations of therapies, flawed ther-
apy recommendations, unpromising treatment attempts, and unneeded clinical studies
(Morishita et al. 2014; Müller S. 2014, p.132).
4. No individual treatment attempts
Individual treatment attempts should generally not be performed. Rather, all new applica-
tions should be investigated in clinical trials of the appropriate size and statistical power
and approved by an ethics committee (Müller S. 2014, p.132). In this context, Fins and
coauthors have rightly criticized the FDA’s humanitarian device exemption for DBS for
OCD (Fins et al. 2011). A humanitarian device exemption allows a manufacturer to mar-
ket a device under certain conditions without subjecting it to a clinical trial. This designa-
tion is available only for devices intended to diagnose or treat conditions that annually
affect 4000 or fewer people in the United States. In case of DBS for OCD, the humanitar-
ian device exemption is misused for bypassing the rigors of clinical trials, since OCD is
not an orphan, but a prevalent condition (Fins et  al. 2011). The designation allows an
institution to conduct an appropriately powered, hypothesis-​driven clinical trial to assess
the device’s safety, efficiency, and mechanism of action (Fins et al. 2011). According to
Fins and his coauthors, the current market-​driven regulatory strategy undermines patient
safety, scientific discovery, and research integrity (Fins et al. 2011).
5. Evidence-​based comparison of different therapeutic approaches
For a valid evaluation and comparison of the efficacy and adverse effects of the differ-
ent psychiatric neurosurgery approaches, head-​to-​head comparative studies with suffi-
cient statistical power, placebo control, and as far as possible, double-​blinded design are
necessary. The scientific standard of randomizing patients to different treatment groups
cannot be met for practical and ethical reasons. However, this limitation is less problem-
atic, since head-​to-​head comparative studies that match patients who undergo different
treatments can provide a valid efficacy comparison, too. Double-​blind studies can be eas-
ily performed with radiosurgery. For DBS, sham-​controlled trials can be performed, in
which patients are randomized to active versus sham DBS treatment in a blinded fashion
for several months followed by an open-​label continuation phase (Dougherty et al. 2015).
6. Inclusion and exclusion criteria
Future studies should use similar inclusion and exclusion criteria and similar standard-
ized assessment instruments in order to make the outcome straightforwardly comparable
(De Zwaan & Schlaepfer 2013). Beyond the accepted medical criteria, it is a large chal-
lenge to establish criteria for selecting patients for a given intervention, since the criteria
have to be both responsible and just, that is, they have to protect vulnerable patients, but
 257

Recommendations 257

should not exclude patients who could profit from a given intervention. Although the
criteria should be formulated as general rules, they should also allow for individual excep-
tions (Müller S. & Christen 2011).
7. No compulsory psychiatric neurosurgery
Psychiatric neurosurgery should not be used as a compulsory treatment for adults or
adolescents (even if demanded by their legal guardians). This prohibition is in accor-
dance with the recommendations on psychosurgery of the National Commission for
the Protection of Human Subjects of Biomedical and Behavioral Research (1977) and
the consensus paper on stereotactic neurosurgery for psychiatric disorders (Nuttin et al.
2014; Müller S. et al. 2015b).
8. Comprehensive investigation of adverse effects, particularly of sociopsychological sequelae
Since the risk:benefit profile of a therapeutic approach is decisive for recommending it to
patients, research about adverse effects has an important role. Information about psycho-
social and economic consequences of interventions in the brain must be gathered (Müller
S. 2014, p.134).
9. Development of instruments for measuring subtle mental alterations
Since personality changes are a main ethical concern and a central factor of patients’ sat-
isfaction with an intervention, instruments to evaluate even subtle changes should be
developed further (Müller S. 2014, pp.134–​135).
10. Long-​term, prospective follow-​up
Long-​term, optimally prospective, follow-​up studies are necessary for ensuring study
quality. Nuttin and colleagues recommend that research and clinical protocols should
include support for long-​term safety and efficacy studies on psychiatric neurosurgery for
at least 5–​10 years of follow-​up (Nuttin et al. 2014).
11. Investigation of single cases
Cross-​sectional group research does not reveal the different individual trajectories and
provides only limited clues about which factors are most relevant in effecting positive
change for an individual. It is important to study individual outcomes, particularly by
identifying subgroup patterns that can become lost in whole-​group analyses (Wilson et al.
2005; Baxendale et al. 2012). Both positive and poor outcomes should be reported sepa-
rately. Particularly cases with unfavorable or unexpected outcome should be investigated,
since they offer extraordinary chances for scientific discovery and improving the tech-
niques used (Christen & Müller S. 2011; Fins et al. 2011; Müller S. 2014, p.133).
12. Comprehensive information for patients
Patients need independent, evidence-​ based information about risks, benefits, and
chances of different therapy options for decision-​making. As we have proposed for DBS
(Müller S. & Christen 2011), a living database should be developed and continuously
updated, ideally for all neurosurgical therapies, with open access for physicians and
patients. It should contain comparative data of single centers about the morbidity, the
258

258 Ethical challenges of modern psychiatric neurosurgery

incidence of complications and adverse effects, the neuropsychological outcome, and

quality of life following neurosurgery (Müller S. 2014, p.135).
13. Patient-​centered, multidisciplinary counselling and shared decision-​making
Patients should be informed comprehensively about different treatment options and
their respective evidence-​based risk:benefit profiles. Individual factors have to be taken
into account because they play a crucial role for decision-​making. These individual fac-
tors comprise the patients’ social situation, individual preferences, and individual atti-
tudes, for example, whether they can tolerate implanted devices, and whether they are
more afraid of the irreversibility of an ablative procedure or of the medical risks of a
craniotomy (Müller S. et al. 2015a). The counselling should also include therapy options,
which are not affiliated with the institution that performs the procedure, even if the
resulting consequence is that the patient will be treated in another institution or lost
as a research participant. Optimally, a multidisciplinary team assists the patients in the
decision-​making process; if such a team does not exist locally, the patients should be
referred to specialists of all relevant therapies. Counseling should also consider the indi-
vidual situation of the patients, especially their professional activity and social integra-
tion (Müller S. 2014, p.136).
14. Advance directives or Ulysses contracts
Advance directives should be offered to the patients, particularly for those at risk of per-
sonality changes or risk of hampered autonomy. Advance directives and the determina-
tion of attorneys are helpful tools for preparing for the worst case. Ulysses contracts are
particularly important for dealing with transient states of psychosis or mania following
neurosurgery, which make consent to any medically indicated change of stimulation
parameters or device explanation problematic (Müller S. 2014, p.137).
15. Individual instead of institution-​specific target selection
Since multiple circuits seem to be involved in psychiatric disorders, targets of DBS or
ablative procedures should be selected specifically with regard to the prominent symp-
toms instead of using the institution-​specific target for all patients with certain diagnoses
(Müller S. et al. 2015a).
16. Temporary DBS
Whether the DBS application should be chronic or whether it is possible to limit its appli-
cation to a confined time-​period is an open question. If a psychiatric disorder is a per-
sonality trait-​related condition of a given patient, then it may be necessary to stimulate
him or her throughout life. In this case, an ablative procedure might be preferable. But if
the psychiatric disorder is a development-​related disorder that occurs only under given
sociocultural circumstances in biologically vulnerable individuals (e.g., anorexia nervosa
or drug addiction), then the stimulation might be stopped when the patient is fully remit-
ted for a certain period of time. If no relapse occurs after a longer period without stimu-
lation, the whole DBS system might be removed, which would also be advantageous for
medical, psychological, and financial reasons (Müller S. et al. 2015b).
 259

References 259

Conclusion
Modern psychiatric neurosurgery has the potential to become a further method for treat-
ing otherwise treatment-​refractory severe psychiatric disorders. However, to be broadly
accepted in both the medical community and the society, it has to conform to rigorous
scientific and ethical standards.

Acknowledgments
The research of Sabine Müller is funded by the German Federal Ministry of Education
and Research (01 GP 1621A).

Note
1. Written communication of Catherine Gilmore-​Lawless, Vice President of Elekta (the only producer of
Gamma Knife®).

References
Andrade, P. and Visser-​Vandewalle, V. (2016). DBS in Tourette syndrome: where are we standing now?
Journal of Neural Transmission (Vienna), 123(7), 791–​796.
Baxendale, S., Thompson, P.J., and Duncan, J.S. (2012). Neuropsychological function in patients who
have had epilepsy surgery: a long-​term follow-​up. Epilepsy & Behavior, 23, 24–​29.
Baylis, F. (2013). “I Am Who I Am”: on the perceived threats to personal identity from DBS.
Neuroethics, 6(3), 513–​526.
Beauchamp, T.L. and Childress, J.F. (2013). The Principles of Biomedical Ethics (7th edn.).
Oxford: Oxford University Press.
Bell, E., Mathieu, G., and Racine, E. (2009). Preparing the ethical future of deep brain stimulation.
Surgical Neurology, 72(6), 577–​586.
Bergfeld, I.O., Mantione, M., Hoogendoorn, M.L.C., et al. (2016). Deep brain stimulation of the
ventral anterior limb of the internal capsule for treatment-​resistant depression. A randomized trial.
JAMA Psychiatry, 73(5), 456–​464.
Breden, T.M. and Vollmann, J. (2006). The cognitive based approach of capacity assessment in
psychiatry: a philosophical critique of the MacCAT-​T. Health Care Analysis, 12(4), 273–​283.
Bronstein, J.M., Tagliati, M., Alterman, R.L., et al. (2011). Deep brain stimulation for Parkinson
disease: an expert consensus and review of key issues. Archives of Neurology, 68(2), 165–​171.
Cavuoto, J. (2013, December). Depressing innovation. Neurotech Business Report. Available from: http://​
www.neurotechreports.com/​pages/​publishersletterDec13.html [accessed May 9, 2016].
Chodakiewitz, Y., Williams, J., Chodakiewitz, J., and Cosgrove, G.R. (2015). Ablative surgery for
neuropsychiatric disorders: past, present, future. In: Sun, B. and De Salles, A. (Eds.) Neurosurgical
Treatments for Psychiatric Disorders, pp.51–​66. Dordrecht: Springer.
Christen, M., Ineichen, C., Bittlinger, M., Bothe, H.W., and Müller, S. (2014). Ethical focal points in
the international practice of deep brain stimulation. AJOB Neuroscience, 5(4), 65–​80.
Christen, M. and Müller, S. (2011). Single cases promote knowledge transfer in the field of DBS.
Frontiers in Integrative Neurosciences, 5, 13.
Christen, M. and Müller, S. (2012). Current status and future challenges of deep brain stimulation in
Switzerland. Swiss Medical Weekly, 142, w13570.
260

260 Ethical challenges of modern psychiatric neurosurgery

Cook, M., O’Brien, T.J., Berkovic, S.F., et al. (2013). Prediction of seizure likelihood with a long-​term,
implanted seizure advisory system in patients with drug-​resistant epilepsy. Lancet Neurology, 12,
563–​571.
Corripio, I., Sarró, S., McKenna, P.J., et al. (2016). Clinical improvement in a treatment-​resistant
patient with schizophrenia treated with deep brain stimulation. Biological Psychiatry, 80(8), e69–​70.
De Salles, A. and Gorgulho, A.A. (2015). Radiosurgery for psychiatric disorders. In: Sun, B. and De
Salles A (Eds.) Neurosurgical Treatments for Psychiatric Disorders, pp.217–​225. Dordrecht: Springer.
De Zwaan, M. and Schlaepfer, T.E. (2013). Not too much reason for excitement: deep brain stimulation
for anorexia nervosa. European Eating Disorders Review, 21, 509–​5011.
Deisseroth, K. (2012). Optogenetics and psychiatry: applications, challenges, and opportunities.
Biological Psychiatry, 71, 1030–​2.
Diering, S.L. and Bell, W.O. (1991). Functional neurosurgery for psychiatric disorders: a historical
perspective. Stereotactic and Functional Neurosurgery, 57, 175–​194.
Dougherty, D.D., Rezai, A.R., Carpenter, L.L., et al. (2015). A randomized sham-​controlled trial
of deep brain stimulation of the ventral capsule/​ventral striatum for chronic treatment-​resistant
depression. Biological Psychiatry, 78, 240–​248.
Dupré, D.A., Tomycz, N., Oh, M.Y., and Whiting, D. (2015). Deep brain stimulation for obesity: past,
present, and future targets. Neurosurgical Focus, 38(6), E7.
Eljamel, S. (2015). Ablative surgery for depression. In: Sun, B. and De Salles, A. (Eds.) Neurosurgical
Treatments for Psychiatric Disorders, pp.87–​94. Dordrecht: Springer.
Erickson-​Davis, C. (2012). Ethical concerns regarding commercialization of DBS for OCD. Bioethics,
26(8), 440–​446.
Fins, J.J., Mayberg, H.S., Nuttin, B., et al. (2011). Misuse of the humanitarian device exemption in
stimulation for obsessive-​compulsive disorder. Health Affairs, 30, 2302–​2311.
Fisher, C.E., Dunn, L.B., Christopher, P.P., et al. (2012). The ethics of research on DBS for depression.
Annals of the New York Academy of Sciences, 1265(1), 69–​79.
Focquaert, F. and DeRidder, D. (2009). Direct intervention in the brain: ethical issues concerning
personal identity. Journal of Ethics in Mental Health, 4(2), 1–​6.
Franzini, A., Broggi, G., Cordella, R., Dones, I., and Messina, G. (2013). Deep-​brain stimulation for
aggressive and disruptive behavior. World Neurosurgery, 80(3–​4), S29.e11–​14.
Friehs, G.M., Park, M.C., Goldman, M.A., Zerris, V.A., Norén, G., and Sampath, P. (2007). Stereotactic
radiosurgery for functional disorders. Neurosurgery Focus, 23(6), E3.
Gilbert, F. (2012). The burden of normality. Journal of Medical Ethics, 38(7), 408–​412.
Gilbert, F. (2013a). Deep brain stimulation for treatment resistant depression: Postoperative feeling of
self-​estrangement, suicide attempt and impulsive-​aggressive behaviours. Neuroethics, 6(3), 473–​481.
Gilbert, F. (2015). A threat to autonomy? The intrusion of predictive brain implants. AJOB Neuroscience,
6(4), 4–​11.
Gilbert, F. and Dodds, S. (2013). How to turn ethical neglect into ethical approval. AJOB Neuroscience,
4(2), 59–​60.
Gilbert, F. and Ovadia, D. (2011). Deep brain stimulation in the media: over-​optimistic portrayals
call for a new strategy involving journalists and scientists in ethical debates. Frontiers in Integrative
Neuroscience, 5, 16.
Gilbert, F., Vranic, A., and Hurst, S. (2013b). Involuntary & voluntary invasive brain surgery.
Neuroethics, 6(1), 115–​128.
Giordano, J., Kulkarni, A., Farwell, J. (2014). Deliver us from evil? Theoretical Medicine and Bioethics,
35, 73–​89.
Glannon, W. (2014a). Neuromodulation, agency and autonomy. Brain Topography, 27(1), 46–​54.
 261

References 261

Glannon, W. (2014b). Intervening in the psychopath’s brain. Theoretical Medicine and Bioethics,
35, 43–​57.
Goldberg, D.S. (2012). Justice, population health, and deep brain stimulation. AJOB Neuroscience,
3(1), 16–​20.
Greenberg, B.D., Price, L.H., Rauch, S.L., et al. (2003). Neurosurgery for intractable obsessive-​
compulsive disorder and depression: critical issues. Neurosurgery Clinics of North America, 14,
199–​212.
Hohagen, F., Wahl-​Kordon, A., Lotz-​Rambaldi, W., and Muche-​Borowski, C. (Eds.) (2015). S3-​
Leitlinie Zwangsstörungen. Berlin: Springer-​Verlag.
Kesey, K. (1964). One Flew Over the Cuckoo’s Nest. New York: The Viking Press, Inc.
Klaming, L. and Haselager, P. (2013). Did my brain implant make me do it? Neuroethics, 6(3),
527–​539.
Kohl, S., Schönherr, D.M., Juigjes, J., et al. (2014). Deep brain stimulation for treatment-​refractory
obsessive compulsive disorder: a systematic review. BMC Psychiatry, 14, 214.
Kraemer, F. (2013). Me, myself and my brain implant. Neuroethics, 6(3), 483–​497.
Lévèque, M. (2014). Psychosurgery: New Techniques for Brain Disorders. Dordrecht: Springer.
Lévèque, M., Carron, R., and Régis, J. (2013). Radiosurgery for the treatment of psychiatric disorders: a
review. World Neurosurgery, 80(3/​4), S32.e1–​e9.
Lidz, C.W., Appelbaum, P.S., Grisso, T., and Renaud, M. (2004). Therapeutic misconception and the
appreciation of risks in clinical trials. Social Science & Medicine, 58, 1689–​1697.
Lindquist, C., Kihlström, L., and Hellstrand, E. (1991). Functional neurosurgery—​a future for the
Gamma Knife? Stereotactic and Functional Neurosurgery, 57, 72–​81.
Lipsman, N., Mendelsohn, D., Taira, T., and Bernstein, M. (2011). The contemporary practice of
psychiatric surgery: results from a global survey of North American functional neurosurgeons.
Stereotactic and Functional Neurosurgery, 89, 103–​110.
Lipsman, N., Woodside, D.B., Giacobbe, P., et al. (2013a). Subcallosal cingulate deep brain
stimulation for treatment-​refractory anorexia nervosa: a phase 1 pilot trial. The Lancet, 381
(9875), 1361–​1370.
Lipsman, N. and Glannon, W. (2013b). Brain, mind and machine: what are the implications of deep
brain stimulation for perceptions of personal identity, agency and free will? Bioethics, 27(9),
465–​470.
Luigjes, J., de Kwaasteniet, B.P., de Koning, P.P., et al. (2013). Surgery for psychiatric disorders. World
Neurosurgery, 80(3/​4), S31.e17–​e28.
Mackenzie, R. (2011a). Who should hold the remote for the new me? AJOB Neuroscience, 2(1), 18–​20.
Mackenzie, R. (2011b). Must family/​carers look after strangers? Post-​DBS identity changes and related
conflicts of interest. Frontiers in Integrative Neuroscience, 5, 12.
Martínez-​Álvarez, R. (2015). Ablative surgery for obsessive-​compulsive disorders. In: Sun, B. and De
Salles, A. (Eds.) Neurosurgical Treatments for Psychiatric Disorders, pp.105–​112. Dordrecht: Springer.
Mendelsohn, D., Lipsman, N., Lozano, A.M., Taira, T., and Bernstein, M. (2013). The contemporary
practice of psychiatric surgery: results from a global survey of functional neurosurgeons. Stereotactic
and Functional Neurosurgery, 91, 306–​313.
Merkel, R., Boer, G., Fegert, J., et al. (2007). Intervening in the Brain: Changing Psyche and Society.
Berlin: Springer Verlag.
Mirzadeh, Z., Bari, A., Lozano, A.M. (2016). The rationale for deep brain stimulation in Alzheimer’s
disease. Journal of Neural Transmission (Vienna), 123(7), 775–​783.
26

262 Ethical challenges of modern psychiatric neurosurgery

Morishita, T., Fayad, S.M., Higuchi, M., Nestor, K.A., and Foote, K.D. (2014). Deep brain stimulation
for treatment-​resistant depression: systematic review of clinical outcomes. Neurotherapeutics, 11,
475–​484.
Müller, S. (2014). Personality and Autonomy in Light of Neuroscience [Cumulative habilitation]. Available
from: http://​www.diss.fu-​berlin.de/​diss/​receive/​FUDISS_​thesis_​000000097489 [accessed January
31, 2017].
Müller, S. and Christen, M. (2011). Deep brain stimulation in Parkinsonian patients—​ethical evaluation
of cognitive, affective and behavioral sequelae. American Journal of Bioethics, 2(1), 3–​13.
Müller, S. and Walter, H. (2010). Reviewing autonomy. Implications of the neurosciences and the free
will debate for the principle of respect for the patient’s autonomy. Cambridge Quarterly of Health
Ethics, (2), 205–​217.
Müller, S., Walter, H., and Christen, M. (2014). When benefitting a patient increases the risk for harm
for third persons—​the case of treating pedophilic Parkinsonian patients with DBS. International
Journal of Law and Psychiatry, 37(3), 295–​303.
Müller, S., Riedmüller, R., and van Oosterhout, A. (2015a). Rivaling paradigms in psychiatric
neurosurgery. Frontiers in Integrative Neuroscience, 9, 27.
Müller, S., Riedmüller, R., Walter, H., and Christen, M. (2015b). An ethical evaluation of stereotactic
neurosurgery for anorexia nervosa. AJOB Neuroscience, 6(4), 50–​65.
Müller, U.J., Voges, J., Steiner, J., et al. (2013). Deep brain stimulation of the nucleus accumbens for the
treatment of addiction. Annals of the New York Academy of Sciences, 1282, 119–​128.
Na, Y.C., Jung, H.H., and Chang, J.W. (2015). Focused ultrasound for the treatment of obsessive-​
compulsive disorder. In: Sun, B. and De Salles, A. (Eds.) Neurosurgical Treatments for Psychiatric
Disorders, pp.125–​141. Dordrecht: Springer.
Northoff, G. (2004). The influence of brain implants on personal identity and personality—​a combined
theoretical and empirical investigation in ‘Neuroethics’. In: Schramme, T. and Thome, J. (Eds.)
Philosophy and Psychiatry, pp.311–​325. Berlin: De Gruyter.
Nuttin, B., Wu, H., Mayberg, H., et al. (2014). Consensus on guidelines for stereotactic neurosurgery
for psychiatric disorders. Journal of Neurology, Neurosurgery, and Psychiatry, 85(9), 1003–​1008.
Pepper, J., Hariz, M., and Zrinzo, L. (2015). Deep brain stimulation versus anterior capsulotomy for
obsessive-​compulsive disorder: a review of the literature. Journal of Neurosurgery, 122, 1028–​1037.
Racine, E., Waldman, S., Palmour, N., Risse, D., and Illes, J. (2007). “Currents of
hope”: neurostimulation techniques in U.S. and U.K. print media. Cambridge Quarterly of Health
Ethics, 16, 312–​316.
Raspe, H., Hüppe, A., Strech, D., and Taupitz, J. (2012). Arbeitskreis Medizinischer
Ethikkommissionen: Empfehlungen zur Begutachtung klinischer Studien. Köln: Deutscher
Ärzte-​Verlag.
Régis, J. (2013). Radiosurgery as a modulation therapy! Acta Neurosurgery Supplement, 116, 121–​126.
Rosin, B., Slovik, M., Mitelman, R., et al. (2011). Closed-​loop deep brain stimulation is superior in
ameliorating Parkinsonism. Neuron, 72, 370–​384.
Rück, C., Karlsson, A., Steele, D., et al. (2008). Capsulotomy for obsessive-​compulsive disorder. Long-​
term follow-​up of 25 patients. Archives of General Psychiatry, 65(8), 914–​922.
Salgado-​López, L., Pomarol-​Clotet, E., Roldán, A., et al. (2016). Letter to the Editor: Deep brain
stimulation for schizophrenia. Journal of Neurosurgery, 125(1), 229–​230.
Schechtman, M. (2009). Getting our stories straight: self-​narrative and personal identity. In: Mathews,
S.J.H., Bok, H., and Rabins, P.V. (Eds.) Personal Identity and Fractured Selves, pp.66–​92. Baltimore,
MD: Johns Hopkins University Press.
Schermer, M. (2011). Ethical issues in deep brain stimulation. Frontiers in Integrative
Neuroscience, 5, 17.
 263

References 263

Schläpfer, T.E. (2015). Deep brain stimulation for major depression—​steps on a long and winding road.
Commentary. Biological Psychiatry, 78, 218–​219.
Schläpfer, T.E., Bewernick, B.H., Kayser, S., Madler, B., and Coenen, V.A. (2013). Rapid effects of deep
brain stimulation for treatment-​resistant major depression. Biological Psychiatry, 73, 1204–​1212.
Schläpfer, T.E. and Fins, J.J. (2010). Deep brain stimulation and the neuroethics of responsible
publishing: when one is not enough. JAMA, 303(8), 775–​776.
Skuban, T., Hardenacke, K., Woopen, C., and Kuhn, J. (2011). Informed consent in deep brain
stimulation. Frontiers in Integrative Neuroscience, 5, 7.
Sun, B. and De Salles, A. (Eds.) (2015). Neurosurgical Treatments for Psychiatric Disorders.
Dordrecht: Springer.
Sun, B., Li, D., Liu, W., Zhan, S., Pan, Y., and Lin, G. (2015). Surgical treatments for anorexia nervosa.
In: Sun, B. and De Salles, A. (Eds.) Neurosurgical Treatments for Psychiatric Disorders, pp.175–​187.
Dordrecht: Springer.
Tan, D.J., Hope, P.T., Stewart, D.A., and Fitzpatrick, P.R. (2006). Competence to make treatment
decisions in anorexia nervosa: thinking processes and values. Philosophy, Psychiatry, & Psychology,
13(4), 267–​282.
Tass, P.A. (2003). A model of desynchronizing deep brain stimulation with a demand-​controlled
coordinated reset of neural subpopulations. Biological Cybernetics, 89, 81–​88.
Torres, C.V., Sola, R.G., Pastor, J., et al. (2013). Long-​term results of posteromedial hypothalamic deep
brain stimulation for patients with resistant aggressiveness. Journal of Neurosurgery, 119, S. 277–​287.
Valenstein, E.S. (1986). Great and Desperate Cures: The Rise and Decline of Psychosurgery and Other
Radical Treatments for Mental Illness. New York: Basic Books, Inc. Publishers.
Vincent, N.A. (2014). Restoring responsibility. Criminal Law and Philosophy, 8(1), 21–​42.
Walter, H. and Müller, S. (2013). Optogenetics as a new therapeutic tool in medicine? A view from the
principles of biomedical ethics. In: Hegemann, P. and Sigrist, S. (Eds.) Optogenetics, pp.201–​211.
Berlin: De Gruyter.
Wilson, S.J., Bladin, P.F., and Saling, M.M. (2001). The “burden of normality”: concepts of
adjustment after surgery for seizures. Journal of Neurology, Neurosurgery, and Psychiatry, 70,
649–​656.
Wilson, S.J., Bladin, P.F., Saling, M.M., and Pattison, P.E. (2005). Characterizing psychosocial outcome
trajectories following seizure surgery. Epilepsy & Behavior, 6, 570–​580.
Witt, K., Kuhn, J., Timmermann, L., Zurowski, M., and Woopen, C. (2013). Deep brain stimulation
and the search for identity. Neuroethics, 6(3), 499–​511.
Woopen, C., Timmermann, L., and Kuhn, J. (2012). An ethical framework for outcome assessment in
psychiatric DBS. AJOB Neuroscience, 3(1), 50–​55.
Wu, H., Gabriels, L., and Nuttin, B. (2012). Neurosurgery for psychiatric disorders in the People’s
Republic of China. AJOB Neuroscience, 3(1), 56–​59.
264

Chapter 14

At the crossroads of civic engagement

and evidence-​based medicine:
Lessons learned from the chronic
cerebrospinal venous insufficiency
experience
Shelly Benjaminy and Anthony Traboulsee

Introduction
Contemporary formulations of science are increasingly shifting from a top-​down model
of expertise toward a more pluralistic approach that encourages the engagement of pub-
lics in the co-​creation and governance of science. This conceptualization, in which non-​
scientific actors are regarded as agents capable of meaningfully contributing to scientific
debates, evinces a systematic shift from a model of public understanding of science to a
new paradigm marked by public participation in science.
A participatory and egalitarian orientation is central in the field of neuroethics, which
at its core aims to align neurotechnological development with societal values. The brain
is widely regarded as the seat of the mind, and is inextricably linked with abstractions
of individuality and personal identity (Leshner 2005). It is therefore not surprising that
new brain technologies that reside at the intimate frontier of personhood are compelling
widespread public interest and engagement (Illes et al. 2005).
It is the civic duty of neuroscientists and neuroethicists to engage with publics in delib-
eration about the development of new research trajectories (Illes et al. 2005). Not only is
this logical, but it is also socially conscientious to ensure that the publics who bear the
burdens and risks of neurotechnological development are included in dialogue about its
formulation and application. As such, public engagement has been a focal area in the
field of neuroethics since its contemporary inception (Marcus 2002). Ongoing neuroethi-
cal debates about controversial issues including the trade-​offs of cognitive enhancement,
implications of brain–​computer interfaces on autonomy, and the management of inciden-
tal findings in neuroimaging require the input of both scientists and lay citizens to inform
the field in a sustainable and socially responsible capacity.
Successful civic engagement in science, however, is not without its risks and chal-
lenges. Public engagement may unveil divergence between expert opinion and public
 265

The media as a platform for public participation in science 265

beliefs. Differing world views—​which may be shaped by disciplinary divides or com-

peting stakes—​can be difficult to reconcile. Moreover, maintaining public trust in
the face of conflicting priorities may pose threats to the sustainability of scientific
enterprises.
Here, we explore the opportunities and challenges of community engagement in the
neurosciences. We discuss prospects for public participation in science through media
outlets, research initiatives, and advocacy. We draw on the contentious case study of
the chronic cerebrospinal venous insufficiency (CCSVI) research trajectory that gener-
ated both hope and skepticism, galvanized substantial international attention, and was
heavily criticized for privileging scientific inquiry driven more by public pressure than
by empirical evidence. We conclude with lessons learned from the cautionary CCSVI
tale, and suggest opportunities for reciprocal and impactful engagement that the field of
neuroethics may foster as novel neurotechnologies are developed.

The media as a platform for public participation in science

Public participation in science and science policy is often supported by a complex infra-
structure of media communications. Being the most accessible source of information
about science in the public sphere, the media have long served as a prominent means
for civic engagement in scientific advances. The media operate at the interface between
scientific communities and lay publics, and thus serve as key gatekeepers of information
between science and the society. The media may exert a substantial influence over public
perceptions and opinions of controversial biotechnologies through deliberate reporting
techniques. Two interrelated methods are prominently used in science reporting: agenda
setting and framing. Agenda setting theory posits that the media can lend salience to
certain topics through selective coverage. Media outlets cover certain issues with greater
prominence (e.g., front-​page news) or frequency to direct public attention to certain
issues while omitting others (McCombs & Shaw 1972). In a similar capacity, frames,
or simplified interpretive packages, are used to direct public opinions about important
issues. Frames help audiences organize and process complex information by drawing
attention to some considerations surrounding controversial topics while downplaying
others (Scheufele 1999). In this manner, the media not only tell people what to think
about (agenda setting), but also shape how people think about scientific controversies
(framing). While the media engage in deliberate processes to direct public attention and
opinions, there is a reciprocal exchange between popular media portrayals and pub-
lic priorities. Indeed, public priorities and concerns also direct media attention just as
media coverage shapes public discourse.
Citizens’ voices have been receiving increasing exposure with the advent of social
media. New forms of media, such as Web 2.0 platforms that allow publics to actively
create content rather than passively absorb information (e.g., blogs, YouTube, Twitter,
Facebook, and wikis) are now reforming traditional models of top-​down science com-
munication and introducing additional avenues for publics to directly contribute to
26

266 At the crossroads of civic engagement and evidence-based medicine

debates about science and policy. While social media platforms have only been widely
utilized for less than two decades, their accessibility and global reach have made them
widely impactful in health-​information sharing and decision-​making. Citizen-​generated
content on online platforms is a powerful information tool for health researchers and
policymakers. Indeed, public use of social media platforms has also been the subject
of a growing body of empirical inquiry, with innovative approaches such as web eth-
nographic and infodemiological methodologies that aim to utilize public knowledge to
inform healthcare delivery and science policy (Eysenbach 2009). For example, real-​time
infodemiological analyses of Twitter content have been used to track public perspectives
about immunization during the H1N1 epidemic, and respond to public concerns using
risk communication approaches to promote health (Chew & Eysenbach 2010). Publics
also increasingly utilize social media platforms in advocacy efforts. In March of 2014, Josh
Hardy, a 7-​year-​old boy who suffered a lifethreatening adenoviral infection, was denied
compassionate access to brincidofovir, an antiviral drug that was under investigation in
adult clinical trials. Brincidofovir’s manufacturer, Chimerix, explained that the company
did not have the resources to support a compassionate use program of the antiviral drug.
In response, Hardy’s parents launched a wide-​reaching Facebook and Twitter campaign
to pressure both the US Food and Drug Administration and Chimerix to provide access.
Catalyzed by public pressure, Chimerix and the Food and Drug Administration designed
an open-​label clinical trial that provided Hardy and 19 other pediatric patients access to
brincidofovir (Goodman 2014).

Success stories for community engagement in science and

policy
While public participation in science is often promoted through traditional and social
media outlets, initiatives that promote reciprocal and porous dialogue at the intersection
of science and society are also bolstered by a rich variety of empirical approaches. These
include community-​based participatory action research, deliberative democracies, and
consensus conferences, among others. Areas of such inquiry are equally diverse, rang-
ing in focus from community-​based research on immunization decision-​making (Kowal
et al. 2015) to deliberative engagements about sequencing of salmon genomes (O’Doherty
et al. 2010). Such research trajectories are based on a celebration of diverse civic ways of
knowing (Stilgoe et al. 2014).
Citizen engagement in science has also taken numerous community-​initiated forms. For
instance, proactive publics have had significant impact on science policy and healthcare
delivery in the neuro-​sphere through advocacy. In this capacity, engaged advocates have
largely articulated a niche for InSite, a supervised injection facility for individuals who
use illicit drugs with an evidence-​based harm reduction mandate in Vancouver, despite
numerous political and social hurdles (Boyd et al. 2009; Jozaghi 2014). Recent years have
also seen patient engagement in science through processes that have blurred the distinc-
tion between patient and researcher. In 2008, a phase II clinical trial originating in Italy
 267

The CCSVI story 267

concluded that lithium carbonate delays the rate of progression of amyotrophic lateral
sclerosis (ALS), an untreatable and invariably fatal neurodegenerative disease. This small
trial, which consisted of a sample of 16 patients who received the experimental interven-
tion and 24 controls followed over a period of 15 months, demonstrated that in contrast
to a 29% incidence of morbidity in the control group, no patient deaths occurred in the
experimental arm (Fornai et al. 2008). Given a scarcity of clinical interventions for ALS
and a limited therapeutic window of opportunity for clinically meaningful intervention,
neurologists began to prescribe lithium off-​label. In response to demands for an ongoing
evidentiary basis for the use of lithium, advocates in the ALS community in collaboration
with PatientsLikeMe—​an online patient network that aims to connect patients, improve
outcomes, and promote research—​initiated a platform for patients who had obtained
lithium off-​label to submit data about their usage and outcomes. Data probes included
dosage, weight, and outcome measures on the ALS functional rating scale. Data from 149
treated ALS patients were matched with historical controls in an observational study that
did not replicate the efficacy data suggested by Fornai and colleagues (Wicks et al. 2011).
This patient-​led research endeavor contributed to the early termination of clinical trials
due to futility considerations, and spared the ALS community significant divestment of
funds from promising areas of inquiry and opportunity costs for patients.
While numerous academic platforms are dedicated to public participation in science,
and successes in community advocacy are many, public controversies have also revealed
challenges in community engagement. We now direct focus to the case study of the
CCSVI research trajectory, as an example of the challenges of community engagement.

The CCSVI story
Multiple sclerosis (MS) is a chronic and progressive neurological disease of the brain
and the spinal cord that affects more than two million individuals worldwide (Multiple
Sclerosis International Federation 2015). In people with MS, the immune system attacks
myelinated axons in the central nervous system. This causes communication problems
between the brain and the rest of the body that lead to a range of symptoms such as
vision loss, fatigue, pain, sensory loss, spasticity, impaired mobility, and cognitive defi-
cits. Initially these symptoms may fluctuate. However, over time these problems accumu-
late and are often irreversible. Since the 1990s, disease-​modifying drugs have decreased
the frequency of developing new symptoms and delayed the onset of progressive decline.
Unfortunately, these treatments only appear to benefit those at the earliest stages of the
disease, and have little impact on improving or reversing chronic symptoms that contrib-
ute to a decrease in quality of life. The unknown etiology of the disease, especially the pro-
gressive forms, presents challenges to finding a cure, and leaves many severely disabled.
Dr. Paulo Zamboni, an Italian vascular surgeon, began to tackle the underlying cause
of MS when his wife was diagnosed with the disease in 1999. His primary area of inquiry,
involving investigation into heavy metal aggregate damage to blood vessels in the leg, led
him to suggest that iron deposits that are caused by narrowed or blocked veins in the neck
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268 At the crossroads of civic engagement and evidence-based medicine

(cerebrospinal venous insufficiency, or CCSVI) are at the root of the disease. Zamboni
believed that such blockage hinders the efficient removal of blood from the brain and
spinal cord, and causes a build-​up of iron that induces inflammation and myelin sheath
attack. Zamboni postulated two hypotheses. First, he proposed that all individuals with
MS have narrowed or blocked veins, and second, that relieving such venous anomalies
using a procedure similar to angioplasty, which he termed liberation therapy, would
cure MS.
To test his first hypothesis, Zamboni performed a cross-​sectional study where he looked
to diagnose CCSVI in 65 MS patients and 235 controls using ultrasound and catheter
venography. Indeed, his hypothesis was supported by results that established a strong
association between MS and CCSVI with vein anomalies in virtually the entire MS cohort
and none of the controls (Zamboni et al. 2009a). To test his second hypothesis, Zamboni
conducted an open-​label trial of the liberation procedure in 65 patients with MS, who
showed symptomatic improvement, reduced clinical relapses and reduced formation
of new lesions on brain magnetic resonance imaging (MRI) following the procedure
(Zamboni et al. 2009b).
Since 2009, several studies have brought Zamboni’s evidence into question. Scholars
expressed skepticism about Zamboni’s studies, pointing to several limitations in the
methods employed. Indeed, Zamboni’s liberation procedure was not conducted through
a randomized control trial and did not account for a potential placebo effect. Additionally,
patients who experienced the most improvement in Zamboni’s study had the relapsing–​
remitting form of MS, where spontaneous remissions in disease activity commonly occur.
Moreover, although a meta-​analysis of ultrasound diagnoses of CCSVI suggests an asso-
ciation between vein abnormality and MS (Laupacis et al. 2011), other studies demon-
strate that CCSVI occurs rarely and with similar prevalence among both patients with MS
and in healthy individuals (Doepp et al. 2010; Mayer et al. 2011; Traboulsee et al. 2014).
Commentators believe that the substantial evidence undermining Zamboni’s hypoth-
eses should have been the end of the CCSVI story (Reekers 2012). The cautionary word
of the medical community, however, was seemingly dwarfed by optimistic anecdotes
that amassed publicly accessible domains. Indeed, despite concerns about the validity
of the data that bolstered the liberation procedure in the neurology community, news
of Zamboni’s study catalyzed a media frenzy and showcased a potent account of evi-
dence: the anecdote.
The procedure was widely covered in international newspapers and was also com-
monly featured in television outlets (Favaro & Philip 2009). However, it was publicity
through social media platforms that fueled widespread activism within the MS commun-
ity. Indeed, CCSVI gained significant momentum in the blogosphere: within 2 years of
the publication about the liberation procedure, thousands of people engaged with more
than 500 Facebook groups, pages, and events about the intervention, and over 4000
YouTube videos were dedicated to CCSVI, many documenting the positive experiences
of patients who underwent the procedure (Chafe et al. 2011). These powerful anecdotes
showcased patient accounts before and after the procedure, which not only described the
 269

What have we learned? 269

amelioration of their symptoms and improved quality of life, but also demonstrated gains
in function (Mazanderani et al. 2013).
Anecdotal evidence motivated thousands of patients to seek access to CCSVI proce-
dures, and when the intervention was unavailable through their local healthcare provid-
ers, many chose to travel abroad at great personal cost to countries like Costa Rica and
Poland that offered the CCSVI procedure (Snyder et al. 2011). Even in the face of several
severe adverse events linked to CCSVI procedures, including deaths (Alphonso 2010;
Samson 2010), patients persisted in advocacy efforts for access to the invasive procedure.
Advocates continued to publicize personal anecdotes of the therapeutic benefits of the
procedure through social media outlets, organize demonstrations, attack the credibility
of parties that advocated for caution, and question potential conflicts of interest of both
the MS societies and MS neurologists. Steadfast advocacy generated enormous pressures
on granting agencies such as MS societies and government funding bodies in Europe,
Australia, and North America to mobilize additional research on CCSVI. The controversy
became particularly pronounced in Canada, where MS is very prevalent (Pullman et al.
2013). In 2010, the Canadian Institutes of Health Research, the primary government fund-
ing agency for health research in Canada, formed an expert panel in collaboration with
the Canadian MS Society about the CCSVI research agenda. The panel initially advised
that only studies that examine the venous anomaly hypothesis receive funds, a stance that
was also adopted by the United States. But despite expert caution, media pressures contin-
ued to hail the potential of the liberation treatment and reputable media platforms began
to exert political pressure to mobilize funding for CCSVI research (Pullman et al. 2013).
For example, The Globe and Mail, one of Canada’s most circulated newspapers, asserted:
“Canada should fund medical trials of revolutionary treatment for multiple sclerosis, and
not act as if rejection of those trials by an expert panel must be obeyed. This is a political
question, not a purely scientific one” (Globe Editorial 2010).
Critics argue that CCSVI research was mobilized by intense social and political pres-
sure, more so than by sound science (Chafe et al. 2011). Commentators believe that the
CCSVI research trajectory has resulted in the unnecessary expenditure of scarce resources,
divestment of funds from more promising areas of inquiry for MS, and caused signifi-
cant therapeutic opportunity costs, adverse events, and preventable fatalities (Rasminsky
2013). Additionally, the CCSVI experience has contributed to unrealized hopes in the MS
community, the impact of which is yet to be determined. Given these costs, it is essential
that we examine the lessons learned from the CCSVI research trajectory to inform future
public engagement in science and science policy.

What have we learned? Drawing lessons from community

engagement in the neurosciences
The CCSVI experience illustrates a divergence between stakeholders’ perspectives on
what constitutes sound evidence. While the CCSVI hypotheses were largely met with
skepticism in the neurology community, the evidence encouraged patient hope that
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270 At the crossroads of civic engagement and evidence-based medicine

mobilized intense public and political pressure to provide access to liberation interven-
tions and invest in their evaluation. Educational initiatives may be needed to address
public evaluation of diverse forms of evidence, particularly in light of the powerful and
readily accessible anecdotes on online fora. The CCSVI experience also emphasizes the
power of the media, particularly newer forms of social media, in influencing science
policy and priority setting in research. Scholarly inquiry should continue to focus on
harnessing the power of social media platforms to foster sustainable support for evidence-​
based science. Education about evidence should be a bidirectional effort. Scientists may
reciprocally consider that the contemporary focus on evidence-​based medicine some-
times overlooks a wide body of knowledge that has been gleaned from medicine-​based
evidence approaches. Indeed, fields such as surgery and oncology have largely seen inno-
vation based on clinical experience. An educational initiative alone, however, would be
a reductionist approach. Indeed, educational approaches do not adequately account for
affective factors, such as hope, that extend beyond a deficit of understanding and exert a
large influence on the decision-​making process.
The CCSVI experience brings the delicate nature of hope to the surface—​a force that
ubiquitously surrounds biomedical research, and can serve to both mobilize and some-
times hinder successful scientific innovation. Hope largely motivated activism in the
CCSVI context, as it often serves to promote developing biotechnologies. Hope is a nat-
ural and necessary component of technological development, and can also serve as an
adaptive mechanism for managing daily living with serious illness (Groopman 2005;
Kimmelman 2009). Successful community engagement about developing neurotechnolo-
gies will therefore need to address the complexities of hope with key end-​users, such as
patients and their families. Clinical conversations about hope may be particularly use-
ful. Neurologists may best serve the interests of their patients by approaching conversa-
tions about hope through a posture of epistemic (knowledge-​based) humility: a stance
that acknowledges the uncertainty associated with decision-​making in medical care, and
one that also appreciates the lived experience that lends expertise to patients (Ho 2009;
Schwab 2012). Honoring patient hope for therapeutic development while grounding prac-
tical advice in current clinical realities may strengthen collaboration between patients and
their clinicians and support shared decision-​making through an emphasis on informed
hope (Reimer et al. 2010; Benjaminy et al. 2015). Conversations through a lens of epi-
stemic humility that privilege openness and understanding over hierarchical assertion
of expertise could also serve to strengthen relationships of trust between patients and
physicians. Indeed, commentators argue that such relationships may have been strained
in the CCSVI context (Pullman et  al. 2013; Snyder et  al. 2014). Additional research is
necessary to explore the impact of the CCSVI research trajectory on community support
in analogous non-​pharmaceutical areas of inquiry that present the possibility for ther-
apeutic development (e.g., stem cell interventions). Such knowledge may be helpful in
understanding the response of communities that have been subject to disappointment
following cycles of hope—​a phenomenon that occurs all too often in biomedical research
(Petersen 2009).
 271

References 271

Finally, it is key that community engagement in science and policy be reciprocally

complemented by responsible scientific citizenship. While the focus of this chapter is on
community engagement, we should not underestimate the importance of engaged schol-
arship. Neuroscientists and neuroethicists have a social obligation to share their knowl-
edge and expertise with the public, particularly as academic pursuits are often resourced
through the public purse. As such, scientists should be encouraged to interface with citi-
zens about the uncertainties, caveats, as well as the promise of their work. Scholars have
suggested that the CCSVI experience illustrates the need to include the voices of scientists
in social media platforms through which many public advocacy campaigns that mobilize
science policy are launched, instead of disregarding such fora as untrustworthy or not
evidence-based (Mazanderani et al. 2013). However, engaged scholarship will not be sus-
tainable unless it is incentivized by the academic infrastructure (Boyer 1996; Illes et al.
2010). It is therefore important that a culture that values engaged scientific citizenship be
embedded into the core of academic training in the long term, and into academic evalu-
ation in the short term.

Conclusion
Public engagement in science is a central value in the field of neuroethics, and reflects a
commitment to social responsibility and accountability in the process of democratizing
science and policy. A commitment to citizen engagement recognizes the possibility that
public controversies may arise as neuroethical issues are deliberated in the public sphere.
The CCSVI research trajectory illustrates some of the challenges that may arise when
public and scientific agendas diverge. Forging successful partnerships between neurosci-
entists, neuroethicists, and the broader community will require both trust and hope as
well as reciprocity between mutually engaged publics and scholars.

Acknowledgments
The quotation attributed to Globe Editorial was reproduced by kind permission of The
Globe and Mail, Copyright © 2016 The Globe and Mail Inc., http://​www.theglobeandmail.
com/​opinion/​editorials/​funding-​ms-​trials-​is-​a-​decision-​that-​goes-​beyond-​expertise/​
article1379043/​.

References
Alphonso, C. (2010, November 19). Death of MS patient fuels debate over new treatment. The Globe
and Mail. Available from: http://​www.theglobeandmail.com/​news/​national/​death-​of-​ms-​patient-​
fuels-​debate-​over-​new-​treatment/​article1314786/​ [accessed January 22, 2016].
Benjaminy, S., Kowal, S.P., MacDonald, I.M., and Bubela, T. (2015). Communicating the promise
for ocular gene therapies: challenges and recommendations. American Journal of Ophthalmology,
160(3), 408–​415.
Boyd, S.C., MacPherson, D., and Osborn, B. (2009). Raise Shit! Social Action Saving Lives. Black Point,
NS: Fernwood.
27

272 At the crossroads of civic engagement and evidence-based medicine

Boyer, E.L. (1996). The scholarship of engagement. Bulletin of the American Academy of Arts and
Sciences, 49(7), 18–​33.
Chafe, R., Born, K.B., Slutsky, A.S., and Laupacis, A. (2011). The rise of people power. Nature,
472(7344), 410–​411.
Chew, C. and Eysenbach, G. (2010). Pandemics in the age of Twitter: content analysis of Tweets during
the 2009 H1N1 outbreak. PloS One, 5(11), e14118.
Doepp, F., Paul, F., Valdueza, J.M., Schmierer, K., and Schreiber, S.J. (2010). No cerebrocervical venous
congestion in patients with multiple sclerosis. Annals of Neurology, 68(2), 173–​183.
Eysenbach, G. (2009). Infodemiology and infoveillance: framework for an emerging set of public health
informatics methods to analyze search, communication and publication behavior on the Internet.
Journal of Medical Internet Research, 11(1), e11.
Favaro, A. and St Philip, E. (2009). The liberation treatment: a whole new approach to MS. CTV News.
Available from: http://​www.ctvnews.ca/​the-​liberation-​treatment-​a-​whole-​new-​approach-​to-​ms-​
1.456617 [accessed February 12, 2016].
Fornai, F., Longone, P., Cafaro, L., et al. (2008). Lithium delays progression of amyotrophic lateral
sclerosis. Proceedings of the National Academy of Sciences of the United States of America, 105(6),
2052–​2057.
Globe Editorial. (2010, September 2). Funding MS trials is a decision that goes beyond expertise. The
Globe and Mail. Available from: http://​www.theglobeandmail.com/​opinion/​editorials/​funding-​ms-​
trials-​is-​a-​decision-​that-​goes-​beyond-​expertise/​article1379043/​ [accessed January 22, 2016].
Goodman, M. (2014). Twitter storm forces Chimerix’s hand in compassionate use request. Nature
Biotechnology, 32(6), 503–​504.
Groopman, J. (2005). The Anatomy of Hope: How People Prevail in the Face of Illness.
New York: Random House.
Ho, A. (2009). ‘They just don’t get it!’ When family disagrees with expert opinion. Journal of Medical
Ethics, 35(8), 497–​501.
Illes, J., Blakemore, C., Hansson, M.G., et al. (2005). International perspectives on engaging the public
in neuroethics. Nature Reviews Neuroscience, 6(12), 977–​982.
Illes, J., Moser, M.A., McCormick, J.B., et al. (2010). Neurotalk: improving the communication of
neuroscience research. Nature Reviews Neuroscience, 11(6), 61–​69.
Jozaghi, E. (2014). The role of drug users’ advocacy group in changing the dynamics of life in the
Downtown Eastside of Vancouver, Canada. Journal of Substance Use, 19(1–​2), 213–​218.
Kimmelman, J. (2009). Gene Transfer and the Ethics of First-​in-​human Research: Lost in Translation.
Cambridge: Cambridge University Press.
Kowal, S.P., Jardine, C.G., and Bubela, T.M. (2015). ‘If they tell me to get it, I’ll get it. If they
don’t...’: immunization decision-​making processes of immigrant mothers. Canadian Journal of Public
Health, 106(4), E230.
Laupacis, A., Lillie, E., Dueck, A., et al. (2011). Association between chronic cerebrospinal venous
insufficiency and multiple sclerosis: a meta-​analysis. Canadian Medical Association Journal, 183(16),
E1203–​1212.
Leshner, A.I. (2005). It’s time to go public with neuroethics. American Journal of Bioethics, 5(2), 1–​2.
Marcus, S.J. (Ed) (2002). Neuroethics: Mapping the Field, Conference Proceedings. Chicago, IL: University
of Chicago Press.
Mayer, C.A., Pfeilschifter, W., Lorenz, M.W., et al. (2011). The perfect crime? CCSVI not leaving a trace
in MS. Journal of Neurology, Neurosurgery & Psychiatry, 82(4), 436–​440.
Mazanderani, F., O’Neill, B., and Powell, J. (2013). “People power” or “pester power”? YouTube as a
forum for the generation of evidence and patient advocacy. Patient Education and Counseling, 93(3),
420–​425.
 273

References 273

McCombs, M.E. and Shaw D.L. (1972). The agenda-​setting function of mass media. Public Opinion
Quarterly, 36(2), 176–​187.
Multiple Sclerosis International Federation. (2015). What is MS? Available from: http://​www.msif.org/​
about-​ms/​what-​is-​ms/​ [accessed February 10, 2016].
O’Doherty, K., Burgess, M., and Secko, D.M. (2010). Sequencing the salmon genome: a deliberative
public engagement. Life Sciences Society and Policy, 6(1), 15.
Petersen, A. (2009). The ethics of expectations: biobanks and the promise of personalized medicine.
Monash Bioethics Review, 28(1), 22–​33.
Pullman, D., Zarzeczny, A., and Picard, A. (2013). Media, politics and science policy: MS and evidence
from the CCSVI trenches. BMC Medical Ethics, 14(1), 6.
Rasminsky, M. (2013). Goodbye to all that: a short history of CCSVI. Multiple Sclerosis Journal, 19(11),
1425–​1427.
Reekers, J.A. (2012). CCSVI and MS: a never-​ending story. European Journal of Vascular and
Endovascular Surgery, 43(1), 127–​128.
Reimer, J., Borgelt, E., and Illes, J. (2010). In pursuit of “informed hope” in the stem cell discourse.
American Journal of Bioethics, 10(5), 31–​32.
Samson, K. (2010). Experimental multiple sclerosis vascular shunting procedure halted at Stanford.
Annals of Neurology, 67(1), A13–​15.
Scheufele, D.A. (1999). Framing as a theory of media effects. Journal of Communication, 49(1), 103–​122.
Schwab, A. (2012). Epistemic humility and medical practice: translating epistemic categories into ethical
obligations. Journal of Medicine and Philosophy, 37(1), 28–​48.
Snyder, J., Crooks, V.A., Adams, K., Kingsbury, P., and Johnston, R. (2011). The ‘patient’s physician
one-​step removed’: the evolving roles of medical tourism facilitators. Journal of Medical Ethics,
37(9), 530–​534.
Snyder, J., Adams, K., Crooks, V.A., Whitehurst, D., and Vallee, J. (2014). “I knew what was going to
happen if I did nothing and so I was going to do something”: faith, hope, and trust in the decisions
of Canadians with multiple sclerosis to seek unproven interventions abroad. BMC Health Services
Research, 14(1), 445.
Stilgoe, J., Lock, S.J., and Wilsdon, J. (2014). Why should we promote public engagement with science?
Public Understanding of Science, 23(1), 4–​15.
Traboulsee, A.L., Knox, K.B., Machan, L., et al. (2014). Prevalence of extracranial venous narrowing
on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy
controls: a blinded, case-​control study. The Lancet, 383(9912), 138–​145.
Wicks, P., Vaughan, T.E., Massagli, M.P., and Heywood, J. (2011). Accelerated clinical discovery using
self-​reported patient data collected online and a patient-​matching algorithm. Nature Biotechnology,
29(5), 411–​414.
Zamboni, P., Galeotti, R., Menegatti, E., et al. (2009a). Chronic cerebrospinal venous insufficiency
in patients with multiple sclerosis. Journal of Neurology, Neurosurgery & Psychiatry, 80(4),
392–​399.
Zamboni, P., Galeotti, R., Menegatti, E., et al. (2009b). A prospective open-​label study of endovascular
treatment of chronic cerebrospinal venous insufficiency. Journal of Vascular Surgery, 50(6),
1348–​1358.
274

Chapter 15

Ethical dilemmas in neurodegenerative

disease: Respecting patients at the
twilight of agency
Agnieszka Jaworska

[A]‌man does not consist of memory alone. He has feeling, will, sensibi­
lities, moral being … And it is here … that you may find ways to touch him.
(A.R. Luria, cited in Sacks 1985, p.32)

Introduction
Neurodegenerative disease can significantly affect the requirements for an ethically
appropriate treatment of an individual. The deterioration of the brain profoundly alters
psychological functioning and capacities, and so profoundly alters the kind of being oth-
ers are called upon to relate to and respond to from the point of view of ethics. Such trans-
formations are easiest to see in cases in which the current preferences and interests of a
patient in a degenerated state come into conflict with the values and choices the person
professed before the neurodegeneration began. Which set of preferences should the care-
giver follow? The answer will be different depending on the ethically relevant metaphysi-
cal and mental properties that the patient still possesses. Thus to resolve such dilemmas
we must get the ethically relevant conceptual distinctions right, but we must also be true
to empirical facts. To the extent that neuroscience has developed a detailed understand-
ing of how various brain disorders undermine psychological functioning and capacity,
it has increasingly become more pertinent to the untangling of such ethical puzzles. The
following case study illustrates the interplay between ethical conceptual analysis and neu-
roscientific findings in the resolution of moral dilemmas that arise in Alzheimer’s disease.
I defend the philosophical view that the immediate interests of an individual cannot
be overridden as long as the individual possesses the capacity to value. In the context of
each particular neurodegenerative disease, this recommendation must be guided by a sci-
entifically informed assessment of when in the course of the disease the capacity to value
could possibly be lost, and when it is likely to be retained. In the case of Alzheimer’s dis-
ease, neuroscientific evidence indicates that the capacity to value is slowly and gradually
weakened, and in some cases may not be completely lost until relatively far along in the
disease’s progression. Similar neuroethical analyses must be carried out for other diseases
and disorders, and will probably yield different results.
 275

Respecting the margins of agency: Alzheimer’s patients and the capacity to value 275

Respecting the margins of agency: Alzheimer’s patients and

the capacity to value
Case scenario: Mrs. Rogoff was always an independent woman. Raised in an immigrant family, she
was used to working hard for what she wanted. Most of her life she ran a successful business selling
liquor. She also developed local fame as an outstanding cook and hostess. She was an introvert, liked
living alone, and always carefully guarded the way she presented herself to others.
In her early eighties, Mrs. Rogoff developed severe motor impairments, which could only be corrected
by a risky neurosurgery. She decided to undergo the procedure, insisting that she would rather die
than be immobile. She prepared a living will, requesting not to have her life prolonged if she became a
burden to her family or if she could no longer enjoy her current quality of life.
The surgery was successful, but shortly thereafter Mrs. Rogoff developed early signs of dementia: mem-
ory and word-​finding difficulties. As she became more and more disoriented, her daughter hired a
live-​in housekeeper, Fran. Fran takes care of Mrs. Rogoff in the way one would take care of a child.
Mrs. Rogoff enjoys the long hours she spends with Fran, and with her grandchildren when they visit,
telling them somewhat disjointed stories about her earlier ventures. She watches television a lot, and
her stories often incorporate the more exciting episodes from television as if they pertained to her own
life. In her more lucid moments, Mrs. Rogoff tells her grandchildren that she is scared to die, that “she
doesn’t want to go anywhere.”
Fran has to make day-​to-​day decisions for Mrs. Rogoff:  Should Mrs. Rogoff get dressed if her
family is coming to visit and she insists on wearing pajamas? Should she take a bath every
day even if she is afraid of water? In general, should the current decisions reflect the care Mrs.
Rogoff used to take in how she presented herself to others? Mrs. Rogoff ’s daughter faces the more
weighty decisions: Should she use up Mrs. Rogoff ’s savings to pay Fran’s salary, allowing Mrs.
Rogoff to keep enjoying her companion, or should she place Mrs. Rogoff in a nursing home,
increasing the likelihood that, when the time comes, there will be some money left to execute
Mrs. Rogoff ’s will? What treatments should she authorize if Mrs. Rogoff develops a dangerous
but treatable infection?1

People who care for Alzheimer’s patients—​family members, nursing home providers,
physicians, medical researchers—​face such dilemmas routinely, and these dilemmas are
becoming more and more familiar as baby-​boomers approach the age of high risk for
Alzheimer’s disease. The particulars of each dilemma may seem unique, but they typi-
cally have the same underlying structure. There is a conflict between the attitudes and
values the patients espoused when they were still healthy and their later interests as peo-
ple afflicted with dementia. The quandary, in a nutshell, is this: should we, in our efforts
to best respect a patient with dementia, give priority to the preferences and attitudes
this person held before becoming demented, or should we follow the person’s present
interests?

Competing theoretical perspectives

There are two dominant theoretical perspectives on how such dilemmas ought to
be resolved, expressed most prominently by Rebecca Dresser and Ronald Dworkin.
According to Dresser, decisions affecting a demented person at a given time must speak
to the person’s point of view as current at that time. Heeding values and wishes that the
patient no longer espouses and that cannot be said to represent his present needs and
interests can do no good for the patient (Dresser 1986).
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276 Ethical dilemmas in neurodegenerative disease

Dworkin directly challenges this line of reasoning, adducing compelling reasons to

adhere to the demented patients’ earlier wishes and values (Dworkin 1993). In Dworkin’s
view, we fail to take seriously both the autonomy and the well-​being of a demented patient
unless we adhere strictly to the patient’s earlier wishes, wishes that originated when he
was still capable of acting autonomously and still able to judge what was required for his
overall well-​being.
In this chapter, I develop an alternative to both Dresser’s and Dworkin’s analyses. Like
Dresser, I want to take seriously the current interests of demented patients, but for very
different reasons: I believe that many of these patients may still be capable of autonomy
to a significant degree and that they may still have authority concerning their well-​being.
Yet I emphasize very different aspects of both autonomy and well-​being than Dworkin,
who predicates autonomy on decision-​ making capacity and for whom well-​ being
depends centrally on promoting one’s own design for one’s life as a whole. I associate
potential for autonomy primarily with the capacity to value, and well-​being with living
in accordance with one’s values (Jaworska 1997). Thus the central question for a care-
giver attempting to best respect an Alzheimer’s patient becomes not, “Can this patient
reason thoroughly and come to a rational decision?” or “Does he grasp what’s best for
his life as a whole?” but “Does this patient still value?” I will argue that the capacity to
value is not completely lost in dementia, and, to the extent that it is not, respect for the
immediate interests of a demented person is contrary neither to his well-​being nor to the
respect for his autonomy.
Dworkin’s arguments are a fruitful point of departure because their kernel is very
plausible. After someone loses his status as an agent—​as a creature capable of guiding
his actions—​his earlier autonomously chosen values should continue to govern what
happens to him, despite his current inability to appreciate these values. This accurately
locates the central issue of our dilemmas: at what point in the course of dementia are
the attributes essential to agency lost? While I consider most of the ideas in Dworkin’s
arguments well founded, I challenge his two crucial premises. In the argument focused
on the patient’s well-​being, I  dispute the claim that demented patients are no longer
capable of generating what Dworkin calls “critical interests.” In the argument concerning
autonomy, I question the premise that demented patients no longer possess the “capac-
ity for autonomy.” In each case, I will trace how the problematic premise arises within
Dworkin’s argument and then develop an alternative account of the relevant capacity.

Reconceiving well-​being
Experiential interests versus critical interests
When we take enhancement of the demented patient’s well-​being as the caregiver’s
goal, we need to distinguish two types of prudential interest that the patient may have.
Dworkin labels these two types of interest “experiential” and “critical.” Experiential
interests concern the quality of the person’s experience, his state of mind. We have an
interest in experiencing pleasure, satisfaction, enjoyment, contentment, lack of pain, and
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Respecting the margins of agency: Alzheimer’s patients and the capacity to value 277

so forth; what states of mind count here and how they can be brought about is deter-
mined fully by how these experiences feel to the person in question. But most of us also
have critical interests—​interests in doing or having in our lives the things we consider
good and in avoiding the things we consider bad, no matter what sorts of experiences
result from fulfilling these interests. For example, a person’s critical interests may include
being a successful soldier or securing contentment and harmony for his family, however
much stress or anguish the pursuit of these goals may engender.
Experiential interests are inherently time-​specific—​to satisfy them at a given time,
the person must still espouse them at that time. For instance, it only makes sense to
want to satisfy your experiential interest in having a good time with your guests if at
the time they arrive you will still be interested in enjoying their company. Not so with
critical interests; it may make sense to have your critical interest satisfied even if you
are unaware of its being satisfied, even if you are dead at the time, or unconscious, or
too demented to grasp what your critical interest has been all along. Fulfillment of a
critical interest bears only on the object of that interest. It involves bringing about what-
ever state of affairs the person in question judged good; the fate of the person himself
is not relevant to this, provided that the object of the interest is external to the person.
Thus fulfilling a father’s critical interest in the well-​being of his family does not require
his awareness of how well they are doing. This critical interest could be advanced, for
example, by obeying a deathbed promise to take care of his wife and children after he
passes away.
Dworkin readily grants that Alzheimer’s patients, even at late stages of their illness,
can experience pleasures as well as frustrations, and thus have the basis for contem-
poraneous experiential interests. He would interpret the dilemmas under discussion
in this chapter as cases of conflict between these experiential interests and critical
interests that the person professed when he was still healthy (e.g. a conflict between
Mrs. Rogoff ’s experiential interest in continuing the enjoyable storytelling sessions
and her critical interest in not being dependent on her family). And here Dworkin
assumes that, at least in the types of cases he wants to address, the demented patient
is not capable of generating contemporaneous critical interests. From this point, there
follows a very plausible analysis. The fact that the demented patient no longer affirms
critical interests in no way implies that he does not have critical interests. Since such
interests are not inherently time-​specific, the prudential importance of satisfying them
may survive the person’s unawareness of their satisfaction, whether due to uncon-
sciousness, dementia, or even death. Thus a demented person who cannot generate
contemporaneous critical interests may still have some of the same critical interests
he professed when he was healthy. And this means that the conflict occurring in our
dilemmas is best described as a conflict between the patient’s ongoing experiential
interests and his ongoing critical interests.
This description helps to clarify how the conflict ought to be resolved. In the case of an
ordinary competent person, when his critical interests (his judgments and values) come
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278 Ethical dilemmas in neurodegenerative disease

into conflict with his experiential interests (what would lead to the optimal state of mind
for him), we do not hesitate to give precedence to his well-​considered values and judg-
ments, and we concede that, overall, this is best for him. For example, we would accept
that it is in the best interest of a devoted father to sacrifice his experiential interest in his
current comfort for the sake of the future of his children, or that it is in the best interest
of a patriotic soldier to forgo his experiential interest in a carefree life and sign up for
demanding military training. The case of our demented person turns out to be no dif-
ferent:  in his conflict between ongoing experiential and critical interests, it is also best
to privilege the latter. We serve Mrs. Rogoff best by satisfying her critical interest in not
being a burden to her family, at the expense of her experiential interest in enjoying tele-
vision and storytelling.
This analysis stands or falls with the assumption that demented patients no longer
originate critical interests. For if they do—​if the conflict in our dilemmas is between the
patient’s contemporarily professed critical interests and the critical interests he professed
before becoming demented—​Dworkin’s framework would readily allow that the contem-
porarily professed critical interests ought to take precedence. In this case, the demented
person would be viewed as any other person whose values and commitments change
over time and whose currently professed values are taken to have bearing on what is best
for him.
The idea that a demented person can originate critical interests need not imply that the
person generates brand new critical interests. What matters is whether the person still
has an ongoing commitment to his critical interests. After all, the most likely scenario of
a conflict between a demented person’s current critical interests and his critical interests
from the pre-​dementia period is not one in which a person’s demented mind generates
completely new critical interests, but rather one in which dementia causes a person to lose
some of his earlier more complex interests, so that in the new simpler configuration the
remaining interests gain import.
Dworkin defends the claim that the demented cannot generate critical interests as
follows:

[B]‌y the time the dementia has become advanced, Alzheimer’s victims have lost the capacity to
think about how to make their lives more successful on the whole. They are ignorant of self—​not
as an amnesiac is, not simply because they cannot identify their pasts—​but more fundamentally,
because they have no sense of a whole life, a past joined to a future, that could be the object of any
evaluation or concern as a whole. They cannot have projects or plans of the kind that leading a crit-
ical life requires. They therefore have no contemporary opinion about their own critical interests.
(Dworkin 1993, p.230)

In contending that demented persons cannot have opinions about their critical interests,
Dworkin presupposes that one needs to have a sense of one’s life as a whole in order to orig-
inate critical interests, a sense that a person may begin to lose relatively early in the pro-
gression of dementia. Dworkin thinks of critical interests as stemming from “convictions
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Respecting the margins of agency: Alzheimer’s patients and the capacity to value 279

about what helps to make a life good on the whole” (Dworkin 1993, pp.201–​202). But do
critical interests have to reflect the person’s comprehensive design for the progression of
his life? An alternative view, tacitly embedded in Dworkin, is more plausible.
Critical interests may well be understood to issue from something less grand—​simply
from convictions about what is good to have, which do not require the ability to grasp or
review one’s whole life. Dworkin himself describes “opinions about my critical interests”
as “opinions about what is good for me” (Dworkin 1993, p.202), indicating that these are
opinions about values, and that the ability to generate critical interests goes hand in hand
with the ability to value. And it does seem possible for a person to value something at a
given time, without referring this value to his conception of his life as a whole. This pos-
sibility is evident in patients with severe loss of memory and linguistic ability who are still
aware of their decline and deeply regret it. I recently observed a patient who, in response
to a simple question about what he did that day, had great difficulty keeping track of the
sequence of his thoughts and of the sequence of words in the sentence he was composing,
and after several starts and long pauses, said slowly, his voice trembling: “Here you can
see Alzheimer’s at work.” There was no doubt that this man, who had little grip on “his
life as a whole,” nevertheless valued the abilities he could no longer command and was
expressing profound regret.

Understanding values
Intuitively, it is easy to recognize when someone expresses a value—​and not merely a sim-
pler attitude such as a craving, a desire, or a wish. But to exhibit more clearly that valuing
need not involve a grasp of one’s life as a whole, let us characterize more systematically
what valuing is and distinguish it from these simpler attitudes, which even Dworkin read-
ily attributes to Alzheimer’s patients.
The main difference between mere desiring and valuing is this: one way to deal with
one’s non-​value-​laden desires is to try to eliminate them—​to try to bring it about that one
does not feel them—​but this would not be a satisfactory response to a valuing. A person
could contemplate being free of a mere desire with a sense of relief, but one would always
view the possibility of not valuing something one currently values as an impoverish-
ment, loss, or mistake. We can all recognize clear cases when a strong desire is definitely
not a value—​think of a priest eager to rid himself of his sexual desires, or a temporarily
depressed person seeking relief from his persistent wish to hurt himself. Also, even if one’s
attitude toward a desire is more neutral—​perhaps one views it only as a nuisance—​as long
as one would not mind lacking it, it is still a mere desire. Cravings for specific food items
are paradigmatic cases here. In contrast, when one values something, say, a particular
friendship or a local community, one cannot be indifferent to whether one happens to
value these things or not—​a state in which one lacked one’s feelings for one’s friend or
one’s need for a sense of belonging would call for regret.2 We can see this in our patient
mourning the losses caused by Alzheimer’s disease—​he would view with horror the pro-
jected future in which he will no longer care about these losses.
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280 Ethical dilemmas in neurodegenerative disease

Thus values have special attributes that do not apply to mere desires: we think that it
would be a mistake to lose our current values—​we hold our values to be correct, or at least
correct for us. This means that we can typically give a rationale for why we consider some-
thing valuable or good, usually by situating this value in a larger normative framework.
Also, since values are the sorts of attitudes that we allow could be correct or incorrect,
they are open to criticism and revision. At minimum, there are consistency requirements
on what one can consider good—​if one values something and also values its opposite,
one will be under rational pressure to resolve the conflict. For example, if you truly value
a committed relationship, you cannot just as easily value the freedom of a lack of com-
mitment; you may well see the merits of both, but you cannot be fully committed to your
spouse unless you cease to care as deeply about your freedom. In contrast, as a matter of
sheer desire, you may surely remain ambivalent without any rational impetus to settle the
conflict—​you may simply keep craving just as strongly the kind of intimacy possible only
in an ongoing partnership as well as the excitement of always being able to walk out and
entice a new partner.
Another mark of valuing as opposed to mere desiring is that a person’s values are
usually entangled with his sense of self-​worth: a person values himself in terms of how
well he lives up to his values. Some people pay little attention to their own value, so
what I am now describing is not a necessary condition of having values. However, it
is a sufficient condition: anyone who has a conception of himself, a set of ideals that
he wants to live up to and in virtue of which he assesses his own value, is no doubt a
valuer.
I have isolated two features essential to, or strongly indicative of, valuing: the person
thinks he is correct in wanting what he wants, and achieving what he wants is tied up with
his sense of self-​worth. Nothing here suggests that valuing would require a grasp of the
narrative of one’s whole life.
Furthermore, for the purposes of the argument I outlined earlier, Dworkin does not
need to interpret the capacity to generate critical interests as anything more than the so-​
specified capacity to value. As we have seen, the backbone of Dworkin’s justification for
disregarding current wishes of patients who can no longer originate critical interests is the
perception that, ordinarily, critical interests take precedence over experiential interests
in determining what is best for a person. But, presumably, critical interests are of such
overriding importance because they stem from the person’s values—​because they reflect
the person’s opinion of what is correct for him. And this standing of critical interests is
independent of whether they encompass the person’s design for his life as a whole. For
instance, a devoted father’s critical interest in the well-​being of his children overrides his
interest in having optimal experiences, no matter whether he came to value his children
by reflecting on the narrative of his whole life. Thus, to endorse Dworkin’s compelling
argument that deference to current wishes of a demented patient ought to depend on
whether the patient can still originate critical interests, we have no need to understand
critical interests in terms of the person’s grasp of what is good for his life as a whole; we can
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Respecting the margins of agency: Alzheimer’s patients and the capacity to value 281

just trace critical interests to the person’s convictions about what would be good and cor-
rect for him—​to the person’s values as understood in the above-​mentioned specifications.

Values do not require assessments of one’s life as a whole

Of the three claims I have made—​that critical interests are values, that conceptually such
values may be understood as quite independent of the agent’s grasp of his life as a whole,
and that this is the interpretation relevant to Dworkin’s argument—​the second is the most
contentious. However, it is confirmed by many real-​life Alzheimer’s cases in which valu-
ing becomes uncoupled from the person’s grasp of the narrative of his whole life.
Consider, for example, Mrs. D, a patient interviewed in a study by Sabat (1998), diag-
nosed with probable Alzheimer’s for 5 years. As for her level of impairment:
[S]‌he was moderately to severely afflicted (stage 4, Global Deterioration Scale, score of 7 on the
Mini-​Mental State Test). She could not name the day of the week, the date, the month, the season,
year, the city and county she was in … She underestimated her age … and had difficulty finding
her way to the bathroom at the day care center she attended two days each week. (Sabat 1998, p.46)

Mrs. D’s memory deficiency was rather acute. Since she could not keep track of the passing
time or of her own age, and had severe difficulties forming new memories, Dworkin could
safely assume that she had lost grasp of the narrative of her whole life, that she lacked a
sense of “a past joined to a future.” However, Mrs. D still conducted herself as a valuer. She
often volunteered as a research subject for tests and experiments at the National Institutes
of Health. Although she did not choose to do so through systematic reflection on the
whole trajectory of her life, she clearly felt that this was, for her, the right choice: “That
was the nicety of it, cause I could have said, ‘no,’ but believe me, if I can help me and my
[fellow] man, I would do it” (Sabat 1998, p.46). Her conviction that it would have been a
mistake to say “no” comes across rather starkly here. And she had no need to review her
life as a whole to affirm this conviction. What mattered for her was that this felt right to
her, then and there. One has the sense that Mrs. D was simply enacting a basic part of her
personality, one that had remained relatively intact despite her other impairments.
For a less altruistic example, consider another of Sabat’s interviewees, Dr.  B, an
Alzheimer’s patient who scored even lower than Mrs. D on cognitive tests. Like Mrs. D,
he “could not recall the day of the week, the month, or the year” (Sabat 1998, p.41). His
ability to evaluate his life as a whole could not have been better than that of Mrs. D. Yet
he too proved capable of valuing. He became very interested in Sabat’s research project.
Although his grasp of its design was rather rudimentary, he thought of the project as his
“salvation,” as a way to engage, despite his impairments, in something other than “filler”
(Sabat 1998, p.41), in something giving him a mark of distinction. He told Sabat more or
less explicitly that he considered the project right and appropriate: “And you know I feel
a way is that, I feel that this is a real good, big project, and I’m sure you do too. This proj-
ect is a sort of scientific thing” (Sabat 1998, pp.41–​42, italics mine). This assessment of
the project went hand in hand with a boost to Dr. B’s sense of pride and self-​worth that
ensued from his participation. The impact on his self-​esteem was most evident whenever
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282 Ethical dilemmas in neurodegenerative disease

he compared the project to various “filler” group activities at the day care center: “If I’m
working with you, I can—​look, I can work in here for 30 times and all that, but in this
group, I’m nothing” (Sabat 1998, p.41, italics mine). That his role in the project could so
alter his self-​image demonstrates most poignantly that he valued the project.
Mrs. Rogoff ’s case also demonstrates that the ability to value may outlast the patient’s
grasp of her life as a whole. Her confusion between a television-​generated world and
events of her own life easily rules out her having an adequate grasp of her life’s narrative.
However, she does remain a valuer, most clearly when her former reputation as a great
cook is at stake. She invariably becomes upset and agitated seeing Fran usurp the mas-
tery of the kitchen. One day, after Fran made a particularly delicious chicken leg roast,
Mrs. Rogoff insisted that she would cook dinner herself, and asked her granddaughter,
in secret, to buy “a hen with five legs,” clearly in the spirit of one-​upmanship with Fran.
At such times, Fran arranges small make-​work kitchen tasks that appease Mrs. Rogoff.
Here, as before, the clearest indication of retained values comes from visible effects on the
person’s self-​esteem: Mrs. Rogoff ’s self-​image suffers whenever she realizes that Fran has
taken over as a culinary expert, and these effects can be mitigated, at least temporarily, by
a semblance of participation in culinary affairs.

Insights from neuroscience
My observations that valuing may be quite independent of grasping the narrative of one’s
life, and that this separation often occurs in Alzheimer’s patients, are also supported by
current findings in neurophysiology and in the neuropathology of Alzheimer’s disease.
The neuronal loss characteristic of Alzheimer’s disease is not distributed evenly in the
cerebral cortex. The disease affects most severely an area of the brain indispensable for
maintaining the sense of one’s life as a whole, but not particularly important for the ability
to value.
In the early stages of Alzheimer’s disease, the neuronal damage affects primarily the
hippocampus. As the damage spreads, the hippocampus continues to be affected much
more severely than other regions of the brain (Geula 1998; Laakso et al. 2000). The hip-
pocampus is of crucial importance in the acquisition and processing of long-​term explicit
memory for facts and events. Although it is not involved in short-​term memory or in the
eventual storage of long-​term memories, the hippocampus nonetheless plays an essential
role in transforming a fresh short-​term memory into a lasting long-​term memory (Squire
& Zola-​Morgan 1991; Riedel & Micheau 2001). Accordingly, while damage to the hippo-
campus affects neither a person’s processing of his immediate experience nor his memo-
ries of events that occurred long before the damage, it causes him to lose track of ongoing
events soon after they happen, so that he typically has no recollection of the previous day
(Squire & Zola-​Morgan 1988). Such damage impairs a person’s ability to come back to
a recent thought or memory after a shift of attention to something new (Squire & Zola-​
Morgan 1991). These very impairments are, of course, the typical first clinical indications
of Alzheimer’s disease. They are also central to Dworkin’s assessment that Alzheimer’s dis-
ease destroys one’s sense of one’s life as a whole. Damage to the hippocampus alone leaves
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Respecting the margins of agency: Alzheimer’s patients and the capacity to value 283

the person unable to update his autobiographical narrative. As he continually forgets his
immediate past, he loses the sense of “a past joined to a future,” which Dworkin deems
necessary for the ability to formulate critical interests.
However, there is no reason to think that impairment of the hippocampus would oblit-
erate one’s ability to espouse critical interests when this is understood, following my
recommendation, as the ability to value. While removal of the hippocampal formations
leads to the memory defects described previously, it does not otherwise compromise the
patient’s mental functions (Young & Young 1997). Moreover, there is neurophysiological
evidence that other regions of the brain are primarily responsible for interactions of rea-
soning and decision-​making processes, especially those concerning personal and social
matters, with feelings and emotions (Damasio 1994). It is damage to these regions that is
most likely to directly compromise a person’s ability to value.
Thus consider Elliot, a patient with brain damage localized in the ventromedial prefron-
tal cortices. He performed normally or even superiorly on a full battery of psychologi-
cal tests (including intelligence, knowledge base, memory, language, attention, and basic
reasoning), and yet was a very poor decision-​maker in everyday life (Damasio 1994). He
showed no abnormalities in means-​ends reasoning and problem-​solving; he was perfectly
able to come up with a full array of options for action in a particular situation as well as to
work out the consequences of each option. As it turned out, his impairment concerned the
ability to choose among the options he could reason through so well. After a full analysis
of all the options he would comment, “I still wouldn’t know what to do!” (Damasio 1994,
p.49). His emotional responses and feelings were severely blunted and this “prevented
him from assigning different values to different options, and made his decision-​making
landscape hopelessly flat” (Damasio 1994, p.51). He lacked the very starting points of the
ability to value: he was no longer sufficiently invested in anything; he ceased to care.
The ability that Elliot lacked is the indispensable core of the capacity to value. When you
value something—​be it a particular friendship or a local community—​your commitment
to these things is first and foremost a form of emotional engagement. You would not call it
“valuing” or “being committed” unless there is some confluence between thinking about
and acting upon what you say you value and your emotional life. True enough, since the
conviction that it is right for you to care about these things and that you would be mis-
taken if you did not care is open to criticism, sophisticated and varied cognitive abilities
are required to develop a robust set of values, values most immune from such criticisms.
But having such convictions in the first place amounts to attaching emotional signifi-
cance to the object of value; it involves having the corresponding emotional attitudes and
reactions, so that some things simply “feel” important to you (Jaworska 1997). Elliot was
unable to value because of the numbing of his affective response.
The neuronal destruction of Alzheimer’s disease eventually reaches the regions of
the brain most responsible for “giving emotional quality to occurrences which renders
them important to the person concerned” (Souren & Franssen 1994 p.52). However, the
destruction and the isolation of the hippocampus are always several steps ahead of the
pathologies in the areas most likely to affect the capacity to value (Braak & Braak 1995).
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284 Ethical dilemmas in neurodegenerative disease

Therefore, on the basis of neuropathological findings, one would expect Alzheimer’s

patients to lose their sense of life as a whole even as the essence of their ability to value
remains relatively robust.
On the neuropathological picture of full-​blown Alzheimer’s disease, the loss of the
sense of one’s life as a whole is typically acute, while the destruction of the areas impli-
cated in valuing remains more selective. Thus we would expect a patient in the moderate
stage to have lost some, but not all, of his former values. With his ability to form new long-​
term memories compromised, he is unlikely to develop any new values. But his selective
loss of former values may well result in changes of values pertinent to our dilemmas: as
I previously observed, once some of the earlier values drop out, the exact content and the
importance of the remaining values are typically reconfigured.

In this section I have chiefly argued that the ability to value is independent of the ability
to understand the narrative of one’s whole life, and that demented people may well retain
the former ability long after they lose the latter. We also saw that, at least when the well-​
being of the demented is the focus, Dworkin’s recommendation to disregard the patient’s
current wishes derives from the loss of the former capacity, the capacity to value. Thus,
for a Dworkinian, the threshold capacity level necessary to lend prudential authority to
a person’s current wishes should not be set at the ability to grasp one’s life as a whole, but
rather at the ability to value. As long as the demented person still espouses values, we have
seen no reason to override these in the name of values he professed earlier—​Dworkin’s
recommendations do not apply.

Rethinking autonomy
Let us now turn to respect for the patient’s autonomy as the primary goal of those car-
ing for demented patients. How should we now approach our dilemmas? According
to Dworkin, we need to consider whether the demented patient, in his current condi-
tion, still possesses the capacity for autonomy. The rationale here is that respecting
people’s autonomy is morally important only because a human being’s very ability to
act autonomously is morally important. If a person is not even capable of making
autonomous decisions, allowing him to carry out his current wishes would do nothing
to promote his autonomy. As Dworkin sees it, the only way to respect the autonomy of
such patients is to respect their earlier ability to act autonomously; if their autonomous
choices from that earlier time can still be satisfied now, these should be the focus of
respect for autonomy. Of course, choices associated with critical interests are often still
satisfiable, since, as we saw earlier, critical interests can be meaningfully fulfilled at a
time when the person no longer espouses these interests. Thus, for Dworkin, the only
way to respect the autonomy of patients who lost their capacity for autonomy is to
adhere to the critical interests that they professed before this loss. He readily concludes
that the types of demented patients he is interested in lack the capacity for autonomy,
and hence that in order to respect their autonomy one must adhere to their earlier
wishes, wishes that expressed this capacity.
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Respecting the margins of agency: Alzheimer’s patients and the capacity to value 285

The claim that demented patients no longer possess the capacity for autonomy is clearly
pivotal to this part of Dworkin’s analysis. But how plausible is the underlying interpreta-
tion of the capacity for autonomy?

Fundamentals of autonomy
Dworkin describes the capacity for autonomy as “the capacity to express one’s own
character—​ values, commitments, convictions, and critical as well as experiential
interests—​in the life one leads” (Dworkin 1993, p.224). So understood, this is the capac-
ity to be fully in charge of one’s life—​to enact one’s own values and convictions in the life
one leads. Demented people may easily lose this capacity, because as they lose the under-
standing of the world around them and become increasingly disoriented, they no longer
know how to translate their values and convictions into appropriate activity in the world.
But suppose that a demented person who still espoused values and convictions received
some help in enacting those values in his environment. Imagine, for instance, a demented
man who values his independence above all else, but who is confused about what he is
still able to do on his own. Were he left to make his own decisions, his choices would
not ultimately enhance his independence, and perhaps would even lead to his harm. But
imagine further that his family makes living arrangements for him that allow a maximum
degree of independence feasible in his predicament. There is an important sense in which
this man is still capable of exercising his capacity for autonomy, of living according to his
convictions and values, albeit with some help in translating ends into means. Thus a pos-
sibility opens up that the capacity for autonomy ought not to be thought of as the capac-
ity to carry one’s convictions into action without external help, a capacity that requires
reasoning through complex sets of circumstances to reach the most appropriate autono-
mous decisions; rather, that the capacity for autonomy is first and foremost the capacity
to espouse values and convictions whose translation into action may not always be fully
within the agent’s mastery.
In his own elaboration of why the demented lack the capacity for autonomy, Dworkin
emphasizes the claim that they have “no discernable even short-​term aims” (Dworkin
1993, p.225). Presumably, Dworkin thinks that Alzheimer’s patients cannot have even
short-​term aims because as soon as they embark on a course of action they forget what
it was they were doing and are forced to start anew. But he should distinguish between
an inability to form and then remember a plan for fulfilling one’s purposes, and a lack of
a stable set of purposes and preferences. For we can imagine an Alzheimer’s patient who
always wants the same set of things—​say, he wants to feel useful and appreciated—​and
yet is unable to set up and carry through a plan for achieving any of them, partly because
he cannot figure out the means to his ends, and partly because he cannot keep track of
the steps he is taking. These latter deficiencies seem to be at stake in Dworkin’s claim that
the demented lack the capacity for autonomy, despite his explicit focus on their lack of
consistent purposes.
For Dworkin, Alzheimer’s patients cannot be autonomous because, left to their own
devices, they cannot lead their lives by their own lights. This is largely because they have
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286 Ethical dilemmas in neurodegenerative disease

lost the ability to reason from their preferences to the appropriate decisions and actions—​
they have lost the adeptness for means-​ends reasoning and planning.
However, there is no good reason to restrict the right to autonomy only to people who
possess these abilities. After all, as the case of Elliot and other patients with prefrontal
brain damage powerfully brings home, the very idea of governing one’s life autonomously
is a complete nonstarter unless the person knows how he wants his life to be governed—​
unless he has his own substantive principles or directives for running his life. These prin-
ciples constitute the foundation of autonomy; means-​ends reasoning and planning are
mere tools for implementing the principles. Moreover, while having one’s own directives
is indispensable for exercising autonomy, we can well imagine that the tools of means-​
ends reasoning and planning could be supplied for the autonomous person from the out-
side. Accordingly, the essence of the capacity for autonomy consists in the ability to lay
down the principles that will govern one’s actions, and not in the ability to devise and
carry out the means and plans for following these principles.3
Dworkin’s analysis, then, focuses on peripheral rather than essential aspects of the
capacity for autonomy. However, to offer a convincing alternative, we must specify more
precisely what the essence of the capacity for autonomy amounts to, and in particular
what counts as one’s own principle or guideline for running one’s life. Presumably this
cannot be just any run-​of-​the-​mill wish or desire, because a person may distance himself
from a mere desire and not recognize it as truly his own.4 So, at the very least, a principle
suitable as a basis for self-​governance must be viewed by the person as correct for him.

Values as starting points of autonomy

To explore this proposal, let us consider whether autonomy would be possible even for a
hypothetical creature unable to judge the correctness or appropriateness of his desires.5
Suppose that this creature can control whether or not he will act on a desire6, and yet he
experiences his desires simply as events in his body. There are two possibilities here. In
one, the creature is ultimately indifferent to whether he will act on his desires—​he finds
himself inclined toward certain things, but upon reflection he never sees anything worth-
while in what he is inclined to do. In the other variant, although the creature finds himself
inclined toward certain choices, he is altogether incapable of reflecting on the merits of
these inclinations. In both cases, the desires, precisely because they lack the approval of
the one who feels them, are too passive to be regarded as authentic directives for self-​
governance. Thus, indeed, to qualify as such an authentic directive, a principle must be
viewed by the person as correct for him.
Following my earlier observations, this means that a principle qualifying as such an
authentic directive must have the status of a value. As I explained previously, a person’s
values specify his own sense of what is correct and appropriate for him; they are his guide-
lines for behavior. Values are also directly connected to a person’s sense of self, since the
person measures his own worthiness according to how well he lives up to his values.
This connection further confirms that values are genuinely the person’s own principles of
behavior, that they are the apt foundation for self-​governance.
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Respecting the margins of agency: Alzheimer’s patients and the capacity to value 287

We can now restate in a more familiar form our earlier finding that the mere laying
down of principles for one’s conduct makes one capable of autonomy. Since such prin-
ciples are values, the very ability to value, even if more instrumental abilities are absent,
supplies the starting points for the exercise of autonomy, and thereby renders the person
capable of autonomy.
Of course, possessing the capacity to value does not guarantee that the person can exer-
cise autonomy to a full degree. Full-​blown autonomy involves not only acting on one’s
own principles and convictions, but also the ability to scrutinize these principles and to
revise them in light of critical evaluation, so that they are well articulated and robust. The
capacity to value merely makes possible the most minimal and basic level of autonomy;
other capacities are necessary to further develop and perfect autonomy. All the same,
the capacity to value by itself does, in a very important sense, render a person capable of
autonomy.

Autonomy of Alzheimer’s patients

Alzheimer’s patients usually retain their ability to value long after other capacities neces-
sary for making their own decisions and fully directing their lives are gone. For example,
Mrs. D’s conviction that she ought to help her fellow man in any way she could certainly
comes across in the interview as a truly self-​given authentic principle of conduct. She
talked of this conviction just as any other person would ordinarily talk of her commit-
ments to her principles. Yet, since Mrs. D struggled even to find her way to the bathroom
in a relatively familiar place, she clearly would have had trouble implementing her altruis-
tic principles on her own; she would not have been able to figure out, for instance, how to
enroll in a research study to help her “fellow man.” However, with the assistance of others
she was able to continue to lead a life informed by her valued self-​selected principles, and
thereby to continue to exercise a measure of self-​government.
The paramount symptom of Alzheimer’s disease, as we saw earlier, is the inability to
form new long-​term memories. This does not significantly affect a person’s ability to
value, but it does directly and severely hamper his efforts to implement his values, even
more than it affects his grasp of his life as a whole. Even a modest impairment of long-​
term memory limits the person’s access to information about the world around him and
distorts his assessment of his own competence, compromising his ability to select the
course of action befitting his values.
In her account of her husband’s battle with Alzheimer’s disease, Ann Davidson pro-
vides beautiful testimony that simultaneously illustrates Julian Davidson’s relatively intact
capacity to value and his slipping ability to implement his values.
Julian insisted that he had to compose a “Thank You” speech to be delivered at a banquet
honoring his scientific contributions. On his own he was only able to produce phrases
such as:
[I]‌t will be a pleasure and joy to come back with and me tu omar see and and attend to the evening
of June and its and day … Although I have not in worked in the day most loved and I will be a per-
sual … strangely I was finished re this important and pleasure. (Davidson 1997, p.210)
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288 Ethical dilemmas in neurodegenerative disease

But when Ann patiently interviewed him about what he wanted to say, he “spoke halt-
ingly, but passionately, about leaving his career. In garbled phrases he described what he
felt about science and why he was quitting. He needed his colleagues to know why he had
left. He wanted them to know, too, that people with Alzheimer’s are still ‘regular folks’ ”
(Davidson 1997, p.210).
Julian communicated his conviction that it was right for him to care deeply about sci-
ence, and likewise that it was appropriate to give his colleagues an explanation. He was
definitely conveying values here, his authentic ideals. At the same time, he needed Ann’s
help to translate these values into appropriate actions—​he could not have figured out on
his own that Ann needed to rewrite his speech and that it would be best if someone else
delivered the speech on his behalf.
There are abundant variations of cases of Alzheimer’s patients who remain valuers
despite severe impairments in their decision-​making capacity. On my analysis, these
patients are still capable of fundamentals of autonomy. Accordingly, a caregiver com-
mitted to respect for autonomy must respect these patients’ contemporaneous autonomy.
This is a perfectly coherent goal, albeit respecting the autonomy of such patients usu-
ally requires much more active participation of the caregivers than what is required for
ordinary competent patients. To properly respect the autonomy of many an Alzheimer’s
patient, one must do quite a bit to enhance his autonomy. One must help the person no
longer able to do so on his own to lead his life according to his remaining values, to the
extent that this is still feasible. This involves figuring out how his values would be best
upheld in a reality he no longer fully understands, as well as helping him implement these
solutions in practice. We saw this approach employed by Julian Davidson’s wife, by Mrs.
Rogoff ’s caregiver Fran, and by the researcher working with Dr. B. Sometimes enhancing
a person’s autonomy in this way may even involve going against his explicit choices. Ann
Davidson did not simply allow Julian to try to deliver his jumbled speech, and Fran would
not simply give in if Mrs. Rogoff insisted on cooking a potholder for dinner. The caregiver
must learn to pay attention to the person’s values rather than to her concrete, yet perhaps
ill-​informed, selection of options. All the same, as long as the patient is still able to value,
respect for autonomy does not license the caregiver to disregard the patient’s immediate
interests altogether.
In sum, contrary to Dworkin’s assumptions, in the context of dementia, the capac-
ity for autonomy is best understood not as the ability to lead one’s life by one’s lights
when one is left to one’s own devices, and not as a full capacity to make a decision from
the beginning to end, but as the capacity to value—​to originate the appropriate bases
for one’s decisions that can then be, if the need arises, partly taken over by others. An
Alzheimer’s patient may be too disoriented to form a life plan or to choose specific
treatment preferences, but as long as he still holds values, he is, in the most basic
sense, capable of self-​governance, and this fact about him commands utmost respect.
Autonomy-​based recommendations to disregard his contemporaneous interests have
no purchase.
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2016 Postscript 289

Conclusion
No matter whether we emphasize well-​being or autonomy of Alzheimer’s patients, we
should approach our dilemmas mindful of Julian Davidson’s insight that many people
with Alzheimer’s disease are still “regular folks.” In some morally very important respects,
many Alzheimer’s patients remain, at least for a time, surprisingly similar to ourselves.
As neuroscience allows us to corroborate, patients moderately afflicted with Alzheimer’s
disease may well remain valuers, and thus retain the essential characteristics by virtue of
which persons and their interests enjoy an exalted moral status.

2016 Postscript
Since I formulated the ideas relayed in this chapter, exciting neuroscience research has
emerged that not only corroborates my key claim that the capacity to care and value is
relatively preserved at least up to the middle stages of Alzheimer’s disease, but also, rather
surprisingly, suggests that the core aspects of this capacity may even be enhanced by the
degeneration typical of Alzheimer’s disease.
This new evidence is tied to a broader finding about the functioning of the brain,
namely, that distinct and often anatomically distant structures in the normal human
brain tend to activate and deactivate together, forming integrated functional units or
networks called intrinsically connected networks (Seeley et al. 2007). The intrinsically
connected network most relevant to Alzheimer’s disease is the so-​called default mode
network. Neuronal degeneration characteristic of Alzheimer’s disease (the degen-
eration due to pathological accumulation of tau protein, to be exact) develops early
on in one key node of this network—​the hippocampus, as we saw earlier—​and then
spreads most prolifically along the pathways of this network (de Calignon et al. 2012;
Raj et al. 2012). In other words, the pattern of the most acute degeneration in a typi-
cal Alzheimer’s brain matches one of the patterns of co-​activation found in a normal
human brain (Seeley et al. 2009).
The default mode network supports not only the hippocampal function of transforming
short-​term memory into long term memory as emphasized in the original chapter, but
also a broader set of abilities that may be loosely described as “time travel”: the ability to
sequence one’s life as a temporally extended agent—​to remember one’s past and to imagi-
natively extend one’s life timeline into the future, for example, through planning—​as well
as the broader ability to imaginatively project oneself into an alternative situation or per-
spective, be it the viewpoint of another person or even an alternative spatial perspective
as in some forms of navigation (Buckner & Carroll 2007; Østby et al. 2012). These abilities
are relevant downstream to valuing and caring, insofar as, for example, once you value or
care about another person you are moved to understand their point of view and to plan
for or with them, as their needs dictate. But these abilities are orthogonal to the ability
to value and care about somebody or something in the first place; they merely affect how
well you are able to live up to what you already value and care about. So the finding that
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290 Ethical dilemmas in neurodegenerative disease

Alzheimer’s disease spreads primarily in the default mode network is consistent with my
claim that this trajectory of degeneration spares, at least for a time, the capacity to value
and care.
However, once we look at the brain from the point of view of intrinsically connected
networks, there is more to this story. It turns out that the default mode network is cou-
pled in an interesting way with another intrinsically connected network, known as the
salience network: in a normal human brain, states of high level of activity in the default
network are associated with decreased activity in the salience network and vice versa
(Raichle et al. 2001; Fox et al. 2005). In parallel with this finding, it also turns out that
as the default mode network becomes compromised in Alzheimer’s disease, this corre-
sponds to increased connectivity and activity in the salience network (Zhou et al. 2010).
The salience network plays a central role in social and emotional processing. More spe-
cifically, as the name “salience” suggests, its key function is thought to be isolating what
the cognitive system will pay attention to and allocate more resources to, out of the vast
amount of internal and external information that the brain is bombarded with and pro-
cessing at any given time. The salience network swiftly identifies what is most relevant
and responds accordingly by generating appropriate emotions that recruit other resources
and guide our spontaneous behavior (Seeley et al. 2007). A paradigmatic example of a
well-​functioning salience network is a quick pivoting to information relevant to safety
or security when one is absorbed in an unrelated task (e.g., running out of class upon
hearing a fire alarm). However, the network has been conceptualized to have the broader
function of focusing attention and cognitive resources not only on what impacts security
or safety but, more generally, on what is personally relevant, and this maps naturally onto
what one values and cares about. Thus, one would expect that the increased connectivity
and activity in the salience network associated with the progression of Alzheimer’s disease
would result in a heightened emotional attunement to what is important to the person,
in a manner characteristic of valuing and caring. While research in this area is only just
beginning to emerge, Sturm and colleagues have already documented a suggestive result
that emotional sensitivity to the emotions of others (so-​called emotional contagion) is
enhanced in mild Alzheimer’s disease compared to normal controls and, perhaps even
more surprisingly, it is further enhanced in moderate Alzheimer’s disease as compared to
mild (Sturm et al. 2013). The increase in emotional contagion was correlated with smaller
volume in the default mode network. These results begin to corroborate the observations
of clinicians and caregivers that some Alzheimer’s patients become more sweet, loving,
and attentive to them as their memory fades.
So far, I have interpreted the finding that connectivity in the salience network increases
as a result of the progression of Alzheimer’s disease as suggestive of an enhancement
of the capacity to care and value, and thus as consistent with my claim that patients
with moderate Alzheimer’s disease possess intact the capacities on the basis of which
we deem persons and their interests worthy of utmost moral respect. Nonetheless, con-
strued differently, this finding may be thought to raise a worry for my account. Might the
increased connectivity in the salience network lead to new cares and values that would be
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2016 Postscript 291

inauthentic in virtue of being mere artifacts of Alzheimer’s disease? If so, the strengthen-
ing of the salience network might be seen not as enhancing the capacity to care and value
but rather as disrupting it in a wayward way. It is one thing if Alzheimer’s disease leads to a
loss of some former values and to a reprioritization of the values that remain (in the man-
ner I discussed earlier), or to a strengthening of some former values, but it is something
quite different if the disease causes values to spring up de novo.
Addressing this issue adequately will need to await a more detailed understanding of
the functioning of the salience network and of the specific ways in which the increased
connectivity associated with Alzheimer’s disease affects the operation of this network.
For example, if the main effect of the increased connectivity is greater attunement to the
emotions of others, this can plausibly be interpreted as an enhancement rather than dis-
ruption of the capacity to value. The attunement to the emotions of others is not, by itself,
a new care or value. Rather, such attunement makes possible a better, more perceptive
and appreciative understanding of other persons—​and also of various ideals involving
other persons such as tolerance, justice, etc.—​as potential objects of care and value. Thus,
greater attunement to the emotions of others can lead to new cares or values but through
a path that, arguably, is not deviant, since it proceeds via greater appreciation of what the
object of care or value is all about. However, if it turned out that increased connectivity
in the salience network can lead in a more direct way to new cares or values, without the
mediation of any new experience or reasoning, there would be much greater reason to
worry that the capacity to care and value is disrupted.

Acknowledgments
A longer version of this chapter appeared in Philosophy and Public Affairs, Volume 28,
Issue 2, pp.105–​38, 1999 (see that version for acknowledgments).
The chapter sans Postscript appeared in Neuroethics: Defining the Issues in Theory,
Practice, and Policy, edited by Judy Illes, pp.87–​101, 2005 (https://​global.oup.com/​aca-
demic/​product/​neuroethics-​9780198567202).
The epigraph at the start of this chapter was reprinted with the permission of Pan
Macmillan via PLSclear, and with the permission of Touchstone, a division of Simon &
Schuster, Inc. from The Man Who Mistook His Wife for a Hat and Other Clinical Tales by
Oliver Sacks. Copyright © 1970, 1981, 1983, 1984, 1985 Oliver Sacks. All rights reserved.
The opinions expressed are those of the author and do not necessarily reflect the poli-
cies or positions of the National Institutes of Health, the Public Health Service, or the US
Department of Health and Human Services. Special thanks to Winston Chiong, Katherine
Rankin, and William Seeley for educating me about the science cited in the Postscript,
and to Winston Chiong for comments that partly shaped the Postscript’s content.

Notes
1. This case was reported to me by a family member. To protect the privacy of the patient, I use a fictitious
name. I also do not list the name of my source, but I would like to thank her for her generous help.
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292 Ethical dilemmas in neurodegenerative disease

2. In the case of some (often less central) values, one may anticipate a gradual transformation and loss of
a value without thinking that it would be a mistake. This is not a counterexample to my characteriza-
tion of valuing, because my claim concerns our attitudes to our present espousal of a value: It is part
of valuing something that one would view the possibility of not caring about it here and now as an
impoverishment, loss, or mistake. Imagining a future without the alleged value is a good test for this in
many cases, but it does not work in every case because some values are dependent on context and are
important only at a specific time in one’s life.
3. None of what I  say here should be taken to imply that, in a normal case, a person’s own exercise
of means-​ends reasoning and planning could be ignored by those aiming to respect his autonomy.
My point is that a person largely incapable of such reasoning may still be able to exercise autonomy,
and not that such reasoning can be taken lightly in an ordinary person who exercises his autonomy
through the use of such reasoning.
4. Some readers may think that this requirement is too stringent, and that the hypothetical individu-
als I go on to describe are still capable of autonomy. If so, it is only easier for me to claim that many
Alzheimer’s patients retain the capacity for autonomy.
5. I speak of a “creature” rather than a “person” here to allow for the view that the ability that my hypo-
thetical creature lacks is essential to personhood.
6. Why this stipulation? If we imagined a creature who was also unable to control his response to a desire,
it would have been easier to see him as lacking the capacity for autonomy. However, I want to show that
our intuition that my imagined creature lacks the capacity for autonomy depends on something else;
even a creature in control of his desires seems to lack the capacity for autonomy if he can never approve
or disapprove of his desires.

References
Braak, E. and Braak, H. (1995). Staging of Alzheimer’s disease-​related neurofibrillary changes.
Neurobiology of Aging, 16(3), 271–​278.
Buckner, R.L. and Carroll, D.C. (2007). Self-​projection and the brain. Trends in Cognitive Sciences,
11(2), 49–​57.
Damasio, A.R. (1994). Descartes’ Error: Emotion, Reason, and the Human Brain. New York: Putnam.
Davidson, A. (1997). Alzheimer’s, a Love Story: One Year in My Husband’s Journey. Secaucus, NJ: Carol.
de Calignon, A., Polydoro, M., Suárez-​Calvet, M., William, C., Adamowicz, D.H., and Kopeikina,
K.J. (2012). Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron, 73(4),
685–​697.
Dresser, R. (1986). Life, death, and incompetent patients: conceptual infirmities and hidden values in
the law. Arizona Law Review, 28(3), 373–​405.
Dworkin, R. (1993). Life’s Dominion: An Argument about Abortion, Euthanasia, and Individual Freedom.
New York: Knopf.
Fox, M.D., Snyder, A.Z., Vincent, J.L., Corbetta, M., Van Essen, D.C., and Raichle, M.E. (2005). The
human brain is intrinsically organized into dynamic, anticorrelated functional networks. Proceedings
of the National Academy of Sciences of the United States of America, 102(27), 9673–​9678.
Geula, C. (1998). Abnormalities of neural circuitry in Alzheimer’s disease: hippocampus and cortical
cholinergic innervation. Neurology, 51(Suppl. 1), S18–​S29.
Jaworska, A. (1997). Rescuing Oblomov: A Search for Convincing Justifications of Value (Ph.D. thesis).
Harvard University, Cambridge, MA.
 293

REFERENCES 293

Laakso, M.P., Hallikainen, M., Hänninen, T., Partanen, K., and Soininen, H. (2000). Diagnosis
of Alzheimer’s disease: MRI of the hippocampus vs delayed recall. Neuropsychologia, 38(5),
579–​584.
Østby, Y., Walhovd, K.B., Tamnes, C.K., Grydeland, H., Westlye, L.T., and Fjell, A.M. (2012).
Mental time travel and default-​mode network functional connectivity in the developing brain.
Proceedings of the National Academy of Sciences of the United States of America, 109(42),
16800–​16804.
Raichle, M.E., MacLeod, A.M., Snyder, A.Z., Powers, W.J., Gusnard, D.A., and Shulman, G.L. (2001).
A default mode of brain function. Proceedings of the National Academy of Sciences of the United
States of America, 98(2), 676–​682.
Raj, A., Kuceyeski, A., and Weiner, M. (2012). A network diffusion model of disease progression in
dementia. Neuron, 73(6), 1204–​1215.
Riedel, G. and Micheau, J. (2001). Function of the hippocampus in memory formation: desperately
seeking resolution. Progress in Neuro-​Psychopharmacological and Biological Psychiatry, 25(4),
835–​853.
Sabat, S.R. (1998). Voices of Alzheimer’s disease sufferers: a call for treatment based on personhood.
Journal of Clinical Ethics, 9(1), 38–​51.
Sacks, O. (1995). The Man Who Mistook His Wife for a Hat and Other Clinical Tales. New York: Summit
Books.
Seeley, W.W., Crawford, R.K., Zhou, J., Miller, B.L., and Greicius, M.D. (2009). Neurodegenerative
diseases target large-​scale human brain networks. Neuron, 62(1), 42–​52.
Seeley, W.W., Menon, V., Schatzberg, A.F., et al. (2007). Dissociable intrinsic connectivity networks for
salience processing and executive control. Journal of Neuroscience, 27(9), 2349–​2356.
Souren, L. and Franssen, E. (1994). Broken Connections: Alzheimer’s Disease, Part I (van der Wilden-​
Fall, R.M.J., trans.). Lisse, the Netherlands: Swets and Zeitlinger.
Squire, L.R. and Zola-​Morgan, S. (1988). Memory: brain systems and behavior. Trends in Neurosciences,
11(4), 170–​175.
Squire, L.R. and Zola-​Morgan, S. (1991). The medial temporal lobe memory system. Science, 253(5026),
1380–​1386.
Sturm, V.E., Yokoyama, J.S., Seeley, W.W., Kramer, J.H., Miller, B.L., and Rankin, K.P. (2013).
Heightened emotional contagion in mild cognitive impairment and Alzheimer’s disease is associated
with temporal lobe degeneration. Proceedings of the National Academy of Sciences of the United States
of America, 110(24), 9944–​9949.
Young, P.A. and Young, P.H. (1997). Basic Clinical Neuroanatomy. Baltimore, MD: Williams and
Wilkins.
Zhou, J., Greicius, M.D., Gennatas, E.D., et al. (2010). Divergent network connectivity changes in
behavioural variant frontotemporal dementia and Alzheimer’s disease. Brain, 133(5), 1352–​1367.​
294

Chapter 16

Anticipating a therapeutically elusive

neurodegenerative condition: Ethical
considerations for the preclinical
detection of Alzheimer’s disease
Hervé Chneiweiss

A case for anticipation
Recent progress in predictive medicine opens new avenues for the concept of health.
The extensive and idealistic definition given by the World Health Organization in 1946
that: “Health is a state of complete physical, social and mental well-​being, and not merely
the absence of disease or infirmity” is no longer pertinent in a world of anticipation where
a biomarker of a disease exists in the absence of any symptom. This is a revolution in
many fields but even more so for neurodegenerative disorders that happen late in a life-
time, making a person’s entire life a period of anticipation.
Among neurodegenerative disorders, Alzheimer’s disease (AD) has gained a special
position during the last 40 years, due to the burden the condition imposes on more than
40 million affected people worldwide. Today’s estimations might only be the beginning, in
fact, since most of the patients are older than 65 years (prevalence of dementia before the
age of 50 years is less than 1 in 4000 with only 30% of cases being attributed to AD), and
projected increases in the prevalence of dementia are higher in developing countries with
young populations (Winblad et al. 2016). Now that we, as a science community, know that
the disease starts two or three decades before any symptoms occur, predictive medicine
may bring forward possibilities for diagnosis or testing. Advances in screening for early
detection may allow for early staging, intervention, and secondary prevention.
Asymptomatic individuals provide the research pool for preventive approaches.
However, is there an interest in diagnosis in the absence of cure? Does no cure mean no
care? Interestingly, results from several European cohort studies have provided evidence
that the age-​specific incidence of dementia has decreased in the past 20 years, thereby
raising expectations for preventive interventions (Scheltens et al. 2016). Thus, the related
ethical debate is not about the clinical stages of AD or the timing of interventions where
early appears to be best, but instead, is on the multiple meanings and the impact of pre-
clinical AD diagnosis before the onset of symptoms.
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A case for anticipation 295

Alzheimer’s disease still baffles scientists and tests the boundaries of therapeutic knowl-
edge. Despite undeniable progress, many uncertainties remain, including the cause of
the pathogenic process where the respective roles of amyloid deposition, tau protein, and
other processes of neurodegeneration are not yet understood. The diagnostic criteria of
the International Working Group (IWG) (Dubois et al. 2014) and the National Institute of
Aging and the Alzheimer’s Association (NIA-​AA) (Albert et al. 2011) still rely on a clinical
phenotype combined with biomarker information, mainly driven by amyloid and tau. The
preclinical AD concept was initially defined from cognitively unimpaired individuals who
displayed AD brain lesions on postmortem examination. With the development of AD
biomarkers, the concept evolved and preclinical AD (NIA-​AA) or at-​risk for AD (IWG)
are now considered when these markers are present in a cognitively normal individual. In
addition, individuals known to carry an autosomal dominant monogenic mutation that
will result in the development of full clinical AD are classified as having presymptomatic
AD. These opportunities of anticipation of clinical AD open many questions that range
from basic scientific and technical validity of the biomarkers and methods, toward ethi-
cal issues such as the impact on the individual, family, and society. Similarly challeng-
ing are the ethical issues associated with the set-​up of clinical trials with asymptomatic
individuals who will have to consent to a hard-​to-​bear treatment of unknown efficacy
and unknown potential side effects for a long period, all while living with the status of
preclinical/​at-​risk AD. Furthermore, while amyloidosis is necessary for an AD diagnosis,
it is not sufficient to reliably predict further progression to a symptomatic stage of disease
given postmortem evidence that demonstrates that a significant proportion of individuals
with typical brain neuropathological AD lesions do not present symptoms of cognitive
impairment (Price et al. 2009). Thus, it is important to understand progression drivers to
determine the proportion of at-​risk individuals who will progress to the clinical stage of
AD. Considering the many uncertainties at hand, how then can protocolization for a pos-
sible early detection and the need for adaptation of taking care of individual peculiarities
be reconciled? What are the implications for the family and the workplace? What recon-
figuration of the care relationship and care course do such developments carry?
The short-​term therapeutic horizon is further worrisome:  effectiveness is not yet
proven. Still, scientists, physicians, and patient organizations agree on the need to
facilitate testing that is as reliable as possible when the first symptoms manifest them-
selves. The precocity of care indeed involves several indisputable advantages. First,
the tested treatments have been proven effective only on patients at the early stage of
AD. Recent clinical trials of three different monoclonal antibodies directed against the
1-​42 beta-​amyloid peptide (Aß42) (aducanumab, crenezumab, and solanezumab) have
suggested slowing of cognitive decline of early/​mild but not moderate AD patients
(Selkoe & Hardy 2016). Second, early care seems to afford economies of scale both
for individuals and the collective. Added to this is the argument that early detection
of the disease could offer patients and their families time to anticipate and look to
the future to consider financial and legal issues, and assert control over the course of
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296 Anticipating a therapeutically elusive neurodegenerative condition

their lives that might not have been otherwise considered or desired. To examine the
values and choices that underlie aspirations for anticipation in more detail, I turn to
lessons from other fields of medicine, such as cancer and the identification of high-​
risk individuals bearing pathogenic genetic mutations that predispose them to disease.
To conduct this examination, I  draw upon fruitful interactions from my work with
a multidisciplinary network of scientists, neurologists, psychologists, philosophers,
representatives of insurance companies, and carers. The effort was carried out under
the auspices of the French national program “Distalz” headed by Professor Philippe
Amouyel, and with the methods established by Professor Emmanuel Hirsch in the
“Espace éthique régional Ile de France” (Forum for Ethics of Care Ile de France), that
became for the occasion “Espace éthique maladies neurodégénératives” (Forum for
Ethics of Neurodegenerative Diseases).

Biomarkers: The building blocks of the ethical debate

Reliable biomarkers allow us to diagnose the AD pathophysiological process in the
absence of clinical symptoms. They also give rise to some ethical questions resulting in
the opportunity for increasingly personalized medicine, such as:
◆ confirmation of diagnosis may avert useless treatment and mitigate confusing results
◆ identification of populations at high risk of developing AD can allow for the deployment
of reinforced testing and preventive treatment based on the predisposition marker
◆ evaluation of prognostic variables can enable the estimation of speed of disease pro-
gression based on the prognostic marker
◆ prediction of therapeutic response can yield precision of intervention based on a pre-
diction marker.

Diagnostic biomarkers
Alzheimer’s disease develops clinically in several stages: a presymptomatic period when
the biological process leading to the disease is active but the patient does not suffer any
disorder, a prodromal phase where the patient suffers from mild cognitive impairment
(MCI), and finally the gradual onset of increasingly severe dementia. In the past, the
diagnosis of AD was based on postmortem neuropathological changes of the brain that
included both positive and negative features. Positive lesions consist of abundant amyloid
plaques and neurofibrillary tangles, and dystrophic neurites containing hyperphosphory-
lated tau protein. Amyloid plaques are found throughout the cortex whereas tangles are
primarily located in limbic and association areas. Early lesions are found in the entorhi-
nal cortex. Later in the progression of the disease, lesions diffuse to the hippocampus,
then association cortex, and finally the primary neocortex. Astrogliosis and activation of
microglia complete this scheme. Negative lesions include losses of neurons and synaptic
elements. Today, biomarkers signal these lesions while the patient is still alive. They are
used to validate the clinical diagnosis and to quantify the level of advancement of the
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Biomarkers: The building blocks of the ethical debate 297

disease through the concentration of the ß-​amyloid protein and of the tau protein (total
and under its hyperphosphorylated form) in the cerebrospinal fluid (CSF) and by brain
imaging.
The pathophysiological process of AD has been modeled as a cascade of progressive
neuropathological events initiated by ß-​amyloid deposition that is mirrored by a low
level of the CSF Aß42, followed by accumulation of tau (levels increased in CSF) preced-
ing structural brain damage, decreased cerebral glucose metabolism, brain atrophy, and
subsequent functional and cognitive impairments (Jack et al. 2016). Structural magnetic
resonance imaging (MRI) allows brain medial temporal cortex atrophy to be identified,
and rules out intracranial causes of dementia such as meningioma or subdural hema-
toma. Additionally, MRI remains the modality of choice for the assessment of vascular
brain changes, such as white matter hyperintensities, lacunes, and microbleeds that have
gained increasing attention because they are frequent side effects in antiamyloid trials
(Winblad et  al. 2016). New techniques of cerebral imaging help to visualize hypome-
tabolism, amyloid plaques, neurofibrillary tangles, and the microglial activation. [18F]
Fluorodeoxyglucose positron emission tomography (FDG PET) reveals focal cerebral
hypometabolism in a very sensible and validated way. A normal FDG PET scan virtually
excludes a diagnosis of neurodegenerative disease. Consequently, FDG PET is increas-
ingly used to follow the disease progression and evaluate the effectiveness of interven-
tions to modify the natural course of the disease. Amyloid PET, namely PET with ligands
for Aβ such as florbetapir, florbetaben, and flutemetamol, which have been approved for
clinical use, has a high negative predictive value since a patient with cognitive impairment
and negative amyloid PET is unlikely to have AD (Jack et al. 2016).
Recent longitudinal studies on subjects without cognitive symptoms at the beginning
of the study have shown that the coexistence of events in the amyloid biological cas-
cade predict brain structural and functional declines (Bateman et al. 2012). Analysis of
natural history in familial AD cases with mutations in the gene coding for the amyloid
protein (APP), or in genes coding for presenilin (PSEN1 or PSEN2) that are the cata-
lytic subunits to the γ secretases enzyme which cleave APP, show that Aß42 levels in
CSF begin to decline 25 years before expected symptom onset (Selkoe & Hardy 2016).
This is followed by the appearance of fibrillar amyloid deposits in the brain, increased
levels of hyperphosphorylated tau in CSF, and progressive brain atrophy (particularly that
of hippocampus) that occur 15 years before the onset of symptoms. Neuronal hypome-
tabolism and short episodes of memory impairments begin 10 years before symptoms
become clinically self-​evident. According to current models, mutations in APP, PSEN1,
and PSEN2 genes in familial AD accelerate the generation of fibrillar amyloid deposits,
whereas in sporadic AD, decreased clearance of Aβ associated with other pro-​aggregating
conditions might have roles in the accumulation of toxic Aβ species. But most authors
consider that the time course of the disease should be similar in familial and sporadic AD
(Villemagne et al. 2013). This is based on the conceptual framework that β-​amyloid and
tau pathologies synergistically potentiate neurodegeneration (Winblad et al. 2016). This
synergistic framework challenges previous AD pathophysiological theories that focused
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298 Anticipating a therapeutically elusive neurodegenerative condition

on either ß-​amyloid or tau pathologies as the main driving forces of disease progression,
the so-​called Baptists and Tauist perspectives respectively. Furthermore, data from ani-
mal models support the synergistic molecular interactions between ß-​amyloid and P-​tau
peptides, which lead to a downstream toxicity. In a recent survey, Dubois and colleagues
consider that: “AD exists and can be recognized before the onset of cognitive symptoms
when there is little doubt about progression to clinical disease over a short period. This
is the case when both tauopathy (tau PET ligand uptake spread to neocortex or CSF) and
amyloidopathy (PET evidence of AD pattern or CSF measured) are present” (Dubois et
al. 2016, p.297). A key lesson that emerges from such studies is that therapeutic interven-
tions must come soon in the course of the disease and certainly before neuronal lesions
are irreversible.
Interestingly, some authors still consider the amyloid hypothesis as controversial.
Among their arguments are that many of the supporting animal studies used nonphysi-
ologically high concentrations of Aß or transgenic mice significantly overexpress APP
or any other gene. As such, they infer that the amyloid cascade hypothesis provides no
explanation for the silent incubation period of AD and pinpoint the many discrepan-
cies between neuropathological observations and clinical outcomes. In a recent review,
De Strooper and Kerran (2016) suggest a model with three phases, a biochemical phase,
a cellular phase, and the final clinical phase. In the biochemical phase, Aß and tau are
still at the beginning of the pathological process. In the cellular phase, compensatory
mechanisms allow a fragile but long-lasting equilibrium that involves neural networks,
microglia, astroglia, and oligodendrocytes. Finally, during the clinical phase, the system
is overwhelmed and collapses. Thus, they state that “AD is indeed not a biochemical or
molecular problem but a physiological one of disrupted cellular connectivity. The disease
can therefore only be fully understood in the context of the complex cellular interactions
that maintain homeostasis in the brain—​i.e., at the level of the neurovascular and glioneu-
ronal units” (De Strooper & Karran 2016, p.612). Consequently, the therapeutic approach
should move from targeting Aß toward a support of the many mechanisms involved in
the cellular phase and allowing compensation: another good reason to make a diagnosis
of AD before the onset of symptoms.

Predisposition, prognostic, and predictive biomarkers

To be of real interest for anticipation, AD biomarkers need not only to be reliable for
diagnosis but also to help determine when the disease will turn from asymptomatic to
symptomatic. Will everyone who presents an Aß decrease in the CSF develop a dementia
syndrome if they live for long enough? If so, which factors determine when a patient will
develop symptoms? We need measures that allow evaluation of a delay to clinical onset.
Even if all PET Aß-​positive individuals were to ultimately develop dementia, there is a
difference between a person who is 80 years old with a predicted onset of dementia in
20 years, and a 50-​year-​old with the onset of cognitive decline imminent within the next
2 years. More importantly, what are actionable protective factors? Several recent findings
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Biomarkers: The building blocks of the ethical debate 299

should help to define individuals at higher risk of developing AD and the speed of pro-
gression of the disease (Lacour et al. 2017). Such data might help to set up a rationale
framework for early interventions in the context of anticipation (Peters et al. 2013; Dubois
et al. 2016).
More than 20 genetic loci associated with an increased risk of AD (Karch & Goate
2015) have been identified so far; a few others could have protective effects. The proteins
encoded by these genes belong to pathways involved in the immune system and inflam-
matory responses, for example, the microglia surface receptor TREM2, cholesterol and
lipid metabolism, and endosomal-​vesicle recycling. Some factors could be age related.
Identification of these genes is important to understand the pathophysiology of AD since
they probably interact with the core mechanisms of the disease. However, they do not
improve our evaluation of the risk for a given person since most of the reported poly-
morphisms are frequent in the population—​more than 30% of the population bear the
allele—​and contribute little to the individual risk for AD (Lacour et al. 2017). That said,
APOE4 is different. APOE proteins are involved in cholesterol metabolism and in the
clearance of Aß. The E4 form has a reduced activity in comparison to E2 and E3, and
APOE4 is considered the major genetic risk factor for AD. APOE4 protein expression
has been associated with degeneration of brain blood vessels, leakage of the blood–​brain
barrier, and neurodegeneration independent of Aβ. Lifetime risk for AD is more than
50% for APOE4 homozygotes and 20–​30% for APOE3 and APOE4 heterozygotes, com-
pared with 11% for men and 14% for women overall irrespective of APOE genotype. Not
only does the frequency matter, but so does age at clinical onset: 68 years in E4 homozy-
gotes, 76 years in E4 heterozygotes, and 84 years in E4 noncarriers (Karch & Goate, 2015).
Consequently, APOE analysis is of importance today to define a population with a clearly
higher risk of AD.
Lifestyle-​related factors also influence the age of onset and the delay to progression,
with much evidence concerned with interventions for cardiovascular risk that improve
cognitive health at the population level. In addition, the prevention or treatment of diabe-
tes, obesity, depression, smoking, increasing physical exercise and prevention of mental
inactivity, increasing level of education, and the so-​called cognitive reserve, and improv-
ing diet, might result in up to a 30% reduction in dementia incidence (Scheltens et al.
2016). By contrast, the additional presence of a biomarker of tau pathology is associated
with a more rapid progression to clinical AD (Vos et al. 2013).
No marker has been described that indicates a rapid onset of symptoms. However, sub-
jective cognitive decline, defined as the personal sensation of cognitive decline despite
results within healthy limits on cognitive tests, is associated with an increased risk of pro-
gression to dementia, especially when the patient is worried about the decline (Scheltens
et al. 2016). Compared with healthy controls, patients with subjective cognitive decline
have more brain abnormalities, including hippocampal volume loss and hypometabolism.
Some data suggest that an evaluation of the progression speed might be possible in
the future, but the results remain at a population level and are not valid for a given
individual (Vos & Fagan 2016). Most of the available data result from the observation
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300 Anticipating a therapeutically elusive neurodegenerative condition

of the progression of the disease in symptomatic patients, either with MCI or pro-
dromal or moderate AD, which might not be informative for asymptomatic patients.
Furthermore, these results need more patients to be really confirmative. One set of evi-
dence correlates patient age with localization of the first lesions: elderly patients with
a predominant limbic form of the disease generally have a slower progression com-
pared to the neocortical form with a hippocampal-​sparing type that can be observed
in younger patients. Brain imaging studies have demonstrated that MCI patients with
hippocampal atrophy or temporoparietal hypometabolism as seen on FDG PET, and
CSF Aβ42, invariably developed dementia, whereas those with negative results for all
three parameters almost never did (Vos et al. 2015). Among new biomarkers measur-
able in the CSF are neurogranin and SNAP25 (De Vos et  al. 2015). Neurogranin is
a dendritic protein involved in acquisition and consolidation of memory. High CSF
concentrations of neurogranin predict progression to AD in patients with MCI and
correlate with rapid cognitive deterioration. SNAP25 is a presynaptic protein and
its concentrations increase during the prodromal stage. Their value in anticipating
the clinical onset delay remains to be determined, and would require repeated CSF
punctures.

Values and choices

Considering the recent knowledge accumulated on the biological processes underlying
the progress toward clinical AD and the possibilities of early detection of some biomark-
ers, one may wonder if it is ethical to keep waiting for symptoms to make a diagnosis of
AD or if it would be better to screen populations in search of at-​risk individuals. Would it
be ethical not to try to prevent AD for these at-​risk individuals? On the other hand, one
must consider the risk of destroying the quality of an asymptomatic life while doing little
to efficiently prevent the disease, or worse, causing adverse effects associated with preven-
tive treatments.
In oncology, the reflection on the expected useful screening was intense. Learning
from the natural history of the disease led to some rationales for the ability to control the
disease. Usually, this ability is stronger upstream of the pathological process and early
symptoms. However, simplistic assertions such as “an early detection of a cancer makes it
still curable” or “if a cancer is discovered too late it is always fatal” must be prevented to
avoid false promises. Therapeutic efficacy may not always be correlated with early diag-
nosis. Observe that if, at some point, a therapeutic innovation brings about a cure even at
an extremely late diagnosis, then screening no longer makes sense. If the patient can be
cured at any stage, early diagnosis loses much of its interest.
In the case of AD, there is a consensus that antiamyloid drugs will be most effective early
in the disease process. Supporting this hypothesis are the results of trials of aducanumab,
crenezumab, and solanezumab, human monoclonal antibodies selective for aggregated
and soluble forms of Aβ, with a dose-​dependent decrease in amyloid charge and a slower
decline in cognition (Selkoe & Hardy, 2016). However, results of trials of the antiamyloid
 301

Values and choices 301

monoclonal antibody gantenerumab and of the γ-​secretase inhibitor avagacestat in

patients with prodromal AD do not show the same results or slow the cognitive decline.
The negative effects of screening also need consideration. In oncology, overdiagnosis
presents a major challenge. When lesions or anomalies are detected at a very early stage
of tumor development, they may have no evolutionary properties. Sometimes, they are
spontaneously regressive, whereas in other cases, they never evolve. The risk of overdi-
agnosis also entails the risk of overtreatment. Take the example of prostate cancer: if a
physician treats a person with an early prostate cancer based on an increase in blood-​
level prostate-​specific antigen, a life may be saved. The quality of life is often dramatically
affected by treatment. However, there is a one in two chance that the treatment is useless
because the cancer is not evolutive. In this perspective, it is clear that early diagnosis can
also result in harm for some individuals.
What might be the most at stake for AD? Certainly, the question of disclosure of the
AD status is central. Arguments against disclosure of biomarker status are numerous.
For a given individual, knowing biomarker status is potentially harmful knowledge as
anxiety and depression can develop. Consider also the impact on the close family whose
emotions will be affected, the friendship networks that may shift when peers distance
themselves, and broader consequences such as the right to drive a car or the insurance
coverage.
In contrast, arguments in favor of a preclinical characterization and disclosure can be
analyzed from the point of view of at-​risk AD subjects, their families and relatives, the
work place, clinicians, and society. Biomarker disclosure may serve as an argument of
respect for individual autonomy since there are moral and legal rights to receive a specific
diagnosis. For the at-​risk individual, this should allow beneficial risk-​lowering behaviors
and the formulation of advance directives. For clinicians, this might facilitate the recruit-
ment to preclinical trials for AD. In one study of public perception in France at the end
of 2014 with more than 1000 people, 90% said that they would like to know their status.
When asked why they would like to know, most answered that this should help them to
choose a better life and alleviate their fears of the disease.
Other studies seem to confirm these rather surprising numbers although while facing a
real at-​risk situation, patients behave differently from those responding to a hypothetical
case. In one study reported at a recent (April 28, 2016) meeting of the French research
network Distalz, recruitment and consent in a preventive clinical trial were at only 25%
of at-​risk individuals. In this case, “at risk” was derived from people who complained
about their memory but performed in the normal range for their age and education level
on the memory tests. What were the determining factors for participation in this clinical
trial using a drug-​prevention protocol? The risk:benefit analysis by the research potential
participants was not at all decisive:  age, gender, and education were not discriminant,
whereas sociological and cultural factors play a role. For example, it is significantly more
difficult to recruit families in which one or more members are physicians. On the con-
trary, if someone had a close relative affected by the disease, that person was more likely
to participate.
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302 Anticipating a therapeutically elusive neurodegenerative condition

One concern about selecting at-​risk individuals for preventive clinical trials is that this
could involve coercive disclosure of unwanted information (Kim et al. 2015). A normative
analysis applying four key ethical criteria—​favorable risk:benefit ratio, informed consent,
fair subject selection, and scientific validity—​investigated the meaning of blinded enroll-
ment where participants are tested but not told of their risk marker status (Kim et  al.
2015). The authors concluded that none of these ethical criteria supports blinded enroll-
ment over transparent enrollment. Furthermore, blinded enrollment protocols have been
criticized ethically for non-​respect of the fundamental rights of a person participating in
biomedical research to have access to information. Among arguments to refuse access to
the personal data is the context of research that does not reach the clinical grade of exams
performed in a healthcare program.
Other studies reported that subjects with increased genetic risk for AD (i.e., carriers of
the APOE4 allele who knew their status), more frequently desired to reduce that risk than
did counterparts who learned they were noncarriers. Moreover, the duration of treatment
that is to be undertaken is crucial. A period of 1 year instead of 5 years can change the
game in terms of acceptability. Inclusion in a clinical trial disrupts daily life. For example,
often a person must be available for sampling in a 10-​day window. Why would someone
accept such constraints on daily life if not affected by the disease? The rationale that doc-
tors and scientists need information about the long natural history and ongoing process
appears insufficiently justified to many individuals. Furthermore, the needs of biomedical
science and hopes of the prospective subjects who have their own life prospects may not
always align.
Such considerations will be even more important in the context of drug trials with
completely asymptomatic patients. The anticipation of consent is in the air. In North
America, records of individuals who volunteer for clinical trials have been established for
solicitation purposes, not necessarily on genetic bases. In a sense, pre-​consent is in play.
Registered individuals decide to volunteer depending on the protocol that is offered. This
type of prearranged consent may be revoked or amended. A conceptual framework for
prevention trials for AD has been proposed (Peters et al. 2013). A first dimension of this
framework focuses on stratification of patients according to their genetic risk for AD and
detection of AD biomarkers. The framework then proposes two gradients that refer to the
risk of developing AD and to a therapeutic risk:benefit ratio. Interestingly, this framework
also considers the critical need to revisit the risk:benefit ratio iteratively during the trial.
The risks that individuals enrolled in an AD clinical trial will face are only beginning
to be known. For example, repeated MRI scans sensitive to microbleeds are mandatory
in clinical trials of antiamyloid drugs to monitor amyloid-​related imaging abnormali-
ties (ARIAs) (Arrighi et al. 2016). These include signal hyperintensities on FLAIR (fluid
attenuation inversion recovery) sequences, which are thought to represent edema, and
signal hypointensities on gradient-​recalled echo/​T2, which are thought to represent hae-
mosiderin deposits, including microhemorrhage and superficial siderosis. ARIAs develop
after removal of amyloid from cerebral microvessels, which leads to endothelial damage,
increased vascular permeability, and leakage of water or blood in the brain parenchyma.
 30

Conclusion 303

Are the risks involved in preventing AD justifiable? This has been the current practice
since the middle of the twentieth century. The relationship between myocardial infarction
and high cholesterol was demonstrated around 1955, resulting in prevention strategies
to lower cholesterol. Several tested molecules such as thyroxin and estrogens performed
worse than hypercholesterolemia. Many clinical trials conducted in the 1960s and 1970s
would end up in court today. What risks are justifiable? In the late 1960s, side effects were
tolerated a risk of 1 in 100. Today no company would want to take a risk of 1 in 10,000.
The sensitivity of the public has changed considerably, calling into question which types of
clinical research in AD prevention and early diagnosis should be accepted and which ones
are unethical. Taking into consideration the conceptual framework mentioned previously
(Peters et al. 2013), it seems highly justified to take some risk when uncertainties are low
(i.e., familial AD or two copies of the APOE4 allele) or when the toxicity is low (i.e., diet
or exercise). Regarding AD, everyone should be aware of the risks inherent in the devel-
opment of new treatments, including lawyers and journalists. Biomedical research in the
field of neurodegenerative disorders may necessarily face devastating unexpected effects
such as cases of encephalitis when testing new molecules. Omitting risk is no longer con-
ceivable. We need to inform. Justifying the search every day is to be able to justify the risks
we take. There are several ways to present a risk (absolute risk, relative, over a period) to a
contact, and we must use appropriate words. Dedicated research on such communication
should be developed and investigators will need to conceptualize the process of consent
as being dynamic rather than static (Peters et al. 2013).
Finally, are we studying the right cases? I cannot stress enough the fact that the aver-
age age of onset of dementia is 80  years. In most cases, there is a combination of a
degenerative neurological factor and a vascular factor. However, it is clear that clinical
trials, at present, involve almost only subjects age 70 years or less with few comorbidi-
ties. A question of representativeness of the real disease in clinical experimentation is
indispensable.

Conclusion
Considering the natural history of AD, there are more and more arguments to antici-
pate and try to prevent the onset of the disease. We may consider similarly a better diet,
exercise, and increase of the cognitive reserve. Apart from the rather soft general control
induced on our lifestyle, one might hardly see ethical issues in such early interventions.
Much more complex remains the question of primary prevention and enrollment of at-​
risk individuals in clinical trials targeted against amyloid. Multidisciplinary research,
including ethical, legal, and social aspects, is needed to investigate how best to inform
and anticipate reactions of patients, and their families, to the knowledge of their sta-
tus, and how to support individuals undergoing long periods of treatments with high
constraints, unknown risks, and unknown benefits. They should be valued as ordinary
heroes fighting against ignorance that is the main enemy. A new partnership needs to
be set up between at-​risk individuals, clinicians, scientists, and society to defeat AD for
once and for all.
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304 Anticipating a therapeutically elusive neurodegenerative condition

References
Albert, M.S., Dekosky, S.T., Dickson, D., et al. (2011). The diagnosis of mild cognitive impairment
due to Alzheimer’s disease: recommendations from the National Institute on Aging-​Alzheimer’s
Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimer’s & Dementia,
7, 270–​279.
Arrighi, H.M., Barakos, J., Barkhof, F., et al. (2016). Amyloid-​related imaging abnormalities-​
haemosiderin (ARIA-​H) in patients with Alzheimer’s disease treated with bapineuzumab: a
historical, prospective secondary analysis. Journal of Neurology, Neurosurgery, and Psychiatry, 87,
106–​112.
Bateman, R.J., Xiong, C., Benzinger, T.L., et al. (2012). Clinical and biomarker changes in dominantly
inherited Alzheimer’s disease. New England Journal of Medicine, 367, 795–​804.
De Strooper, B. and Karran, E. (2016). The cellular phase of Alzheimer’s disease. Cell, 164, 603–​615.
De Vos, A., Jacobs, D., Struyfs, H., et al. (2015). C-​terminal neurogranin is increased in cerebrospinal
fluid but unchanged in plasma in Alzheimer’s disease. Alzheimer’s & Dementia, 11, 1461–​1469.
Dubois, B., Feldman, H.H., Jacova, C., et al. (2014). Advancing research diagnostic criteria for
Alzheimer’s disease: the IWG-​2 criteria. Lancet Neurology, 13, 614–​629.
Dubois, B., Hampel, H., Feldman, H.H., et al. (2016). Preclinical Alzheimer’s disease: definition,
natural history, and diagnostic criteria. Alzheimer’s & Dementia, 12, 292–​323.
Jack, C.R., Jr., Bennett, D.A., Blennow, K., et al. (2016). A/​T/​N: an unbiased descriptive classification
scheme for Alzheimer disease biomarkers. Neurology, 87(5), 539–​547.
Karch, C.M. and Goate, A.M. (2015). Alzheimer’s disease risk genes and mechanisms of disease
pathogenesis. Biological Psychiatry, 77, 43–​51.
Kim, S.Y., Karlawish, J., and Berkman, B.E. (2015). Ethics of genetic and biomarker test disclosures in
neurodegenerative disease prevention trials. Neurology, 84, 1488–​1494.
Lacour, A., Espinosa, A., Louwersheimer, E., et al. (2017). Genome-​wide significant risk factors for
Alzheimer’s disease: role in progression to dementia due to Alzheimer’s disease among subjects with
mild cognitive impairment. Molecular Psychiatry, 22(1), 153–​160.
Peters, K.R., Lynn Beattie, B., Feldman, H.H., and Illes, J. (2013). A conceptual framework and ethics
analysis for prevention trials of Alzheimer disease. Progress in Neurobiology, 110, 114–​123.
Price, J.L., McKeel, D.W., Jr., Buckles, V.D., et al. (2009). Neuropathology of nondemented
aging: presumptive evidence for preclinical Alzheimer disease. Neurobiology of Aging, 30,
1026–​1036.
Scheltens, P., Blennow, K., Breteler, M.M., et al. (2016). Alzheimer’s disease. The Lancet, 388, 505–​517.
Selkoe, D.J. and Hardy, J. (2016). The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO
Molecular Medicine, 8, 595–​608.
Villemagne, V.L., Burnham, S., Bourgeat, P., et al. (2013). Amyloid beta deposition, neurodegeneration,
and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurology,
12, 357–​367.
Vos, S.J. and Fagan, A.M. (2016). Alzheimer’s disease biomarker states. Lancet Neurology, 15, 25–​26.
Vos, S.J., Xiong, C., Visser, P.J., et al. (2013). Preclinical Alzheimer’s disease and its outcome: a
longitudinal cohort study. Lancet Neurology, 12, 957–​965.
Vos, S.J., Verhey, F., Frolich, L., et al. (2015). Prevalence and prognosis of Alzheimer’s disease at the
mild cognitive impairment stage. Brain, 138, 1327–​1338.
Winblad, B., Amouyel, P., Andrieu, S., et al. (2016). Defeating Alzheimer’s disease and other
dementias: a priority for European science and society. Lancet Neurology, 15, 455–​532.
 305

Chapter 17

When bright lines blur: Deconstructing

distinctions between disorders
of consciousness
David B. Fischer and Robert D. Truog

Introduction
Of the many disorders of the brain, disorders of consciousness are among the most devas-
tating. They have profound implications for whether an individual is considered capable
of experiencing the world, or even considered alive. However, despite the critical implica-
tions, there remains substantial uncertainty about how they are defined and diagnosed,
leading to uncertainty in how these patients are understood and managed. What makes a
person conscious, and how can one person know if another is conscious? What makes a
person dead, and how can one know if another is dead? These questions have challenged
philosophers for centuries. Meanwhile, however, the ability to ethically manage patients
who suffer from disorders of consciousness critically depends upon the answers to these
questions.
Distinguishing between disorders of consciousness has been vital to guiding impor-
tant clinical decisions. However, we argue that disorders of consciousness are not suf-
ficiently distinct to dictate these decisions. After defining each disorder of consciousness
and discussing the decisions that hinge upon the diagnostic distinctions, we will outline
the factors that, upon closer inspection, obscure these distinctions. We argue that the
non-​distinct diagnostic boundaries reflect an inherent continuity between disorders of
consciousness. Then we consider a new way of thinking about disorders of conscious-
ness, permitting these diagnoses to more effectively guide decisions. We believe that these
considerations bring clarity to disorders of consciousness, and can improve the ethical
management of patients suffering from them.

Disorders of consciousness: Conceptual definitions and

diagnostic criteria
Disorders of consciousness can be divided into four main categories. Each category can
be understood in two distinct ways: through a conceptual definition and a set of diag-
nostic criteria. The conceptual definition of a condition describes what that condition
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306 When bright lines blur

is thought to fundamentally represent. In contrast, the diagnostic criteria of a condition

are a set of empirical characteristics by which that condition is recognized clinically. The
conceptual definitions and diagnostic criteria can sometimes be conflated, but explicitly
distinguishing between the two is important. Discrepancies between them can lead to
problems in the diagnosis and understanding of the disorders, as we will later explore.

Brain death
We will describe each disorder in order of severity, beginning with the most severe. Thus,
the first we will consider is brain death. (Table 17.1) Though not classically included
among other disorders of consciousness—​as it is often considered a more severe form
of brain injury with more grave implications—​brain death represents a state of disor-
dered consciousness following brain injury. We include it among the other disorders of
consciousness here.
Conceptually, brain death is considered a form of death. Death has been a challenge
to define precisely, and its medical definition has evolved continuously since the 1700s
(Powner et al. 1996). In 1981, neurologist James Bernat built from these concepts to pro-
pose death as the “permanent cessation of functioning of the organism as a whole” (Bernat
et al. 1981, p.390). Bernat argues that the “whole” of an organism consists in the “highly
complex interaction of its organ subsystems,” and “the spontaneous and innate activities
carried out by the integration of all or most subsystems … and at least limited response
to the environment” (Bernat et al. 1981, p.390). Wholeness of an organism can also be
understood through thermodynamic principles: an organism perhaps can be considered
living so long as it employs energy-​consuming processes to oppose entropic forces and
maintain homeostasis, thereby preserving itself as an entity distinct from the surrounding
world (Truog 2015).
How does one recognize when an organism has permanently ceased to function as a
whole? In the same year that Bernat offered his conceptual definition of death, the 1981
President’s Commission proposed a legal framework by which this definition could be
recognized, which led to the Uniform Determination of Death Act (Medical Consultants
on the Diagnosis of Death 1981). Under this definition, any individual is considered
dead if he or she has (1) irreversible cessation of circulatory and respiratory functions,
or (2) irreversible cessation of all functions of the entire brain, including the brainstem.
The latter criterion comprises the diagnostic criterion for brain death. That is, a person is
thought to meet the conceptual definition of death (the permanent cessation of function-
ing as a whole) if he/​she exhibits the irreversible cessation of all brain function. Bernat
argues that the irreversible cessation of all brain functions is sufficient for the permanent
cessation of functioning of the organism of the whole, “because the brain is necessary
for the functioning of the organism as a whole. It integrates, generates, interrelates, and
controls complex bodily activities” (Bernat et al. 1981, p.391).
The diagnostic criterion of brain death as the irreversible cessation of all brain func-
tions was subsequently fleshed out with more specific criteria. In 1995, the American
Academy of Neurology published a set of such criteria (Report of the Quality Standards
 307

Disorders of consciousness: Conceptual definitions and diagnostic criteria 307

Table 17.1  Conceptual definitions and diagnostic criteria of disorders of consciousness

Conceptual definition Diagnostic criteria

Brain death A form of death, where ◆ The irreversible cessation of all functions of the
death is defined as the entire brain, including the brainstem
permanent cessation of • Prerequisites:
functioning of the organism • Clinical or neuroimaging evidence of acute
as a whole central nervous system injury
• Exclusion of confounding medical conditions
• No drug intoxication or poisoning
• Core temperature ≥32°C (≥90°F)
• Coma
• Absence of brainstem reflexes
• Apnea

Coma Absence of both wakeful- ◆ No eye opening spontaneously or to vigorous

ness and awareness sensory stimulation
◆ Low cortical arousal on EEG (e.g., polymorphic
delta, burst-​suppression)
◆ Only reflexive and postural motor function
◆ No response to auditory or visual stimuli

Vegetative Wakefulness without aware- ◆ Eye opening and closing that appear to follow
state/​ ness of self or environment sleep–​wake cycles
unresponsive ◆ Incapable of interaction with others
wakefulness ◆ No language comprehension or expression
syndrome ◆ Reflexive behavior only, without any purposeful
behaviors. Behaviors can include:
• Spontaneous breathing
• Move trunk or limbs non-​purposefully, arch
back, posturing
• Blink, roving eye movements, nystagmus,
and brief, unsustained visual pursuit
• Move head or eyes briefly toward sound or
movement
• Auditory startle and startle myoclonus
• Grimace to pain
• Yawn, chewing movements,
swallowing saliva
• Reflexive crying, smiling without provoking
stimuli
• Vocalizations without words
• Withdrawal from noxious stimuli
Minimally Wakefulness with partial ◆ Eye opening and closing that appear to follow
conscious state awareness of self or sleep–​wake cycles
environment ◆ One or more of the following behaviors on a
reproducible or sustained basis:
• Following simple commands
• Gestural or verbal yes/​no responses (regard-
less of accuracy)

(continued)
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308 When bright lines blur

Table 17.1  Continued

Conceptual definition Diagnostic criteria

• Intelligible verbalization
• Purposeful behavior, including movements or
affective behaviors that occur in contingent
relation to relevant environmental stimuli and
are not due to reflexive activity. Such behaviors
include:
• Appropriate smiling or crying in response
to emotional stimuli
• Vocalizations or gestures that occur in direct
response to linguistic content of questions
• Reaching for objects that demonstrates a
clear relationship between object location
and direction of reach
• Touching or holding objects in a manner
that accommodates the size and shape of
the object
• Pursuit eye movement or sustained fixation
that occurs in direct response to moving or
salient stimuli

Source: data from Bernat et al. 1981; Medical Consultants on the Diagnosis of Death to the President’s Commission
for the Study of Ethical Problems in Medical and Biomedical and Behavioral Research 1981; Report of the Quality
Standards Subcommittee of the American Academy of Neurology 1995; Wijdicks et al. 2010 (Brain death); Giacino
et al. 2002; Laureys et al. 2004; Bernat 2006; Posner et al. 2007 (Coma); The Multi-​Society Task Force on PVS 1994a;
Giacino 2004; Bernat 2006 (Vegetative state/​unresponsive wakefulness syndrome); Giacino et al. 2002 (Minimally
conscious state).

Subcommittee of the American Academy of Neurology 1995; Wijdicks et  al. 2010):  in
addition to coma (described in more detail later), patients must have an identifiable cata-
strophic brain injury, no confounding conditions (e.g., medical instability, drug toxicity,
hypothermia), absent brainstem reflexes (e.g., pupillary, ocular, facial sensation/​motor,
pharyngeal and tracheal reflexes), and apnea (i.e., an absent respiratory drive). Optional
ancillary assessments, which are not required for the diagnosis of brain death, include
a repeat evaluation 6 hours after initial assessment (required by some US states), con-
ventional angiography, magnetic resonance angiography, electroencephalography (EEG),
transcranial Doppler ultrasonography, cerebral scintigraphy, and other technological
assessments. Together, these clinical criteria were proposed as a means of determining
that all functions of the entire brain, including the brainstem, have been irreversibly lost.

Coma
Coma, a component of the diagnostic criteria for brain death, represents the next most
severe disorder of consciousness. To understand the conceptual definition of coma, it
is first important to consider what comprises consciousness. Like death, consciousness
is difficult to define, and so its precise definition has been a matter of debate among
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Disorders of consciousness: Conceptual definitions and diagnostic criteria 309

philosophers and scientists for centuries. However, there is general agreement that con-
sciousness consists of two primary components:  arousal (i.e., wakefulness) and aware-
ness (i.e., the content of experience) (Posner et al. 2007; Laureys et al. 2009). Awareness
requires arousal, in that one must be awake in order to be aware (Posner et  al. 2007;
Laureys et al. 2009).1 However, one can be awake without being aware, as in other disor-
ders of consciousness described later in this chapter.
Within this framework, coma is conceptually defined as the total absence of conscious-
ness, where wakefulness, and therefore also awareness, are both lost (Giacino et al. 2002;
Laureys et al. 2004; Posner et al. 2007). Diagnostically, the loss of wakefulness is identified
by the absence of eye opening, either spontaneously or to vigorous sensory stimulation,
and low cortical arousal (e.g., polymorphic delta, burst-​suppression) on EEG (Giacino
et al. 2002; Laureys et al. 2004; Bernat 2006; Posner et al. 2007). Behaviorally, comatose
patients exhibit only reflexive and postural responses, without responding to auditory
or visual stimuli (Giacino et al. 2002; Bernat 2006; Posner et al. 2007). These diagnostic
features must persist for more than an hour, to ensure that they are not attributable to a
transient state of unconsciousness, such as syncope or concussion (Laureys et al. 2004).
It should also be noted that, in comparison to the other disorders of consciousness
described here, coma may be a more temporary state, rarely lasting longer than a month,
with most patients dying, regaining consciousness, or progressing to another disorder of
consciousness (Bernat 2006).

Vegetative state/​unresponsive wakefulness syndrome

The term vegetative state was first proposed in 1972 by neurosurgeon Bryan Jennett and
neurologist Fred Plum, based on the Oxford English Dictionary definition of “vegeta-
tive” as “an organic body capable of growth and development but devoid of sensation
and thought” (Jennett & Plum 1972, p.736). Jennett and Plum used this term to describe
patients who, conceptually, are awake but lack awareness of the self or environment.
In the 1990s, the Multi-​Society Task Force on the Persistent Vegetative State estab-
lished diagnostic criteria for the vegetative state, intended to outline objective measures
of preserved wakefulness and absent awareness. Diagnostically, wakefulness is evidenced
by spontaneous eye opening and eye closing, which appear to follow sleep–​wake cycles
(The Multi-​Society Task Force on PVS 1994a). Patients are determined to lack awareness
if they do not produce any purposeful or voluntary behavior in response to auditory,
visual, tactile, or noxious stimulation; cannot interact with others; and show no evidence
of language comprehension or expression (The Multi-​Society Task Force on PVS 1994a).
Importantly, such patients without awareness are not necessarily immobile, but their
movements must be purely non-​purposeful, that is, must be purely reflexive: for example,
they may move their trunk or limbs (or both) in non-​purposeful ways; display roving eye
movements and brief, unsustained visual pursuit; yawn and make chewing movements;
move head or eyes briefly toward sound or movement; startle to auditory stimuli; and
smile, cry, make meaningless vocalizations, or a combination of these, in the absence of
any provoking stimuli (The Multi-​Society Task Force on PVS 1994a; Giacino 2004; Bernat
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310 When bright lines blur

2006). Bowel/​bladder incontinence and preserved autonomic/​hypothalamic function are

also thought to be diagnostically characteristic of the vegetative state, although they do
not necessarily reflect the state’s conceptual definition.
Variations of the vegetative state have been proposed. The term persistent vegetative
state is used to describe a vegetative state that persists for greater than 1 month, and is not
intended to portend prognosis (The Multi-​Society Task Force on PVS 1994a, 1994b). The
permanent vegetative state refers conceptually to an irreversible vegetative state (hence
carrying an implication of prognosis), and is identified based on a vegetative state persist-
ing over 3 months following non-​traumatic injury, or over 12 months following traumatic
injury (The Multi-​Society Task Force on PVS 1994a, 1994b). As these subcategories of
the vegetative state are frequently confused and intermix diagnosis and prognosis, they
are contentious and inconsistently accepted, and thus will not be considered further here
(Bernat 2006).
As the vegetative state, to much of the lay public and media, carries the pejorative con-
notation that affected patients are “vegetable-​like,” a new name for the condition was pro-
posed in 2010: the unresponsive wakefulness syndrome (Laureys et al. 2010). This title
better captures the conceptual definition of the state as a condition in which awareness is
lost but wakefulness is preserved. Thus, we will hereafter refer to this state as the vegeta-
tive state/​unresponsive wakefulness syndrome (VS/​UWS).

Minimally conscious state
Following establishment of the VS/​UWS, clinicians recognized that some awake patients
were neither fully unaware (i.e., in a VS/​UWS) nor fully aware, exhibiting signs of par-
tial awareness. In 2002, neuropsychologist Joseph Giacino and colleagues proposed a
new diagnostic category to describe such patients, labeled the minimally conscious state
(MCS) (Giacino et  al. 2002). The MCS is conceptually defined as a state of preserved
wakefulness with only partial awareness of the self or environment.
In terms of diagnostic criteria, like VS/​UWS patients, MCS patients exhibit sleep–​wake
cycles through spontaneous eye opening and eye closing. Unlike VS/​UWS patients, MCS
patients exhibit awareness of themselves or the environment, albeit only partially and
intermittently. Giacino and colleagues proposed that empirical evidence of such aware-
ness is the reproducible and sustained demonstration of one or more of the following
behaviors: simple command following, answering of yes/​no questions, intelligible verbal-
izations, or any other purposeful, non-​reflexive behaviors, including appropriate smiling/​
crying in response to emotional stimuli, reaching for objects, or eye-​tracking a target
(Giacino et al. 2002).

Significance of diagnostic categories and their distinction

The disorders of consciousness described in the previous section have significant impli-
cations for how patients are understood and managed. Thus, the ability to distinguish
 31

Significance of diagnostic categories and their distinction 311

between these various conditions is critical to ensuring that patients are treated ethically.
Two distinctions between these disorders are especially crucial in dictating how patients
are managed: the distinction between brain death and coma, and between the VS/​UWS
and MCS.

Coma versus brain death: The boundary between life and death

As described, brain death and coma are diagnostically similar. Indeed, the diagnostic cri-
teria for brain death consist of coma, plus absent brainstem reflexes, apnea, and a few pre-
requisite conditions. However, conceptually, the distinction is stark: patients with brain
death are considered dead, while patients in a coma are considered alive. This conceptual
distinction carries tremendous implications for clinical management, not to mention for
families and loved ones: patients who are dead no longer justify medical treatment, and
can have their organs legally procured for transplantation.
Once a patient is considered dead, as in the case of brain death, there is understood to be
the permanent cessation of functioning of the organism as a whole. Brain death therefore
fulfills the most stringent interpretation of futility, as a situation where it is conceptually
impossible for an intervention to work. When patients are declared brain dead, clinicians
are therefore relieved of any obligation to treat, and so may remove life-​sustaining treat-
ment (LST) without the family’s or surrogate’s permission. In contrast, because patients in
a coma are considered alive, clinicians caring for such patients are under a greater obliga-
tion to honor requests from families and surrogates for LST and intensive care.
The diagnosis of brain death also justifies organ procurement for transplantation. While
patients with this diagnosis are claimed to no longer function as a whole, individual organs
may remain intact and offer benefit to other ill individuals. On the assumption that these
patients are dead, organ procurement is considered ethically appropriate. Though this
intuition was implicitly accepted as an ethical and legal requirement for organ procure-
ment since the beginning of transplantation in the 1960s (Truog 2015), it was explicitly
articulated in 1999 as the “dead donor rule” (Robertson 1999). The dead donor rule states
that vital organs for transplantation may only be procured from patients who are dead, or
alternatively, that physicians may not cause death when procuring vital organs for trans-
plantation (Robertson 1999). Though the dead donor rule is not, strictly speaking, a law, it
is understood to follow logically from existing laws and ethical standards related to homi-
cide. Thus, because brain death is considered death, diagnosing a patient as brain dead
allows the procurement of their organs for transplantation, assuming it is consistent with
that patient’s wishes. In contrast, vital organs cannot be legally procured from comatose
patients, who are considered alive.

MCS versus VS/​UWS: The boundary between conscious

and unconscious
As described, there are at least two aspects of consciousness: wakefulness and awareness.
However, the colloquial understanding of consciousness aligns much more closely with
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312 When bright lines blur

the notion of awareness; an individual is typically considered conscious only if he or she

is aware. Experts in disorders of consciousness will also often adhere to this conventional
conception, defining consciousness as awareness of the self or environment. Furthermore,
many more social and ethical implications hinge on one’s capacity to experience the
world than on whether one maintains sleep/​wake cycles, as will be explored further later.
Awareness of the self or environment is lost in the VS/​UWS, but maintained (albeit only
partially) in the MCS. Thus, to reflect the conventional conception of consciousness and
for the purposes of these ethical implications, the conceptual distinction between these
states (i.e., between unawareness and awareness of the self or environment) will be con-
sidered the distinction between unconsciousness and consciousness in the discussion that
follows.
One major implication of this distinction pertains to LST. Decisions to withdraw LST
often depend upon judgments about the quality of a patient’s life. As quality of life depends
upon conscious experience, VS/​UWS patients, by the conceptual definition of the state,
necessarily lack any quality of life. Thus, many may feel compelled to withdraw LST if
the VS/​UWS diagnosis is made. In 1989, the American Academy of Neurology issued
a statement claiming that LST “provides no benefit to patients in a persistent vegetative
state” (Executive Board of the American Academy of Neurology 1989, p.126), and other
guidelines have claimed that the maintenance of consciousness should be the minimum
objective of LST (Rubin & Bernat 2011). Accordingly, studies have shown that decisions
to withdraw LST are frequently made soon after patients are found to have a disruption
of consciousness and lose decision-​making capacity (Fins et al. 1999; Becker et al. 2001).
Ethicist and physician Joseph J. Fins summarizes:
[T]‌he loss of consciousness in routine medical care takes on so much prognostic and ethical mean-
ing. In the context of routine end-​of-​life care in the general hospital, most decisions about with-
holding or withdrawing life-​sustaining therapy hinge on the presence or absence of consciousness.
When consciousness (and resulting decision-​making capacity) is lost, surrogate decision makers
take it as an important prognostic sign and use this loss as a prompt to make end-​of-​life decisions
… in the acute care setting DNR orders get written and ventilators are removed. (Fins 2015, p.184)

Thus, for many, determining whether a patient has lost consciousness (as in the VS/​UWS)
or retains consciousness (as in the MCS) plays an important role in determining whether
LST is continued.
Second, some have suggested that the presence of consciousness has important impli-
cations for civil rights. Fins, in his book Rights Come to Mind: Brain Injury, Ethics, and
the Struggle for Consciousness, writes that “to my mind, there is nothing more important
than knowing that a patient may be conscious” (Fins 2015, p.201). Fins argues that being
conscious means being entitled to civil rights. Because MCS patients are conscious (albeit
minimally so) he argues that they are therefore entitled to the same civil rights as anyone
else, and that to treat MCS patients otherwise is an act of segregation. Though Fins centers
his arguments on MCS, the implication is that, by virtue of having lost conscious aware-
ness, VS/​UWS patients are no longer entitled to that same range of civil rights. If indeed
the presence of consciousness is what dictates a person’s entitlement to civil rights, the
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Problems with discrete diagnostic boundaries 313

distinction between MCS and VS/​UWS has major implications for whether patients are
granted or denied these rights.
A third more mundane but still significant implication of this diagnostic distinction is
a humanistic one. To family and loved ones, it matters if a patient is “in there” and aware
of their presence and attempts at communication, which may influence how they inter-
act with the patient (Fins 2015). For clinicians and healthcare providers, knowing that
a patient is conscious, with a quality of life, may encourage them to talk to the patients,
to reposition them, and to provide comfort in other ways. These everyday differences in
how patients are perceived and treated critically depend upon whether they are felt to be
conscious or unconscious, and therefore hinge on the distinction between the MCS and
VS/​UWS.

The importance of discrete distinctions in disorders of consciousness

These implications have profound social, legal, and ethical significance. To decide whether
a patient is brain dead or comatose is to decide whether a patient is legally alive or dead.
Similarly, to decide whether a patient is in a MCS or VS/​UWS is to decide whether a
patient is aware of the world, with a quality of life, or not. These determinations, in turn,
have tremendous consequences, influencing whether LST is withdrawn, organs are pro-
cured, civil rights are granted, and even whether basic forms of respect and comfort are
offered on an everyday basis.
Importantly, many of the critical decisions that hinge upon these diagnoses are
discrete, binary, and without a middle ground. Withdrawal of LST and procurement
of vital organs, for example, are serious and permanent decisions without gradation.
Thus, these decisions require that the diagnostic distinctions that dictate them are
similarly discrete. For example, the distinction between brain death and coma must be
discrete enough to determine whether a patient is dead or alive, which in turn deter-
mines whether vital organ procurement is appropriate or forbidden. Otherwise, if it
were possible for a patient to be 50% brain dead and 50% comatose, or even 99% brain
dead and 1% comatose, then the patient would be neither clearly alive nor dead, and
would therefore confound decisions about organ procurement. With regard to decid-
ing whether or not to continue treatment, Fins echoes the necessity of discrete diag-
nostic distinctions, emphasizing that “those who were minimally conscious [merit]
… a bright-​line distinction with patients who were unconscious” (Fins 2015, p.128).
Thus, to properly determine how significant, discrete decisions should be made, the
distinction between brain death and coma, and between MCS and VS/​UWS, must be
clearly delineated.

Problems with discrete diagnostic boundaries

But are these diagnostic distinctions as discrete as they are presented or required to
be? Closer inspection reveals that the distinctions between brain death and coma, and
between VS/​UWS and MCS, are both problematic, though in different ways.
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314 When bright lines blur

Problems distinguishing between brain death and coma

In terms of their diagnostic criteria (see Table 17.1), brain death and coma can be distin-
guished relatively cleanly. To be considered brain dead a patient must exhibit, in addition
to coma, absent brainstem reflexes and apnea, and must meet certain prerequisite condi-
tions (e.g., minimum core temperature and absence of confounding medical conditions).
Such criteria represent largely objective and discrete outcome measures, as they are either
observably absent or present. While some of these findings may be subtle and require
clinical expertise (e.g., to determine whether a brainstem reflex is diminished or totally
absent), in principle, brain death and coma can be discretely distinguished diagnostically.
The problem, however, is that the diagnostic criteria do not accurately reflect the con-
ceptual definition of brain death, and it is this conceptual definition that justifies major
decisions such as organ procurement. There are at least two levels on which this dis-
crepancy occurs. Recall that the diagnostic criteria for brain death (e.g., coma, apnea,
and absent brainstem reflexes) are intended to represent an overarching diagnostic (and
legal) criterion: the irreversible cessation of all functions of the entire brain, including the
brainstem. This overarching diagnostic criterion, in turn, is thought to reflect the con-
ceptual definition of death, as the permanent cessation of functioning of the organism as
whole. Both connections are necessary in order for the diagnostic criteria for brain death
to reflect its conceptual definition, but closer inspection reveals that both are flawed.
First, the diagnostic criteria for brain death do not necessarily represent the irreversible
cessation of all functions of the entire brain, including the brainstem (Halevy & Brody
1993; Truog 1997, 2007, 2015). Many patients who fulfill the diagnostic criteria for brain
death continue to show evidence of preserved brain function: many are capable of regu-
lating body temperature, indicative of a functioning hypothalamus (indeed, ironically,
the brain death criterion mandating a core temperature of at least 32°C often signifies
intact temperature regulation and thereby brain function) (Truog 1997); many continue
to control fluid and salt homeostasis through the neurologically mediated secretion of
pituitary hormones (Schrader et al. 1980; Gramm et al. 1992; Halevy & Brody 1993; Truog
1997); many respond to surgical incisions with elevations in heart rate and blood pres-
sure, reflecting a potential brainstem response to noxious stimuli (Pennefather et al. 1993;
Truog 1997); and some (20% in one series) continue to exhibit electrical activity on EEG,
which may represent continued function of some brain regions, though this remains con-
troversial (Pallis 1983; Rodin et al. 1985; Grigg et al. 1987; Truog 1997). Based on these
findings, there is now general agreement that the diagnostic criteria for brain death do not
necessarily correspond to the overarching diagnostic criterion, and legal definition, which
is the irreversible cessation of all brain function (Truog 1997, 2015).
Second, even if we assume that the diagnostic criteria for brain death do reflect the
irreversible cessation of brain function, this overarching diagnostic criterion still does not
adequately correspond to the conceptual definition of death, as the permanent cessation
of functioning of the organism as a whole (Truog 2015). Bernat justified his proposal—​
that brain death meets the conceptual definition of death as the permanent cessation of
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Problems with discrete diagnostic boundaries 315

functioning of the organism as a whole—​by his observation that “[d]‌estruction of the

brain produces apnea and generalized vasodilation; in all cases, despite the most aggres-
sive support, the adult heart stops within 1 week, and that of the child within 2 weeks”
(Bernat et al. 1981, p.392). While his observation was probably true at the time—​patients
invariably suffered cardiac arrest soon after the diagnosis of brain death—​advances in
intensive medical care now allow some patients to maintain cardiac and pulmonary
function for years after the diagnosis (Shewmon 1998). In one case, a child who fulfilled
the diagnostic criteria for brain death at 4 years old was kept on a ventilator and gastric
tube for about 20  years, during which he grew and developed, maintained cardiopul-
monary function, digested and excreted food, and mounted immune responses to infec-
tions; at autopsy, his brain had become a calcified mass, void of any remaining brain cells
(Repertinger et al. 2006). There have also been numerous cases of women who suffered
brain death during pregnancy, and were subsequently maintained on a ventilator and
feeds throughout the gestation and delivery of their children (Lane et  al. 2004; Ecker
2014). These cases illustrate that even without the brain, the body can maintain a level of
integrated functioning and homeostasis, enough to support the gestation of a fetus. Thus,
the overarching diagnostic criterion of brain death, as the loss of brain function, may not
accurately represent the cessation of all functioning of the organism as a whole.
The President’s Council on Bioethics confronted the discrepancy between the diag-
nostic criteria and conceptual definition of brain death in a 2008 report (The President’s
Council on Bioethics 2008). They acknowledged that:
[i]‌f being alive as a biological organism requires being a whole that is more than the mere sum of
its parts, then it would be difficult to deny that the body of a patient with [brain death] can still be
alive, at least in some cases. (p.57)

They also asserted that:

[t]‌he reason that these somatically integrative activities continue … is that the brain is not the
integrator of the body’s many and varied functions…  . [N]o single structure in the body plays
the role of an indispensable integrator. Integration, rather, is an emergent property of the whole
organism. (p.40)

Having acknowledged the inconsistency between the diagnostic criteria and conceptual
definition of brain death, they attempted to solve the problem by proposing a revised
conceptual definition of death. They suggested that death represents the inability to per-
form the “vital work” of the organism as a whole, where “vital work” consists of three
components:
1. [R]‌eceptivity to stimuli and signals from the surrounding environment.
2. The ability to act upon the world to obtain selectively what it needs.
3. The basic felt need that drives the organism to act as it must, to obtain what it needs. (p.61)

However, this conceptual definition is also problematic (Miller & Truog 2009; Truog
2015). If “vital work” requires conscious awareness (as implied by an “ability to act upon
316  3

316 When bright lines blur

the world” and a “felt need”), then VS/​UWS patients and perhaps even MCS patients
would be considered dead, a position the Council specifically rejected. If, alternatively,
“vital work” only refers to unconscious bodily functions that respond to the environment
(e.g., mounting an immune response to infection) and interact with the environment in
accordance with the body’s needs (e.g., absorbing oxygen and digesting nutrients), then
the same diagnostic–​conceptual discrepancy remains; as described, many patients who
meet the diagnostic criteria for brain death are capable of several such bodily functions.
Thus, the Council’s proposition does not solve the incongruity between the diagnostic
criteria and conceptual definition of brain death.
It is also worth noting that the irreversibility/​permanence required of both the over-
arching diagnostic criterion of brain death (the irreversible cessation of brain functions)
and conceptual definition (the permanent cessation of functioning of the organism as
a whole) imposes an additional discrepancy between the diagnostic criteria and con-
ceptual definition of brain death. Irreversibility and permanence are both statements of
prognosis, or predictions for the future. While diagnoses may be associated with certain
prognoses, even with high probability, it is problematic to require a prognosis in the very
conceptual definition of a diagnosis, as doing so theoretically requires a certain predic-
tion of the future. Even if, ignoring the earlier arguments, the diagnostic criteria for brain
death actually reflected the cessation of all brain function or the cessation of all integrated
functioning of the organism, and even if all patients who met the diagnostic criteria for
brain death to date had never recovered those functions, it would still not be absolutely
certain that those diagnostic criteria would predict permanent/​irreversible cessation
of those functions in 100% of future cases. Thus, while the diagnostic criteria for brain
death may be associated with an overwhelmingly poor prognosis, the requirement of the
prognosis in brain death’s very definition impossibly demands a prediction of the future,
thereby ensuring that the diagnostic criteria could, in principle, never match the over-
arching diagnostic criterion or conceptual definition with certainty.
To summarize, in order to effectively guide discrete decision-​making, the distinction
between brain death and coma must be similarly discrete. Although the diagnostic crite-
ria for brain death and coma are in principle sufficiently discrete, the brain death criteria
do not accurately reflect the conceptual definition of brain death. As it is the conceptual
definition of brain death, as death, that justifies major decisions such as organ procure-
ment, this diagnostic/​conceptual discrepancy indicates that the current diagnostic crite-
ria cannot adequately guide these decisions. That is, while one can definitively determine
that a patient fulfills the diagnostic criteria for brain death, as distinct from coma, one
cannot be confident that those diagnostic criteria meaningfully signify death in a way
that justifies organ procurement. We should also note that while we currently focus on
this problem as it pertains to the scientific and medical definition of death, this prob-
lem also extends to alternative religious and cultural definitions of death (Posner et al.
2007). Many, particularly those of orthodox religious groups and those with cultural
roots in Asia and the Middle East, feel that the diagnostic criteria for brain death do not
reflect their personal conceptions of death; in Japan, for example, two types of “death”
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Problems with discrete diagnostic boundaries 317

are commonly recognized—​one suitable for patients who wish to be organ donors, and
another for everyone else (Lock 2002). Given the heterogeneity of views on brain death,
US states such as New Jersey and New York have chosen to accommodate religious and
moral objections to brain death testing (Kimura 1991; Posner et al. 2007). Thus, overall,
the diagnostic distinction between brain death and coma does not accurately reflect their
conceptual distinction as death and life, respectively, thus undermining the utility of these
diagnostic distinctions in guiding decisions.

Problems distinguishing between VS/​UWS and MCS

As described, the ability to discretely distinguish VS/​UWS patients from MCS patients—​
that is, unconscious from conscious patients—​is important in guiding discrete decisions
that hinge upon whether consciousness has been lost or retained. However, closer inspec-
tion of the distinction between VS/​UWS and MCS reveals two problems: first, the diag-
nostic distinction is not, in principle, discrete, and second, the diagnostic distinction does
not wholly correspond to the conceptual distinction.
The diagnostic criteria distinguishing VS/​UWS from MCS do not discretely delineate
the two conditions. The crux of the diagnostic distinction is that while VS/​UWS patients
exhibit only reflexive behaviors, MCS patients exhibit both reflexive and purposeful
behaviors, such as through intelligible verbalizations, answering yes/​no questions, and
reaching for objects in a goal-​directed manner. However, it is unclear how purposeful
behavior can be recognized and distinguished from reflexive behavior (Fischer & Truog
2015). It is not merely that reflexive behaviors are triggered by an external stimulus, while
purposeful behaviors are internally motivated, as the “reflexive crying or smiling” (Table
17.1) that can be observed in the VS/​UWS occurs without a triggering stimulus. Nor
can they be distinguished by consistency, since in some instances purposeful behaviors
are more consistent than reflexive behaviors (e.g., deliberate eye tracking versus transient
pursuit), while in other instances the reverse is true (e.g., a patellar deep tendon reflex
versus a volitional kick). Nor can they be distinguished by complexity, since, while pur-
poseful behaviors can be complex, brain stimulation and seizures can also produce com-
plex but non-​volitional behaviors (Fischer & Truog 2015). Indeed, while some behaviors
are clearly purposeful (e.g., holding a conversation) and others clearly reflexive (e.g., the
pupillary light reflex), there is a wide range of behaviors between the two which cannot
be clearly classified. Because the diagnostic distinction between the VS/​UWS and MCS
relies upon the distinction between reflexive and purposeful behaviors, the uncertainty in
distinguishing these two types of behaviors creates uncertainty in clinically distinguishing
the VS/​UWS from the MCS.
This diagnostic ambiguity is compounded by an additional problem:  as with brain
death and coma, there is incongruity between the diagnostic criteria and conceptual
definitions of VS/​UWS and MCS. That is, even if purposeful behaviors and reflexive
behaviors could theoretically be discretely distinguished, this diagnostic distinction
does not clearly signify the presence or absence of consciousness, respectively. Again,
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318 When bright lines blur

the crux of the diagnostic distinction is that while VS/​UWS patients exhibit only reflex-
ive behaviors, MCS patients exhibit both reflexive and purposeful behaviors. The logic
of these diagnostic criteria is that purposeful behaviors reflect volition, which can exist
only in those who are conscious. While this is true, the same logic does not follow
in the absence of these behaviors. Patients are given a VS/​UWS if they exhibit only
reflexive behaviors, that is, if they are not observed exhibiting any purposeful behav-
iors. However, first, just because purposeful behaviors are not observed or recognized
does not necessarily mean that purposeful behaviors are absent. Second, the absence
of purposeful behaviors does not necessarily imply the absence of volition. And third,
the absence of volition does not necessarily imply the absence of awareness. We can
imagine many scenarios—​patients who are blind, deaf, aphasic, confused, apathetic,
paralyzed, or even intermittently conscious, for example—​where conscious patients are
not recognized as such on the basis of observable purposeful behaviors. Thus, in clini-
cally distinguishing VS/​UWS from MCS, the absence of evidence is not necessarily the
evidence of absence; the diagnostic criteria for these disorders imperfectly reflect their
conceptual definitions.
Neuroimaging technology has poignantly revealed the danger of assuming that the
absence of purposeful behaviors represents the absence of consciousness. In 2006,
neuroscientist Adrian Owen and colleagues published a study on a 23-​year-​old woman
who sustained traumatic brain injury after a road traffic accident (Owen et al. 2006).
She continued to demonstrate sleep–​wake cycles, but was behaviorally unresponsive,
and so was given the diagnosis of VS/​UWS. However, using functional magnetic reso-
nance imaging (fMRI), Owen and colleagues found that she could reliably respond to
commands through fMRI signals. When asked to imagine playing tennis, she exhib-
ited activity in the supplementary motor area, a region associated with planning move-
ment. When asked to imagine walking through the rooms of her house, she exhibited
activity in regions associated with spatial navigation, such as the parahippocampal
gyrus. These activity patterns were indistinguishable from those observed in healthy
individuals. Moreover, these activations did not appear to be reflexive reactions to the
words “tennis” or “house,” but rather intentionally generated; the patient’s responses
lasted up to 30 seconds (longer than would be expected from a transient, automatic
reaction) and only until the experimenters asked her to stop (Hopkin 2006). Another
study found additional patients who, despite being behaviorally unresponsive, were
similarly able to complete this fMRI task (Monti et al. 2010). One of these patients,
who was behaviorally noncommunicative, could correctly answer yes-​or-​no questions
with this task, imagining one scenario to signal “yes” and the other scenario to sig-
nal “no.” These neuroimaging studies demonstrated that a subset of patients who are
behaviorally unresponsive and meet the diagnostic criteria for VS/​UWS in fact do have
conscious awareness, thereby meeting the conceptual definition of MCS, and perhaps
even retaining higher levels of consciousness (Fischer & Truog 2013). These instances
further illustrate a significant discrepancy between the conditions’ diagnostic criteria
and conceptual definitions.
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Non-discrete diagnostic boundaries reflect a continuum between conditions 319

To summarize, in order to effectively guide discrete decision-​making, the distinction

between the conscious and the unconscious, that is, between MCS and VS/​UWS, must
be similarly discrete. However, the VS/​UWS cannot be discretely distinguished from the
MCS for at least two reasons. First, uncertainty in distinguishing between purposeful and
reflexive behaviors obscures the diagnostic distinction between the VS/​UWS and MCS.
Second, the diagnostic criteria of these conditions do not wholly correspond to their
conceptual definitions: their diagnostic criteria do not account for conscious individuals
incapable of purposeful behaviors, a danger confirmed with neuroimaging studies. These
sources of ambiguity undermine the utility of the current diagnostic criteria for VS/​UWS
and MCS in guiding decisions.

Non-​discrete diagnostic boundaries reflect a continuum

between conditions
The distinction between brain death and coma, as well as between VS/​UWS and MCS, are
important for guiding discrete decisions: the former represents a distinction between the
dead and the living, and the latter between the unconscious and the conscious. However,
neither distinction between conditions is, in reality, discrete. While the diagnostic dis-
tinction between brain death and coma is in principle discrete, this diagnostic distinc-
tion does not accurately correspond to the conceptual distinction between death and life.
The distinction between VS/​UWS and MCS is even more problematic: not only does the
diagnostic distinction between VS/​UWS and MCS inadequately reflect their conceptual
distinction, but the diagnostic distinction itself is inherently ambiguous. Why are the dis-
tinctions between these conditions, which are often presented as discrete and relied upon
to dictate discrete decisions, so problematic? It is likely that these difficulties stem from
a continuity between the conditions, hampering strict delineation. This continuity can
be considered in at least two ways:  as an ontological continuity, or an epistemological
continuity.

Ontological continuity between disorders of consciousness

By ontological continuity, we refer to the possibility that the conceptual distinctions
between life and death, and between consciousness and unconsciousness, are inher-
ently non-​discrete. First we will consider how this applies to the life/​death distinction.
Death has been defined as the permanent cessation of the functioning of the organism
as a whole, so life can be understood as the functioning of the organism as a whole. The
“wholeness” of an organism, however, is challenging to define. Bernat defined wholeness
as consisting in the “highly complex interaction of… [an organism’s] organ subsystems”
and “the spontaneous and innate activities carried out by the integration of all or most
subsystems” (Bernat et al. 1981, p.390). This description reflects the philosophical view of
wholism (also known as holism or organicism), which posits that:
complex wholes are inherently greater than the sum of their parts in the sense that the properties
of each part are dependent upon the context of the part within the whole in which they operate.
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320 When bright lines blur

Thus, when we try to explain how the whole system behaves, we have to talk about the context of
the whole and cannot get away talking only about the parts. (Gilbert & Sarkar 2000, p.1)

Thus, the definition of life is an inherently wholistic one: life emerges not through inde-
pendently functioning tissues and organ systems, but through the interactions and inte-
gration of those organ systems to produce a whole.2 Importantly, because the whole
must emerge from the interactions of its parts, wholism depends upon emergentism, the
notion that:
properties at one level of complexity (for instance, tissues) cannot be ascribed directly to their com-
ponent parts but arise only because of the interactions among the parts. Such properties that are
not those of any part but that arise through the interactions of parts are called emergent properties.
(Gilbert & Sarkar 2000, p.2)

For example, wetness and temperature can be considered emergent properties of mole-
cules; while an individual water molecule cannot be considered wet or to have a tempera-
ture, it is the larger-​scale interaction of many water molecules through which wetness or
temperature emerges. Similarly, life can be considered an emergent property of the inter-
actions between tissues and organ systems, a view endorsed by The President’s Council
on Bioethics, which has written that the integrated functioning of life “is an emergent
property of the whole organism” (The President’s Council on Bioethics 2008, p.40).
Life, so considered, has important implications for death. Given that emergent proper-
ties typically arise gradually out of increasingly complex interactions between constitu-
ent parts, so too do emergent properties disappear gradually from decreasingly complex
interactions. For instance, just as there is no defined number of water molecules above
which wetness appears—​wetness emerges gradually out of an increasing number of water
molecules—​there is also no defined number of water molecules below which wetness
is suddenly lost. Similarly, just as life emerges gradually from the increasingly complex
interactions of tissues and organ systems (as has been argued in the case of fetal devel-
opment (Gilbert & Sarkar 2000)), so too may death occur continuously, not discretely,
from the loss of those interactions. It should be noted that certain organ systems play a
particularly critical role in sustaining the interactions between organ systems; if the heart
stops beating, the loss of organ interactions, the loss of the organism as a whole, and hence
the death of the organism, occurs more rapidly than if the kidneys stopped functioning.
However, even in the case of cardiac arrest, death can still be understood as the continu-
ous, albeit rapid, cessation of the organ interactions that sustain the emergent property
of life.
Thermodynamic principles have been used to justify the discreteness of the life/​death
distinction. An organism perhaps can be considered whole so long as it employs energy-​
consuming processes to oppose entropic forces from the surrounding world. Thus,
perhaps at the moment when the entropic forces of the surrounding world exceed the
self-​sustaining homeostatic forces of the organism, death can be said to discretely occur.
However, an organism may continue to exist after entropic forces exceed homeostatic
forces, just as beaches persist, while shrinking, after erosive forces exceed the accretive
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Non-discrete diagnostic boundaries reflect a continuum between conditions 321

forces. Thus, the moment at which the entropic forces exceed the homeostatic forces
of an organism may merely signify the beginning of dying, with death itself occurring
more continuously as entropic forces erode at the wholeness of the organism. Moreover,
because the entropic forces of the universe can vary in strength—​natural disasters and
extreme temperatures may suddenly give way to calm weather—​one can imagine scenar-
ios in which, at one moment the entropic forces exceed an organism’s homeostatic forces,
while in the next moment the entropic forces drop below that organism’s homeostatic
forces. It would seem implausible that that organism has died and returned to life, simply
due to variability in environmental forces. Thus, though in many cases it occurs rapidly,
death appears likely to be a fundamentally continuous occurrence.
If death is indeed a continuous occurrence, then no discrete diagnostic criteria can
perfectly segregate all live patients from all dead patients. Selecting discrete criteria for
death would be akin to selecting a number of water molecules below which wetness is
lost:  no matter how they are defined, they will oversimplify an inherently continuous
range of conditions as binary categories. Depending on where the criteria are drawn,
some patients will be incorrectly considered dead (when they continue to function par-
tially as a whole), and/​or some patients will be incorrectly considered alive (when their
wholeness has been partially lost).
The distinction between consciousness and unconsciousness is likely also a continu-
ous one. Like life, many consider consciousness to be an emergent property of the brain
(Edelman 1999). Philosopher John Searle writes that:
Just as one cannot reach into a glass of water and pick out a molecule and say “This one is wet,” so,
one cannot point to a single synapse or neuron in the brain and say “This one is thinking about my
grandmother.” (Searle 1992, cited in Gilbert & Sarkar 2000, p.2)

Conscious awareness, which involves the higher-​order integration of different sensory

modalities and cognitive faculties, is commonly considered to emerge from the dynamic
interplay of neurons and networks, just as wetness emerges from the interactions of water
molecules (Gilbert & Sarkar 2000). Thus, just as consciousness emerges continuously
from the increasingly complex interactions between neurons, so too may consciousness
be lost continuously through decreasingly complex interactions. Of note, just as certain
organ systems (e.g., the heart) are particularly vital to maintaining the organ interactions
necessary for life, so too are certain parts of the brain particularly vital to maintaining
the interactions between neurons necessary for consciousness; injury to the brainstem
and the ascending activating system, for instance, will more quickly diminish neuronal
interactions, and thus consciousness, than injury to a region of cortex.
Moreover, even apart from considerations of its biological underpinnings, conscious-
ness appears to exist along a continuum. Consider that the conceptual distinction between
the MCS and VS/​UWS is the presence or absence of consciousness, where the presence
of consciousness means awareness of the self or environment. What constitutes aware-
ness of the self or environment? Though never explicitly defined, a certain sophistica-
tion of awareness was likely implied by this conceptual definition when it was proposed.
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322 When bright lines blur

Because the diagnostic criteria for MCS includes following simple commands, answer-
ing yes/​no questions, smiling/​crying in response to emotional content, or reaching for
objects in a goal-​directed manner, MCS patients were likely imagined to hear language
and comprehend its meaning, to see objects and perceive their desirability/​purpose, and/​
or to see people and recognize emotional valence. Awareness of the self also implies a
relatively sophisticated integration of sensation and cognition into a coherent sense of
self. However, one can imagine much more rudimentary forms of awareness: awareness,
for instance, only of color, sounds, or sensations, without awareness of objects or even of
a coherent environment per se, let alone of people, language, or a self. Thus, though the
MCS was created as an intermediary between the VS/​UWS and normal consciousness,
the discrete distinction between VS/​UWS and MCS may still be too crude, separated
by a continuum of consciousness between complete unawareness and awareness of the
self or environment. As in the distinction of life and death, if the distinction between
consciousness and unconsciousness is indeed a continuous one, then no discrete diag-
nostic criteria for MCS or VS/​UWS will perfectly distinguish the conscious from the
unconscious.

Epistemological continuity between disorders of consciousness

One might reject the possibility that the distinction between life and death, or between
consciousness and unconsciousness, is continuous, insisting upon a conceptual bright
line between these states. However, even if such discrete distinctions exist, there remains
an additional problem:  we frequently do not know, and perhaps cannot know, when
patients have crossed these lines. We do not have empirical characteristics that perfectly
mark the transitions between these states, and thus while certain empirical charac-
teristics clearly signify life versus death (e.g., someone holding a conversation versus
someone with clinical findings of rigor mortis, respectively) or consciousness versus
unconsciousness (e.g., someone holding a conversation versus someone whose brain
has been removed, respectively), there remains a spectrum of empirical characteristics
between these extremes which ambiguously signify whether a patient is alive versus dead,
or conscious versus unconscious. We refer to this range of indeterminate characteristics
(i.e., characteristics whose significance we do not know), and the resultant appearance of
continuity between these states, as an epistemological continuity.
We have no metrics to determine when functioning of the organism as a whole has
been permanently lost, and thus cannot distinguish life from death with perfect accu-
racy. Again, many characteristics can clearly signify life or clearly signify death, but of
the range of characteristics in between, it is unclear which reliably mark the transition
from life to death. Patients with brain death exhibit characteristics that fall within this
spectrum. For the reasons discussed earlier, apnea and the loss of brainstem reflexes,
while in principle measurable, do not clearly reflect the loss of functioning of the organ-
ism as a whole, and thus do not adequately represent death. Moreover, it is possible
that, in principle, no characteristics within this spectrum could ever mark the life/​death
distinction with perfect accuracy; that is, the line between life and death in a person may
 32

Non-discrete diagnostic boundaries reflect a continuum between conditions 323

be inherently unknowable, for at least three reasons. First, there is no clear “output” of
a person functioning as a whole. For example, the heart has the function of pumping
blood; thus, the functioning of the heart as a whole (i.e., the extent to which its compo-
nent tissues are operating and interacting properly) can be assessed by its cardiac output,
or its ability to effectively pump blood. In contrast, a person has no clear function, and
thus we have no functional output from which to gauge a person’s wholeness. Second,
even if, in theory, there exists some empirical metric—​a certain behavior, or a particular
type of physiologic activity—​that perfectly corresponds to the functioning of the organ-
ism as a whole, we have no way of identifying or validating it. That is, we could not know
that this metric corresponds to life, because for us to know, we would need to observe a
correspondence between this metric and life, and we have no way of knowing whether
life is present. For us to know that life is present, we would need a metric that perfectly
corresponds to the functioning of the organism as a whole, which traps us in circular-
ity. Third, the required permanence of the cessation of functioning of the organism as a
whole also makes death inherently unknowable, by demanding knowledge of prognosis
(a prediction of the future), as described earlier. Thus, the distinction between life and
death is empirically unknown, and may in principle be unknowable.
The detection of consciousness similarly suffers from an epistemological continuity, as
we have no set of empirical criteria that will perfectly distinguish those aware of the self
or environment from those who are not. Moreover, the line dividing consciousness from
unconsciousness may also be inherently unknowable. The adage that “the only conscious-
ness that we can truly know is our own” (Fins 2015, p.197) reflects the inherent subjectiv-
ity of consciousness. Thus, as in the distinction between life and death, the notion that an
empirical metric could perfectly distinguish consciousness from unconsciousness gener-
ates circularity, as defining such a metric would require us to distinguish consciousness
from unconsciousness in the first place. Thus, even if the distinction between conscious-
ness and unconsciousness is in principle discrete, we do not, and perhaps cannot, have an
empirical way of identifying it with precision.

How continuity problematizes diagnostic boundaries

Due to ontological continuity, epistemological continuity, or a combination of the two,
we cannot discretely distinguish between life and death, or between consciousness and
unconsciousness. The transitions between these states are inherently non-​discrete, and/​or
we do not (and perhaps cannot) know when these transitions have occurred. Even Fins,
who endorses a bright line distinction between the conscious and unconscious, echoes
this sentiment, writing that neuroimaging data demonstrating consciousness in those
who are behaviorally unresponsive:
will add nuance and complexity to decision making and remove the haven of the simplicity afforded
by dichotomous outcomes. It will not be as simple as we had all been led to believe: outcomes are
not purely binary. Brain injuries are not just either catastrophic or miraculous. Like all things bio-
logical, they exist on a continuum with grey zones in between the extremes. (Fins 2015, p.112–​113)
324  3

324 When bright lines blur

Given the continuity between these conditions, it is no wonder that the current diagnostic
distinctions between brain death and coma, or between VS/​UWS and MCS, do not suc-
cessfully draw discrete delineations. One can imagine, however, why they were intended
to. As described earlier, many significant, discrete decisions, such as whether to withdraw
LST or to procure vital organs for transplantation, hinge upon the conceptual distinctions
between life and death, or consciousness and unconsciousness. The desire to make these
discrete decisions likely drove the diagnostic criteria to become similarly discrete. This is
perhaps most clearly exemplified in the case of organ procurement in brain death. The
very conception of brain death can be traced back to the first heart transplant, conducted
in 1967 in South Africa (Barnard 1967; Truog 2015). The donor for the transplant was
selected on the basis of devastating neurological injury, though she was maintained on a
ventilator (Truog 2015). Recognizing that the criteria for devastating neurological injury
would need to be formalized if organ transplantation was to ethically continue, anesthe-
siologist Henry Beecher organized and chaired a committee to propose the first defini-
tion of brain death (Ad Hoc Committee of the Harvard Medical School to Examine the
Definition of Brain Death 1968; Truog 2015). Given that the very notion of brain death
was born out of a need to definitively determine when organ procurement was ethical,
it is not surprising that the diagnostic criteria for brain death were made to be discrete.
The drive to establish discrete diagnostic distinctions for these continuous disorders
resulted in different problems in each case. For brain death and coma, the diagnostic
distinction succeeded in being discrete, but failed to reflect their conceptual distinction.
For VS/​UWS and MCS, the diagnostic distinction was not discrete, nor did it reflect the
conceptual distinction.

Rethinking decisions in disorders of consciousness

We would like to make decisions—​such as whether to withdraw LST or procure organs
for transplantation—​based on whether patients are alive or dead, or conscious or uncon-
scious. However, our current diagnostic criteria do not permit us to discretely distinguish
between these states; perhaps, in principle, no empirical criteria ever could. If we are
unable to distinguish between these fundamental, conceptual states, how are we to make
these difficult decisions? We must rely upon what we have left: namely, the characteristics
we can actually observe about patients.

Using diagnostic criteria as a legal fiction

One way of using empirical characteristics to guide decisions is by employing a “legal
fiction.” We may decide that despite the discrepancies we know to exist between diagnos-
tic criteria and conceptual definitions, those who fulfill the diagnostic criteria for brain
death should be considered dead, and those who fulfill the diagnostic criteria for VS/​
UWS should be considered unconscious. In other words, while we know that, technically
speaking, the diagnostic criteria do not perfectly correspond to the conceptual defini-
tions, we could treat them as if they do in order to guide decisions. In many ways, this
 325

Rethinking decisions in disorders of consciousness 325

approach best describes the mentality currently adopted, explicitly or implicitly, by the
medical community.
While this type of pretending may seem outlandish, there is indeed legal precedent for
it. Deliberately accepting a discrepancy between an entity’s legal status and its biological
reality for the purpose of the public good—​called a legal fiction—​can be traced back as
far as the 1893 case of Nix v. Hedden, when the US Supreme Court had to decide whether
a tomato should be considered a fruit or a vegetable (US Supreme Court 1893; Shah &
Miller 2010; Shah et al. 2011; Truog 2015). At the time, a tax was imposed on the impor-
tation of vegetables, and tomato importers argued that they should be exempt from the
tax because tomatoes are technically fruit. The Supreme Court stated that, “Botanically
speaking, tomatoes are the fruit of the vine … But in the common language of the peo-
ple… these are vegetables” (US Supreme Court 1893, p.307), and so determined that
tomatoes should legally be considered vegetables.
There are different types of legal fictions that could apply in the distinctions between
brain death and coma, or between VS/​UWS and MCS. The first is a “bright-​line fic-
tion,” which refers to creating legally discrete categories by drawing a bright line at a
point along a continuum. An example of a bright-​line fiction already established in
medicine and law is that of legal blindness (Shah & Miller 2010). While visual acu-
ity falls along a spectrum, once an individual’s visual acuity falls below 20/​200 he or
she is considered legally blind, despite technically retaining limited sight. This legal
classification carries implications for rights (e.g., eligibility for disability benefits)
as well as for restrictions (e.g., driving prohibitions). Thus, while the discrete, legal
definition of blindness does not perfectly correspond to the biological definition of
blindness, this bright line fiction serves an important function in dictating social and
legal decisions.
A second type of legal fiction potentially relevant to disorders of consciousness is the
status fiction, in which A is treated as if it were B (Shah et al. 2011). One example of a well-​
established status fiction is that corporations are assigned the same legal status as people
(i.e., corporations are treated “as if they were” people), so that the body of law developed
for people can be applied to corporations. While a corporation is not technically a person,
this legal fiction is helpful in guiding many practical decisions, such as when a corpora-
tion can be sued, and how a corporation can contribute money to a political campaign
(Shah et al. 2011).
Applying these legal fictions to disorders of consciousness would mean either consider-
ing the diagnostic criteria for brain death or VS/​UWS to signify death or unconsciousness,
respectively (in the case of a bright line fiction), or treating those who fulfill the diagnostic
criteria for brain death or VS/​UWS as if they were dead or unconscious, respectively (in
the case of a status fiction). As described, these forms of pretending can serve useful social
and legal functions. In the case of disorders of consciousness, the fiction that discrete
diagnostic criteria reflect discrete conceptual categories (i.e., of life and death, or of con-
sciousness and unconsciousness), could be useful in guiding discrete decisions that rely
upon these conceptual distinctions.
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326 When bright lines blur

But the problem with this approach is: who would we be pretending to? The legal fic-
tions currently established are generally transparent to society and those involved. It is
understood that a corporation is not literally a person, and those who are legally blind
but retain vision understand that they are not literally blind. But in the case of disorders
of consciousness, people could be unfairly misled. If we tell families and surrogates, or
even medical students and physicians in training, that patients are dead if they meet the
criteria for brain death, or are unconscious if they meet the criteria for VS/​UWS—​as we
often currently do—​these groups may not understand the fiction and actual uncertainty
that underlie these statements. They may not understand that such patients are not liter-
ally dead or unconscious. Thus, such fictions could be more deceptive than clarifying,
resulting in incompletely informed decisions. The alternative is to disclose these fictions
to families and surrogates, to tell them that although we consider these patients to be
dead or unconscious (or treat them as such) for legal purposes, we cannot actually be sure
that they are dead or unconscious. In this case, these fictions would cease to effectively
serve as fictions at all, and families and surrogates would need to decide if the diagnostic
criteria themselves are sufficient to justify their decisions, bringing us to a second possible
approach.

Using empirical characteristics that reflect values

Many of our decisions currently hinge upon whether a patient is alive or dead, or con-
scious or unconscious. However, these conceptual states cannot be distinguished for many
patients. Though we could pretend that the diagnostic criteria signify these conceptual
states, as through a legal fiction, the deception inherent to this approach raises significant
ethical concerns. Thus, in order to continue making these decisions, we are forced to con-
sider an alternative approach: to abandon the hope of definitively distinguishing between
these conceptual states, and instead to rely upon empirical characteristics to guide deci-
sions. That is, instead of trying, perhaps futilely, to determine whether any given patient
is alive or dead, or conscious and unconscious, we must instead focus on what we can
observe about a patient in order to make decisions. If we are to rely on empirical char-
acteristics to justify decisions, we should be thoughtful about how those characteristics
are selected. If they cannot reliably distinguish between conceptual states, then they must
instead account for our values. What empirical characteristics matter to us when making
decisions about a patient?
First, we will consider how this approach applies to decisions that typically hinge
upon the distinction between brain death and coma—​perhaps the most notable being
whether or not to procure vital organs. What empirical characteristics should dictate
whether organ procurement is acceptable? Or put another way, what empirical char-
acteristics, if exhibited by a patient, would convince us that procuring his/​her organs
is ethically justified? Some may endorse the dead donor rule because of the value that
patients should be dead before their organs are procured. This group may therefore
favor an empirical criterion for organ procurement that signifies death as certainly as
 327

Rethinking decisions in disorders of consciousness 327

possible—​perhaps something akin to clinical signs of rigor mortis. However, selecting

such a criterion would significantly limit the value of the procured organs, since wait-
ing for rigor mortis would cause substantial organ hypoxia and injury. Moreover, oth-
ers might disagree that the certainty of death is the most important value in deciding
whether organs can be procured. Perhaps instead, the values most important to our
current system of organ procurement are that of autonomy (that one should be able
to choose if his or her organs are donated) and nonmaleficence (that one should not
be harmed by the donation of his or her organs). The empirical characteristics we cur-
rently use as the diagnostic criteria for brain death may already capture these values,
since it is widely accepted that those who fulfill these criteria are not conscious (there
is no documented case of such patients regaining consciousness) and therefore argu-
ably cannot experience harm. There is indeed evidence that for most, these diagnostic
criteria for brain death justify organ procurement, independently of what they signify
about death. A survey of over 1000 American adults presented participants with a case
of a man who, after an automobile accident, fulfilled the diagnostic criteria for brain
death (including irreversible unconsciousness and apnea); however, the term “brain
death” was not used, and the man was explicitly described as alive (Nair-​C ollins et al.
2015). The survey determined that 71% of the participants thought it should be legal
for the patient to donate his organs, 70% thought that doctors should be able to pro-
cure organs from similar patients (assuming consent), and 67% reported wanting to
donate their own organs if in the patient’s circumstances. This study suggested that the
empirical criteria for brain death and what they represent about an individual’s neu-
rological function, and not necessarily the conceptual state of death per se, for many
justify the procurement of organs.
Second, how might this approach apply to decisions that typically hinge upon the
distinction between VS/​UWS and MCS? Perhaps the most critical decision that is often
influenced by this distinction is whether or not to withdraw LST. There are numerous
reasons why a surrogate might choose to withdraw LST for a patient, but as discussed,
for many, a major determinant is whether a patient retains consciousness, as an uncon-
scious patient necessarily lacks any quality of life. Such decisions are discrete, yet as
we have shown, the current criteria distinguishing VS/​UWS from MCS rely upon the
inherently uncertain distinction between reflexive and purposeful behaviors, and as
such do not form a discrete boundary on which such decisions can be based (Fischer &
Truog 2015). Moreover, the current diagnostic criteria for the VS/​UWS and MCS per-
tain only to behavior, and thus neglect patients who might only show signs of con-
sciousness through emerging technologies such as fMRI. So, if we cannot rely upon the
current diagnostic criteria for guiding these discrete decisions, what empirical char-
acteristics can we rely upon that are both discrete and consistent with our values? Or
in other words, what characteristics matter most when making decisions that hinge
upon whether a patient is conscious or unconscious, when this conceptual distinction
remains inherently unclear?
328  3

328 When bright lines blur

We have previously proposed one such criterion for guiding these decisions: interac-
tive capacity, or the ability to receive communicated information and generate a coherent
response (Fischer & Truog 2013, 2015). Under this proposal, a patient should be con-
sidered conscious only if they demonstrate interactive capacity. We have also stipulated
that the patient’s response must be potentially intentional in order to signify interactive
capacity; that is, responses that are inherently non-​volitional, even if performed by a con-
scious individual (e.g., automatic brain activity in response to voice or pain), cannot be
considered interactive (Fischer & Truog 2015).
Interactive capacity circumvents the problematic distinction between reflexive and pur-
poseful behaviors by falling safely among the latter, that is, by intuitively signifying con-
sciousness. Fins relays the thoughts of a woman whose mother suffered from a disorder
of consciousness:
[S]‌he told us why restoring her mother’s ability to communicate was most important to her.
“I think,” she said, “it’s because speech and language are a clear sign that she’s in there.” (Fins
2015, p.199)

Fins elaborates:
Ultimately, communication … helps families know if their loved one is conscious … Although
the only consciousness that we can truly know is our own, in practice we know the consciousness
of others through communication, which is a proxy for the cognitive experience within. Without
communication, others cannot know a patient’s level of awareness … It limits knowledge of the
patient’s current state and their future capabilities. (Fins 2015, p.197)

Along the spectrum of reflexive and purposeful behaviors, interactive behaviors can
be assumed to be purposeful, and thus trusted to signify consciousness. Perhaps this is
because, while spontaneous behaviors without context can be ambiguously interpreted,
behaviors in coherent response to external cues are more likely purposeful. The Turing
test offers an analogous application of the same intuition (French 2000; Stins 2009). In
this test, an examiner enters questions into a computer, and must determine whether the
responses are generated by a human respondent or an automated algorithm. The Turing
test thus assesses an algorithm’s ability to simulate human consciousness based on its
interactivity. Assessing the consciousness of a patient is conceptually similar: one com-
municates to a patient and evaluates whether the responses are sufficiently coherent to
signify consciousness.
In intuitively falling among purposeful, or conscious, behaviors, interactive capacity
solves two problems. First, it serves as a more discrete criterion than the current diagnos-
tic criteria for consciousness. The current criteria require clinicians to determine where
any given behavior falls along the spectrum between reflexive and purposeful behaviors.
As such, a patient whose behavior falls only within this indeterminate spectrum will be
difficult to categorize as either conscious or unconscious. In contrast, because interactive
behaviors are more readily identifiable, deciding whether interactive capacity is present or
absent, rather than whether a behavior is reflexive or purposeful, represents a more dis-
crete diagnostic determination. As such, it can more effectively guide discrete decisions.
 329

Rethinking decisions in disorders of consciousness 329

Second, the intuitiveness with which interactive capacity signifies consciousness reflects
the value we place on interaction. For example, for many, a patient’s ability to interact is
crucial when deciding whether or not to withdraw LST. Fins writes that:

Most decisions to withhold or withdraw care are made when a patient loses consciousness and the
capacity to interact and participate in the decision-​making process … It is this loss of conscious-
ness, the ability to interact with the other, that becomes the moral prompt for the conversation
(Fins 2015, p.30)

Given that we often cannot definitively know whether consciousness has been lost, it is
the loss of the “ability to interact” that prompts the conversation to withdraw LST, high-
lighting the value we place on interactive capacity when deciding if someone is conscious.
Fins also relays the thoughts of someone whose loved one suffered from a disorder of
consciousness:

“First of all I wanted her alive and I wanted her to recover, but I didn’t know what I wanted her to
recover the most. And it’s the ability to speak and communicate … ” The restoration of functional
communication was “ … The world.” (Fins 2015, p.197)

Surely the speaker would have wanted the patient to recover awareness, but it is telling
that the speaker chose communication as the most important function to recover. For
many, among the various empirical characteristics that might signify consciousness, it is
interaction that is the most meaningful. It is also worth noting that the current behav-
ioral criteria for the MCS (e.g., following commands, answering yes-​or-​no questions)
already do center on interactive behaviors, another indication that interactive capacity
intuitively matters to us when determining if another is conscious.
There are additional, more practical advantages to adopting interactive capacity as
a criterion for consciousness. First, whereas the current diagnostic criteria for con-
sciousness pertain specifically to behavior, interactive capacity is more generaliz-
able, and thus can apply to technologically mediated forms of interaction. This is an
important consideration in the context of emerging technologies, such as the fMRI
tasks described earlier, which can demonstrate interactive capacity in patients who
are behaviorally unresponsive. Second, selecting a criterion such as interactive capac-
ity that falls safely among purposeful behaviors prevents tests for consciousness from
becoming overly reductive (Fischer & Truog 2013). After fMRI studies revealed that
behaviorally unresponsive patients could interact through neuroimaging, people began
developing even more sensitive technological biomarkers for consciousness. However,
as these tests began to stray from intuitive conceptions of consciousness (e.g., EEG
responses to auditory stimuli (Faugeras et  al. 2011), positron emission tomography
responses to painful stimuli (Boly et al. 2008), fMRI responses to voice (Di et al. 2007),
and correlations between spontaneous fluctuations in fMRI signals (Vanhaudenhuyse
et al. 2010)), they risked over-​attributing consciousness to subconscious neural phe-
nomena. Interactive capacity is anchored in an intuitive conception of consciousness,
thereby minimizing the risk of overly reductive tests.
30  3

330 When bright lines blur

Further considerations when incorporating values into decisions

Given that we cannot distinguish whether every patient is alive or dead, or conscious or
unconscious, we have argued that the best alternative is to rely on what we know—​that is,
the characteristics of patients that we can observe—​in order to guide decisions. As such,
we have suggested that these empirical characteristics should be selected in accordance
with our values. In other words, we should make these decisions based on the empirical
characteristics that matter most to us for those decisions. However, if we are to incorpo-
rate values into our decisions, there are further issues to consider.
First, it is important to account for individual differences in values. For example, in
the case of organ procurement, a survey conducted by Nair-​Collins and colleagues in
2013 showed that most believe that the brain death criteria (e.g., coma and apnea) jus-
tify organ procurement, regardless of what they signify about death (Nair-​Collins et al.
2015). However, approximately 30% of participants in the survey believed that the cur-
rent diagnostic criteria for brain death do not justify organ procurement. This group may
place a higher value on the certainty of a patient’s death when procuring organs, and
thus may favor more stringent criteria for organ procurement. Yet others might favor less
stringent criteria, feeling that coma alone justifies organ procurement, regardless of apnea
or the absence of brainstem reflexes. This view was exemplified in the case of a young
girl named Jaiden, who became comatose after a strangulation accident (Sanghavi 2009;
Truog 2015). Her parents wished to donate her organs, but because she maintained a few
brainstem reflexes, she could not be considered brain dead. As a result, her organs could
not be properly procured, a source of significant distress for Jaiden’s parents who felt that
donating her organs would lend an element of meaning to an otherwise tragic situation.
Many others share the view of Jaiden’s parents, that coma may justify organ procure-
ment (Halevy & Brody 1993; Veatch 1993). Bioethicist and brain-​injury survivor, William
Winslade, has written that:
Merely the organic functioning of our bodies doesn’t constitute being human. Being persons
requires having a personality, being aware of our selves and our surroundings, and possessing
human capacities, such as memory, emotions, and the ability to communicate and interact with
other people … [I]‌n the case [of] … the permanently unconscious, we are no longer human beings;
hence society no longer has a moral responsibility to sustain our lives. A physician who orders a
stop to artificial feeding and hydration in such a case ends a life, but only an organic life. He or she
doesn’t commit murder. (Winslade 1998, p.121)

Thus, whether based on values of autonomy, nonmaleficence, or personhood, many feel

that coma alone (along with the permission of the patient or surrogate) may justify organ
procurement. Ultimately, these examples illustrate the range in values that might apply to
organ procurement.
The same variation in values likely pertains to other decisions that hinge on a patient’s
consciousness. As described, there are reasons to believe that interactive capacity reflects
commonly held values about what “matters” for decisions about consciousness. However,
this criterion will likely not match everyone’s values. Some might place greater value on
 31

Incorporating values into disorders of consciousness 331

lesser degrees of consciousness—​for example, intact perception of visual stimuli but no

cognitive capacity to interact—​when making decisions. Though we have no way of detect-
ing these lesser forms of consciousness, some may so value these states as to select differ-
ent criteria for their decisions. For example, perhaps this group might only be convinced
that a patient is unconscious if a patient is comatose (i.e., lacks signs of arousal in addi-
tional to lacking signs of awareness). While selecting interactive capacity as a criterion
might risk producing “false negatives” (i.e., may misclassify some conscious but non-​
interactive patients as unconscious), this alternative approach would risk “false positives”
(i.e., may misclassify unconscious patients as conscious). Determining which of these
consequences is more troubling, and therefore which criterion to choose, will depend
upon one’s values.
Beyond variation in values between people, a second consideration is that values may vary
depending on the decision. For example, one might feel that the empirical characteristics
that justify organ procurement are different from those that relieve clinicians of their obliga-
tion to treat; one might like the criteria for the latter to be more stringent (i.e., more certainly
signify death) than for the former. Currently, the diagnostic category of brain death, by
virtue of the assumption that it signifies death, is thought to justify both of these decisions.
However, if we cannot be certain of such assumptions, we can no longer rely on one set of
diagnostic criteria to guide different types of decisions. Thus, there may be added nuance to
how different empirical characteristics are used in the context of different decisions.

Incorporating values into disorders of consciousness

Here, we argue that the distinctions between disorders of consciousness are not discrete,
and thus cannot reliably guide discrete decisions as they currently do. Each disorder of
consciousness has a conceptual definition, which is recognized based on diagnostic cri-
teria. The conceptual distinctions between these disorders correspond to fundamental
divisions—​between life and death, and between consciousness and unconsciousness—​
and thus have significant implications for decisions. However, these conditions cannot be
discretely distinguished, due to a continuum between these conceptual states: the distinc-
tions between life and death, and between consciousness and unconsciousness, are inher-
ently continuous and/​or cannot be empirically recognized. Thus, as the current diagnostic
criteria do not reliably distinguish between these conceptual states (in fact, perhaps no
empirical criteria could), we cannot rely upon these conceptual distinctions to guide deci-
sions as we currently do. If we are to continue making these decisions, we must instead
rely upon what we have left: what we can empirically observe about patients. We argue
that these empirical characteristics should be selected in accordance with our values.
This conclusion contradicts common convictions about how diagnostic criteria for
death and unconsciousness should be defined. Many diagnoses are based on objec-
tive data (e.g., exam findings, laboratory results, or imaging), and given the profound
implications of disorders of consciousness, we have preferred to view these diagnoses in
32  3

332 When bright lines blur

this way. In 2004, Fins and influential neurologist Fred Plum published an article titled
“Neurological diagnosis is more than a state of mind: diagnostic clarity and impaired con-
sciousness” (Fins & Plum 2004), in which they advocate for the objectivity of the diagnos-
tic criteria for disorders of consciousness. As Fins has argued, “Values should not distort
the clinical reality” (Fins 2015, p.253). This stance has virtue; as mentioned, the variability
in values between people will complicate how we think about disorders of consciousness.
However, given that the “clinical reality” is deeply obscured in disorders of consciousness,
values may indeed be necessary when managing these patients in the face of significant
uncertainty. Indeed, other diagnoses that reflect complex and unknown pathophysiology
have similarly incorporated values. For example, the diagnostic criteria for many psy-
chiatric disorders, such as personality disorders, include significantly impaired function;
what constitutes “function,” let alone what it means to be significantly impaired, will often
depend upon an individual’s values.
Yet, perhaps we should not be thinking about disorders of consciousness in terms of
discrete diagnostic categories at all. If we cannot reliably distinguish between the differ-
ent conceptual states—​between life and death, consciousness and unconsciousness—​and
if the empirical characteristics we value to make decisions will vary depending on the
person and decision, then any attempt to standardize these criteria will inevitably conflict
with the values of some. Indeed, the current standardized diagnostic criteria for brain
death have already conflicted with the values of certain religious and cultural groups,
leading some states to accommodate objections to brain death testing (Kimura 1991;
Posner et al. 2007). Thus, perhaps instead of focusing on distinguishing between discrete
diagnoses, we should focus on the range of empirical characteristics we can observe about
patients. From there, clinicians may collaborate with families and surrogates, or ideally
may refer to advance directives specified by the patients themselves, to determine which
empirical characteristics matter most for the decisions to be made. This approach will
certainly add complexity and nuance to our understanding of these disorders, but will
also assure that our decisions are made in an intellectually honest and ethical manner.
Disorders of consciousness represent an enigmatic corner of the medical world, chal-
lenging physicians, scientists, philosophers, and ethicists alike. Unlike most other medical
conditions, these disorders degrade our most fundamental attributes—​those of life and
consciousness. As such, they are as perplexing as they are critical to understand. These
conditions present profound philosophical and scientific challenges, while also devastat-
ing the lives of patients, families, and loved ones. We have a responsibility to ensure that
these patients are offered the most ethical treatment possible, which will require care-
ful consideration of these complex philosophical problems. While we would like to base
our management of these patients on whether they are alive or dead, or conscious or
unconscious, we often cannot make these distinctions. By accepting the limitations in our
knowledge, we can develop a more honest and thoughtful approach to these disorders and
improve the ethical management of these patients.
 3

References 333

Notes
1. Dreaming during rapid eye movement (REM) sleep might appear to violate this relationship, but in
fact REM sleep shares many neuronal characteristics with wakefulness (Steriade et al. 1993).
2. Of note, wholism as applied to life is sometimes called vitalism. However, the term vitalism connotes a
nonmaterial “life force” that enters an organism once whole, a notion largely rejected by the scientific
and medical community.

References
Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death (1968).
A definition of irreversible coma. JAMA, 205(6), 337–​340.
Barnard, C. (1967). A human cardiac transplant: an interim report of a successful operation performed
at Groote Schuur Hospital, Cape Town. South African Medical Journal, 1271–​1274.
Becker, K.J., Baxter, A.B., Cohen, W.A., et al. (2001). Withdrawal of support in intracerebral
hemorrhage may lead to self-​fulfilling prophecies. Neurology, 56(6), 766–​772.
Bernat, J. (2006). Chronic disorders of consciousness. The Lancet, 367(9517), 1181–​1192.
Bernat, J., Culver, C., and Gert, B. (1981). On the definition and criterion of death. Annals of Internal
Medicine, 94(3), 389–​394.
Boly, M., Faymonville, M.E., Schnakers, C., et al. (2008). Perception of pain in the minimally conscious
state with PET activation: an observational study. The Lancet Neurology, 7(11), 1013–​20.
Di, H.B., Yu, S.M., Weng, X.C., et al. (2007). Cerebral response to patient’s own name in the vegetative
and minimally conscious states. Neurology, 68(12), 895–​9.
Ecker, J. (2014). Death in pregnancy—​an American tragedy. The New England Journal of Medicine,
370(10), 889–​891.
Edelman, G.M. (1999). Building a picture of the brain. Annals of the New York Academy of Sciences,
882(2), 68–​89.
Executive Board of the American Academy of Neurology (1989). Position of the American Academy of
Neurology on certain aspects of the care and management of the persistent vegetative state patient.
Neurology, 39, 125–​126.
Faugeras, F., Rohaut, B., Weiss, N., et al. (2011). Probing consciousness with event-​related potentials in
the vegetative state. Neurology, 77(3), 264–​268.
Fins, J.J. (2015). Rights Come to Mind: Brain Injury, Ethics, and the Struggle for Consciousness.
New York: Cambridge University Press.
Fins, J.J. and Plum, F. (2004). Neurological diagnosis is more than a state of mind: diagnostic clarity and
impaired consciousness. Archives of Neurology, 61(9), 1354–​1355.
Fins, J.J., Miller, F.G., Acres, C.A., Bacchetta, M.D., Huzzard, L.L., and Rapkin, B.D. (1999). End-​
of-​life decision-​making in the hospital: current practice and future prospects. Journal of Pain and
Symptom Management, 17(1), 6–​15.
Fischer, D.B. and Truog, R.D. (2013). Conscientious of the conscious: interactive capacity as a threshold
marker for consciousness. AJOB Neuroscience, 4(4), 26–​33.
Fischer, D.B. and Truog, R.D. (2015). What is a reflex? A guide for understanding disorders of
consciousness. Neurology, 85(6), 543–​548.
French, R. (2000). The Turing test: the first 50 years. Trends in Cognitive Sciences, 4(3), 115–​122.
Giacino, J. (2004). The vegetative and minimally conscious states: consensus-​based criteria for
establishing diagnosis and prognosis. NeuroRehabilitation, 19, 293–​298.
34  3

334 When bright lines blur

Giacino, J.T., Ashwal, S., Childs, N., et al. (2002). The minimally conscious state: definition and
diagnostic criteria. Neurology, 58(3), 349–​353.
Gilbert, S.F. and Sarkar, S. (2000). Embracing complexity: organicism for the 21st century.
Developmental Dynamics, 219(1), 1–​9.
Gramm, H.-​J., Meinhold, H., Bickel, U., et al. (1992). Acute endocrine failure after brain death?
Transplantation, 54(5), 851–​857.
Grigg, M.M., Kelly, M.A., Celesia, G.G., Ghobrial, M.W., and Ross, E.R. (1987).
Electroencephalographic activity after brain death. Archives of Neurology, 44(9), 948–​954.
Halevy, A. and Brody, B. (1993). Brain death: reconciling definitions, criteria, and tests. Annals of
Internal Medicine, 119(6), 519–​525.
Hopkin, M. (2006). “Vegetative” patient shows signs of conscious thought. Nature, 443(7108), 132–​133.
Jennett, B. and Plum, F. (1972). Persistent vegetative state after brain damage: a syndrome in search of a
name. The Lancet, 299(7753), 734–​737.
Kimura, R. (1991). Japan’s dilemma with the definition of death. Kennedy Institute of Ethics Journal,
1(2), 123–​131.
Lane, A., Westbrook, A., Grady, D., et al. (2004). Maternal brain death: medical, ethical and legal issues.
Intensive Care Medicine, 30, 1484–​1486.
Laureys, S., Owen, A.M., and Schiff, N.D. (2004). Brain function in coma, vegetative state, and related
disorders. Lancet Neurology, 3(9), 537–​546.
Laureys, S., Boly, M., Moonen, G., and Masquet, P. (2009). Two dimensions of consciousness: arousal
and awareness. Encyclopedia of Neuroscience, 2, 1133–​1142.
Laureys, S., Celesia, G.G., Cohadon, F., et al. (2010). Unresponsive wakefulness syndrome: a new name
for the vegetative state or apallic syndrome. BMC Medicine, 8(68), 1–​4.
Lock, M. (2002). Twice Dead: Organ Transplants and the Reinvention of Death (Vol. 1). Berkeley,
CA: University of California Press.
Medical Consultants on the Diagnosis of Death to the President’s Commission for the Study of
Ethical Problems in Medicine and Biomedical and Behavioral Research (1981). Guidelines for the
determination of death: report of the medical consultants on the diagnosis of death to the President’s
Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral
Research. JAMA, 246, 2184–​2186.
Miller, F.G. and Truog, R.D. (2009). The incoherence of determining death by neurological criteria: a
commentary on “Controversies in the determination of death”, a white paper by the President’s
Council on Bioethics. Kennedy Institute of Ethics journal, 19(2), 185–​193.
Monti, M., Vanhaudenhuyse, A., Coleman, M.R., et al. (2010). Willful modulation of brain activity in
disorders of consciousness. New England Journal of Medicine, 362(7), 579–​589.
Nair-​Collins, M., Green, S.R., and Sutin, A.R. (2015). Abandoning the dead donor rule? A national
survey of public views on death and organ donation. Journal of Medical Ethics, 41, 297–​302.
Owen, A., Coleman, M.R., Boly, M., Davis, M.H., Laureys, S., and Pickard, J.D. (2006). Detecting
awareness in the vegetative state. Science, 313, 1402.
Pallis, C. (1983). ABC of brainstem death: the arguments about the EEG. British Medical Journal, 286,
209–​210.
Pennefather, S.H., Dark, J.H., and Bullock, R.E. (1993). Haemodynamic responses to surgery in brain-​
dead organ donors. Anaesthesia, 48(12), 1034–​1038.
Posner, J., Saper, C.B., Schiff, N., and Plum, F. (2007). Plum and Posner’s Diagnosis of Stupor and Coma
(4th edn.). Oxford: Oxford University Press.
Powner, D.J., Ackerman, B.M., and Grenvik, A. (1996). Medical diagnosis of death in adults: historical
contributions to current controversies. The Lancet, 348(9036), 1219–​1223.
 35

References 335

Repertinger, S., Fitzgibbons, W.P., Omojola, M.F., and Brumback, R.A. (2006). Long survival following
bacterial meningitis-​associated brain destruction. Journal of Child Neurology, 21(7), 591–​596.
Report of the Quality Standards Subcommittee of the American Academy of Neurology (1995). Practice
parameters for determining brain death in adults (summary statement). Neurology, 45, 1012–​1014.
Robertson, J.A. (1999). The dead donor rule. Hastings Center Report, 29(6), 6–​14.
Rodin, E., Tahir, S., Austin, D., and Andaya, L. (1985). Brainstem death. Clinical
Electroencephalography, 16(2), 63–​71.
Rubin, E.B. and Bernat, J.L. (2011). Ethical aspects of disordered states of consciousness. Neurologic
Clinics, 29(4), 1055–​71.
Sanghavi, D. (2009). When does death start? The New York Times Magazine, December 16.
Schrader, H., Krogness, K., Aakvaag, A., Sortland, O., and Purvis, K. (1980). Changes of pituitary
hormones in brain death. Acta Neurochirurgica, 52(3–​4), 239–​248.
Searle, J.R. (1992). The Rediscovery of the Mind. Cambridge, MA: MIT Press.
Shah, S.K. and Miller, F.G. (2010). Can we handle the truth? Legal fictions in the determination of
death. American Journal of Law and Medicine, 36(4), 540–​585.
Shah, S.K., Truog, R.D., and Miller, F.G. (2011). Death and legal fictions. Journal of Medical Ethics,
37(12), 719–​22.
Shewmon, D. (1998). Chronic “brain-​death”: meta-​analysis and conceptual consequences. Neurology,
51, 1538–​1545.
Steriade, M., McCormick, D.A., and Sejnowski, T.J. (1993). Thalamocortical oscillations in the sleeping
and aroused brain. Science, 262(5134), 679–​685.
Stins, J.F. (2009). Establishing consciousness in non-​communicative patients: a modern-​day version of
the Turing test. Consciousness and Cognition, 18, 187–​192.
The Multi-​Society Task Force on PVS (1994a). Medical aspects of the persistent vegetative state (1).
New England Journal of Medicine, 330(21), 1499–​1508.
The Multi-​Society Task Force on PVS (1994b). Medical aspects of the persistent vegetative state (2).
New England Journal of Medicine, 330(21), 1572–​1579.
The President’s Council on Bioethics (2008). Controversies in the Determination of Death: A White
Paper by the President’s Council on Bioethics. Washington, DC: The President’s Council on Bioethics.
Truog, R.D. (1997). Is it time to abandon brain death? The Hastings Center Report, 27(1), 29–​37.
Truog, R.D. (2007). Brain death—​too flawed to endure, too ingrained to abandon. Journal of Law,
Medicine and Ethics, 35(2), 273–​281.
Truog, R.D. (2015). Defining death: getting it wrong for all the right reasons. Texas Law Review, 93,
1885–​1914.
US Supreme Court (1893). Nix v. Hedden 149 U.S. 304.
Vanhaudenhuyse, A. et al. (2010). Default network connectivity reflects the level of consciousness in
non-​communicative brain-​damaged patients. Brain, 133, 161–​171.
Veatch, R.M. (1993). The impending collapse of the whole-​brain definition of death. Hastings Center
Report, 23(4), 18–​24.
Wijdicks, E.F.M., Varelas, P.N., Gronseth, G.S., Greer, D.M., American Academy of Neurology.
(2010). Evidence-​based guideline update: determining brain death in adults: report of the Quality
Standards Subcommittee of the American Academy of Neurology. Neurology, 74(23), 1911–​1918.
Winslade, W.J. (1998). Confronting Traumatic Brain Injury: Devastation, Hope and Healing, New Haven,
CT: Yale University Press.
36  3

Chapter 18

Brain death and the definition

of death
James L. Bernat

Introduction
Brain death remains a controversial subject even now, 60 years after the publication of
its original cases. The idea that a person whose brain functions have ceased irreversibly
is dead (despite the continuation of heartbeat, circulation, and visceral organ function
because of respiratory support) is the oldest and most enduring debate in neuroethics.
Notwithstanding its growing acceptance among societies in the developed and develop-
ing world, a trend accompanied by its parallel incorporation into medical practices and
laws, brain death remains inadequately understood by both medical and nursing pro-
fessionals as well as by the general public (Bernat 2006). Within the academy, scholars
continue to debate its conceptual validity (Truog 1997), a dispute amplified by a chorus
of new opponents (Joffe 2010; Nair-​Collins 2015). Yet while opponents cite certain valid
conceptual inadequacies of brain death, their critiques for over four decades have not
gained sufficient traction or public support to change prevailing medical practices or laws
(Bernat 2014a).
In the first part of this chapter, I  trace the history of brain death by explaining the
technological, medical, and societal factors stimulating its origin and acceptance; discuss
its medical, legal, religious, and social recognition; highlight a few of its controversies,;
examine a recent commission report; and discuss two highly publicized cases that have
reignited debates. In the second part, I provide the conceptual basis for brain death by
analyzing the definition and criterion of death. I offer an analytic framework for a biophi-
losophical account of death that justifies the practice of brain death, pinpoints the areas of
contention, and compares competing concepts of death. I conclude with thoughts about
brain death as a contemporary neuroethical issue and predict the future landscape of the
debate over brain death and the definition of death.

Brain death
Prior to the development of the mechanical ventilator and endotracheal intubation,
human death was a unitary phenomenon. When illness or injury led to the cessation of
heartbeat or breathing, brain function necessarily ceased and all organs lost functioning
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Brain death 337

irreversibly. It did not matter which of the three vital functions (heartbeat/​circulation,
lungs/​breathing, and brain) ceased first, their mutual interdependence required that the
others inevitably also ceased within minutes. Physicians declaring death showed that cir-
culation, respiration, and brain functions had ceased by simply examining the patient for
the absence of heartbeat, breathing, responsiveness, and pupillary reactivity to light. Thus,
prior to the 1950s, death always was a unitary phenomenon and its operational definition
was the straightforward cessation of the three vital functions.
With the development of endotracheal intubation, positive-​pressure ventilation, and
cardiopulmonary resuscitation in the 1950s, for the first time, the cessation of heartbeat
and breathing could be reversed or supported. It then became possible for a person
to have sustained brain damage so widespread and severe that all brain functions had
ceased irreversibly. Yet, with technological support of breathing and circulation, the
person could be physiologically maintained for a short time, permitting the continua-
tion of spontaneous heartbeat and systemic circulation to visceral organs though not
to the brain. French neurologists, who offered the first detailed descriptions of such
cases, labeled these patients le coma dépassé to indicate that they were in a state beyond
coma (Mollaret & Goulon 1959).1 Over the next decade, physicians began to assert
that these patients were not merely deeply comatose from profound brain damage: they
were dead.
The life status of these patients was ambiguous in the context of the prevailing unitary
understanding of death because they had lost some vital functions but not others. The
traditional unitary concept of death was not equipped to categorize the life status of such
patients because, prior to technological advances in physiological support, such cases
were impossible. A quick survey of their physical examination findings showed that they
had some characteristics traditionally associated with death but not others. Favoring their
classification as dead, they were utterly unresponsive to any stimuli, had no voluntary
or reflex movement, and did not breathe. Favoring their classification as alive, they had
heartbeat and systemic circulation, with intact visceral organ functioning to digest food
introduced into the stomach and to make urine. Achieving consensus on whether such
patients were alive or dead was impossible because they shared features of both states.
Nor could physicians determine whether they were alive or dead until it was first agreed
what death actually meant in the brave new technological world in which respiratory and
circulatory support was possible after these functions had ceased.
In the 1960s, a growing consensus developed among physicians and scholars that these
patients were, in fact, dead. In 1968, a committee of the Harvard Medical School faculty
proposed the first set of clinical criteria to diagnose the emerging concept that they called
brain death (Ad Hoc Committee 1968).2 Although their pioneering work both established
a new criterion of death and influentially fostered its widespread legal and public accep-
tance, their unfortunate choice of the term brain death promoted misunderstanding and
confusion that has persisted to the present.3 The term brain death now has become uni-
versal; it can be found in medical, scientific, scholarly, and legal contexts, has been trans-
lated into many languages, and has entered the public vernacular.
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338 Brain death and the definition of Death

Factors stimulating the acceptance of brain death

Three factors accelerated the societal acceptance of brain death in the 1960s: technologi-
cal developments in physiological support, the need to lawfully permit withdrawal of
physiological support in hopeless cases, and the demand for donors for organ transplanta-
tion. Although these factors by themselves cannot justify the validity of the equivalence
of brain death and human death, appreciating them offers insight into how the concept of
brain death became accepted so quickly by the medical and legal communities. But not-
withstanding brain death’s obvious instrumental value, its validity as a concept of human
death must stand or fall not on its utilitarian value but on its biophilosophical and scien-
tific coherence.
Life-​support technologies were developed in the 1940s to sustain respiration in patients
with acute poliomyelitis whose respiratory failure was caused by weakness of the respira-
tory muscles. Negative-​pressure ventilators (“iron lungs”) could assist breathing when it
became weak but could not replace breathing in the presence of complete apnea. In the
early 1950s, endotracheal intubation and positive-​pressure mechanical ventilation (tra-
cheal positive-​pressure ventilation (TPPV)) became available, technologies that were suf-
ficient to maintain the lives of patients with complete respiratory failure by fully breathing
for them. Although the intended usage of these technologies was by conscious patients or
those who would later recover consciousness, they were also applied to support patients
with deep coma from profound brain damage, including those with irreversible cessation
of all brain functions. Physicians who examined these “brain dead” patients intuited that
there was something essentially different about them from all comatose patients previ-
ously reported. Several authors asserted that, because of their complete absence of brain
functions, they were dead.
Cardiopulmonary resuscitation (CPR) was first described in 1960, a technique allow-
ing restarting heartbeat in patients during cardiac arrest from ventricular fibrillation or
asystole, all of whom previously would have died. Although the goal of CPR was to restore
circulation to permit complete recovery, some patients were belatedly resuscitated after
the brain already had been destroyed by lack of oxygen and blood flow during the pro-
longed cardiac arrest. Many of the patients with the newly described condition of brain
death acquired it through this mechanism. For them, CPR to restored circulation was not
a successful life-​saving intervention but rather was an ironic and tragic failed application
of medical technology.
In the 1960s when TPPV was initiated to support respiration in a patient who had
stopped breathing, there was no lawful (and, some argued, ethical) means to discontinue
this therapy even when the presence of profound brain damage made the prognosis hope-
less. There was general agreement that if the physician ordered discontinuation of TPPV
and the patient died as a result of tracheal extubation, the physician would be liable for
criminal homicide given the obvious causality of the physician’s act. At that time, no laws
had been enacted or high court cases decided that would legally permit physicians to
take such an action. If, however, such a patient previously had been declared dead on the
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Brain death 339

grounds of brain death, there would be no ethical or legal prohibition to discontinuing

treatment. By the mid 1970s, the first legal rulings had been issued in the United States
that permitted physicians to withdraw mechanical ventilator therapy under certain con-
ditions. Once physicians had a lawful recourse to discontinue supportive therapy in hope-
less cases, declaring brain death no longer had this instrumental benefit.
The role of organ transplantation in the development of brain death remains contro-
versial but most medical historians of this era concluded that it played an important but
often sub rosa role (Belkin 2003). The organ transplantation surgeon, Joseph Murray, pre-
sumably was chosen as a member of the Harvard Medical School Ad Hoc Committee
because of the perceived relevance of organ donation to the new determination of death.
Yet, the Ad Hoc Committee report offered little discussion of organ procurement from
the brain dead donor. Although later, Ad Hoc Committee member and historian, Everett
Mendelsohn, commented that he did not recall much discussion about organ procure-
ment during committee meetings, an analysis of the papers of the committee chairman,
Henry Beecher, reveals considerable concern over this issue (Pernick 1999). Because of
the concern that the utility of organ transplantation might influence death determina-
tion standards, recent committees empaneled to draft uniform guidelines for circulatory
death determination in organ donors purposely restricted any participation or influence
by organ transplantation surgeons to prevent this conflict of interest.4

Societal acceptance of brain death

Legal acceptance
One measure of the degree of societal acceptance of a new idea or practice is the extent to
which it becomes enshrined in public law. The emerging idea that brain death was equiva-
lent to human death quickly became established in law in the United States. In retrospect,
the rapid legalization of this new medical practice appears to have been more the result of
the legal recognition of an advance in medical practice than it was a product of reasoned
debate over its coherence as a biophilosophical concept. Only later did scholars seriously
debate the essential conceptual question of whether and why brain dead patients were
truly dead.
In 1970, Kansas became the first state to statutorily recognize brain death, only 2 years
following publication of the Harvard Medical School Ad Hoc Committee report.5 This
development was followed shortly by the enactment of other state death statutes permit-
ting physicians to use brain death as a determination of death. In 1981, the United States
President’s Commission for the Study of Ethical Problems in Medicine and Biomedical
and Behavioral Research published their inaugural report Defining Death in which they
provided a philosophical and physiological rationale for the new concept of brain death
and in which they proposed and promoted the Uniform Determination of Death Act
(UDDA) as a model statute of death that incorporated brain death. Working with the
United States National Council of Commissioners on Uniform State Laws, the President’s
Commission urged all states to adopt the UDDA as their statute of death. Since then,
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340 Brain death and the definition of Death

nearly all states have adopted the UDDA or a close variant of it. The statute is drafted so
simply and clearly that all attempted legal challenges to brain death statutes in the United
States have failed (Burkle et al. 2011). The UDDA provides:
An individual who has sustained either (1)  irreversible cessation of circulatory and respiratory
functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem,
is dead. A determination of death must be made in accordance with accepted medical standards.
(President’s Commission 1981)

Although in its concise text, the UDDA does not clarify the relationship between the
circulatory–​respiratory and brain criteria, the discussion in Defining Death implies that
the brain criterion is the fundamental criterion of death. In model death statutes pro-
posed by other countries, most notably Canada, the brain criterion is offered within the
statute as the fundamental criterion of death but one that may be tested by physicians at
the bedside in two different ways: by showing the prolonged cessation of circulation and
respiration in patients who are not on ventilators or who will receive CPR, and by show-
ing the irreversible cessation of brain functions in patients who are maintained on ventila-
tors (Law Reform Commission of Canada 1981).6
A few studies have examined the extent of international acceptance of brain death. In
a 2002 survey study by Wijdicks, 80 countries reported medical practices or laws permit-
ting brain death determination (Wijdicks 2002). In a more comprehensive study of 91
countries in 2015, Wahlster and colleagues found that brain death practices were preva-
lent worldwide but with a great variability among testing guidelines and laws (Wahlster
et al. 2015). They found that 70% of countries had established legal provisions for brain
death declaration and that the most powerful predictor of the presence of a lawful proto-
col was a functioning organ donation network. A smaller survey of developed countries
also reported a high rate of brain death acceptance (Gardiner et al. 2012). Thus, despite
academic debates during the past several decades over the conceptual and scientific valid-
ity of equating brain death with human death, during this same time, more countries in
the developed and developing world have permitted or promoted brain death practices.
Thaddeus Pope (2014) comprehensively summarized the current state-​by-​state legal sta-
tus of brain death in the United States.

Religious acceptance
A second measure of social acceptance is the extent to which a new practice is consistent
with prevailing religious traditions. Whether death determination using a brain criterion
was consistent with the tenets, teachings, and beliefs of the world’s principal religions
has been a documented concern since the first writings on brain death. In early influen-
tial articles, Veith and colleagues asserted that brain death practice was compatible with
the world’s major religious beliefs (Veith et al. 1977a, 1977b). Although their claim was
based on a selective reading of religious opinion, since then, their generalization has been
shown to be mostly true although the actual situation is more complex.
There has been relatively little debate over brain death within Christianity. In
Protestantism, brain death acceptance is essentially universal, even among fundamentalist
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Brain death 341

sects (Campbell 1999). In Roman Catholicism, acceptance is official but not univer-
sal. Four Vatican Pontifical Councils and Academies charged with studying this issue,
beginning in the 1980s, concluded that brain death was consistent with Roman Catholic
beliefs and teachings (Furton 2002). The Roman Catholic Church Magisterium first took
an official position in 2000, when, in an address to the International Congress of the
Transplantation Society in Rome, Pope John Paul II formally endorsed brain death as
fully consistent with Roman Catholic teachings (Pope John Paul 2000). In response to
questions within the Vatican hierarchy after the death of Pope John Paul, the Pontifical
Academy of Sciences later reaffirmed this position (Pontifical Academy 2007).7
Judaism lacks Roman Catholicism’s top-​down ecclesiastical hierarchy that dictates rul-
ings on religious law; instead it relies on learned rabbis and other Talmudic scholars to
interpret contemporary questions in light of ancient Jewish law and teachings. Given the
opportunity for disagreement intrinsic to this method of interpretation, it is not surpris-
ing that a rabbinic debate over brain death persists. In general, Reform and Conservative
Jews accept brain death but the debate over it continues to rage within Orthodox Judaism.
One group of Orthodox Jewish scholars holds that brain death is consistent with Jewish
tradition, citing the writings of Maimonides and Talmudic passages emphasizing the
equivalence of breathing (arising from the brainstem) with life. Opponents counter that
Talmudists correlated the loss of breathing with the loss of heartbeat and therefore brain
dead patients with intact heartbeat remain alive.8
The acceptance of brain death within Islam remains partial and dependent on local
Islamic rulings. Following a fatwah approving brain death determination, the Ullamah
Council in Saudi Arabia confirmed the practice of brain death and permitted it in the
kingdom of Saudi Arabia (Yaqub & Al-​Deeb 1996). Yet brain death is not permitted
in several other Islamic societies. The religious basis and varying interpretations of the
acceptability of brain death and the laws governing it among various Islamic countries
have been reviewed recently (Padela et al. 2013; Miller et al. 2014).
Other religious traditions also have addressed brain death. Hindu acceptance of brain
death was the topic of conferences held in Bombay and Madras. In 1993, the Indian leg-
islature enacted the Transplantation of Human Organs Act that contains provisions for
determining brain death (Jain & Maheshawari 1995). In Japan, traditional Shinto and
Buddhist concepts of death requiring cessation of heartbeat and breathing have collided
with technological attempts to Westernize Japanese medicine including the introduction
of brain death and organ transplantation (Lock 1995). Scholarly works, medical and sci-
entific society advocacy, and public debates over the past two decades have led Japanese
society to gradually accept the practices of brain death and deceased donor organ pro-
curement (Lock 2002) but this practice was first supported explicitly in Japanese law only
in 2009 (Aita 2009).
One area in which the prerogatives of religion, law, and public policy overlap is in
the enactment of state laws incorporating religious exemptions for declaring brain
death. In 1991, New Jersey became the first American jurisdiction to enact an exemp-
tion from brain death determination when family members of a patient could show
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342 Brain death and the definition of Death

that its declaration violated the religious beliefs of the patient (Olick 1991). New York
initially provided administrative regulations accomplishing the same goal that later
became a statutory exemption. Since then, California and Illinois have enacted simi-
lar religious exemptions. New York’s and California’s religious exemption admonishes
physicians also to make reasonable efforts to accommodate moral objections to brain
death. In these states, when the allowable circumstances are verified, physicians can
declare death only by using circulatory–​respiratory tests. Given the prevailing varia-
tion in state laws, an important public policy question remains over the extent of the
elasticity of death statutes to accommodate personal religious and moral preferences
before they become incoherent or unmanageable (Brock 1999; Miles 1999; Fry-​Revere
et al. 2010).

Professional and public acceptance

A third indicator of societal approval of brain death is the extent to which the general
public and professionals accept it. Medical professional societies have uniformly accepted
brain death since the first guidelines of the Harvard Ad Hoc Committee were published
in 1968 (Wijdicks 2011). Medical expert groups continue to refine and publish evidence-​
based testing guidelines that have been accepted for adults (Wijdicks et al. 2010) and for
infants and children (Nakagawa et al. 2011). In fact, the debates raging about brain death
are largely restricted to the academy and generally are absent from medical practice where
it has been uniformly accepted. Disagreements about brain death among practicing phy-
sicians usually involve only the technical issues of clinical and ancillary testing (Bernat
2013c).
One exception to this rule is the contention made by a few physicians and scholars
that brain death represents a “legal fiction” to permit organ donation (Taylor 1997; Shah
and Miller 2010). A legal fiction is a societal rule that compromises biological reality to
accomplish a social good. Legal blindness is a good example. Many countries provide
people with severe visual impairment the same social benefits as is given to those who
are completely blind under the rubric “legal blindness” despite acknowledging that they
are not truly blind. Scholars making this analogy claim that we all know that brain dead
patients are not really dead but society creates the legal fiction of brain death to allow
them to be declared dead for the societal benefits of organ donation.
Despite the strong endorsement of the practice of brain death from medical societies
around the world, one generally accepted conclusion that has resulted from a number of
surveys is a persistently broad level of misunderstanding and confusion over the meaning
of brain death by both medical professionals (Joffe et al. 2011) and the public (Siminoff
et al. 2004). This problem has been stubbornly immune to decades of professional educa-
tional interventions by the American Academy of Neurology and other groups.
Misunderstanding of brain death by laymen is even more widespread and has been
chronically exacerbated by popular press accounts that describe and explain it inaccu-
rately and misleadingly. Analyses of popular press accounts of brain death cases reveal
the use of contradictory words like “life support” to describe ongoing treatment and
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Brain death 343

commenting that the brain dead person “died” once the ventilator was disconnected
(Racine et al. 2008; Daoust & Racine 2014).
The depth of lay and professional understanding of brain death varies widely (Bernat
2014a). The most rudimentary and common level is intuitive. Many people find it logical
that patients whose brain functions have totally and irreversibly ceased occupy a qualita-
tively different state than those who continue to possess brain functions because the brain
is the master organ and the seat of consciousness and human behavior. This superficial,
intuitive level constitutes a sufficient degree of understanding to allow many people to
accept brain death even though their concept remains only vague and inchoate.
Medical acceptance constitutes a higher level of understanding. Physicians and others
with scientific sophistication may accept brain death because of their greater understand-
ing of the role of the brain in the functioning of the human organism. They may regard
the absence of consciousness, cognition, breathing, circulatory control, and centrally con-
trolled homeostasis as equivalent to death because the remaining bodily functions in a
brain dead patient are only those supported by mechanical devices. They may consider
such patients suitable for organ donation and “as good as dead” even if they remain unde-
cided over whether they are biologically dead.
The most profound level of understanding requires justifying the equivalence of brain
death and human death as a result of a rigorous biophilosophical analysis. This level may
be achieved by conducting an analysis that studies the concept of the human organism
and the meaning of death in our technological era in which organs and organ subsys-
tems, particularly circulation and respiration, can be maintained in modern intensive care
units. This understanding requires appreciating the distinction between the life status of
the human organism and of its component parts. In the next section of the chapter on the
definition and criterion of death, I discuss the biophilosophical justification of the equiva-
lence of brain death and human death and offer my response to criticisms.
Within the practice of death determination, brain death is not unique in generating mis-
understanding or controversy. There remains a raging debate over the exact moment of
death when physicians apply the circulatory–​respiratory criterion. This controversy cen-
ters on whether death occurs once circulatory and respiratory functions have ceased irre-
versibly (i.e., they cannot return) or when these functions have ceased permanently (i.e.,
they will not return) as discussed in the second part of this chapter (Bernat 2010a, 2013a).
A recent survey of medical and nursing professionals yielded the surprising finding that
those surveyed felt greater confidence in the accuracy of a brain death determination
than in the accuracy of a circulatory–​respiratory death determination (Rodriguez-​Arias
et al. 2013).
Several high-​profile councils have weighed in on the brain death debate. The most
recent effort, in 2008, by the United States President’s Council on Bioethics yielded a white
paper entitled Controversies in the Determination of Death. Their work was stimulated by
their earlier unpublished study of ethical questions in organ transplantation. The Council
heard testimony from brain death opponents who explained why they believed that the
concept was invalid. Despite acknowledging the shortcoming of relying on the loss of
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344 Brain death and the definition of Death

integration of bodily subsystems as the conceptual grounds for accepting the equivalency
of brain death as human death, the Council “concluded that the neurological standard
remains valid” (President’s Council 2008, p.x).
Two tragic and highly publicized cases of brain death in the United States refocused
public attention in 2014–​2015 and led to controversy. The teenager Jahi McMath was
diagnosed as brain dead following complications after throat surgery but her mother
refused to accept the diagnosis and insisted upon continued treatment even following a
second opinion that agreed with the finding (Magnus et al. 2014). The pregnant Marlise
Muñoz was diagnosed as brain dead but the Texas hospital in which she was admitted
insisted on continuing ventilator treatment against the wishes of her family by claiming
that regulations in the Texas Health and Safety Code mandated treatment in pregnant
women for the welfare of the fetus (Ecker 2014). These cases stimulated much controversy
(and confusion) about the definition, conceptual validity, religious relevance, and legality
of brain death (Gostin 2014). Much of the reporting of these cases by the popular press
compounded the controversy by publishing often incorrect and misleading descriptions
of the medical condition, treatment, and prognosis of both women (Bernat 2014a).9
Even within communities with laws and religions accepting brain death, family mem-
bers of brain dead patients sometimes reject the diagnosis and insist that their loved one
is not really dead and therefore requires continued treatment (Lewis et al. 2016). This was
the tragic situation with McMath even before her mother cited her religious opposition
to brain death. This poignant situation creates a dilemma for physicians caring for such
patients and which requires compassionate and clear communication (Olick et al. 2009).
It is essential for physicians to carefully explain the medical and legal rationale for brain
death, to emphasize its hopelessness, and to clearly distinguish it from coma and other
potentially reversible brain states.
Nevertheless, some families insist on continued treatment, hoping for improvement.
Physicians managing such cases should use their judgment to decide whether or for how
long to acquiesce to this request. Second consultations may be helpful as well as frequent,
empathetic counseling sessions. Valid religious exemption claims should be accommo-
dated to the extent consistent with maintaining good medical practice (Spike & Greenlaw
1995; Orr & Genesen 1997). If the principal barrier to acceptance is emotional, assistance
from chaplains, nurses, social workers, or the hospital bioethics committee may be ben-
eficial (Bernat 2008a). After reviewing several instructive cases, Flamm and colleagues
provided guidelines for physicians to compassionately handle such difficult situations
(Flamm et al. 2014).

The definition and criterion of death

The debate over whether brain death is equivalent to human death centers on the mean-
ing of death in a technological era in which organ subsystems other than the brain can be
restored and maintained after they have failed from illness or injury. Scholars advocating
the equivalence of brain death and human death believe that once the brain is destroyed,
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The definition and criterion of death 345

the artificial maintenance of respiration and circulation allows portions of the body to
remain alive but that the human organism (“as a whole”) is dead. Those scholars who
advocate that the brain dead person remains alive counter that the brain enjoys no special
status over other organs in a determination of death and that death as a biological phe-
nomenon requires that all organ function must cease as a result of absence of circulation
(Shewmon 2010). Defining what it means to be dead in our technological era, therefore,
is a prerequisite for settling the brain death–​human death equivalency argument and
accepting or rejecting the biological foundation of brain death.
During the early era of brain death acceptance, scholars began to offer systematic
analyses of death to show that brain death people were dead. These brain death defense
arguments ultimately progressed to a definition of death argument. In this section, I offer
analytic approaches to the definition and criterion of death and discuss critiques of the
conceptual basis of brain death.

A biophilosophical analysis of death

The analyses of death by Capron and Kass (1972) and Bernat et al. (1981) asserted that
physicians cannot develop and validate tests for death until biologically sophisticated
philosophers settle the conceptual definitional question of what death is. In an influen-
tial legal-​philosophical analysis targeted at developing a model statute of death, Capron
and Kass (1972) proposed four sequential levels for an analytic framework:  definition,
standard, criterion, and test. In a similar vein, Bernat et al. (1981) chose preconditions,
definition, criterion, and test as the essential conceptual categories. Each analysis recog-
nized that the definitional question of what do we mean when we say “death” had to be
agreed upon before criteria or tests to determine death could be formulated. Each of these
biophilosophical frameworks had the virtue of logically progressing from the theoretical/​
conceptual to the tangible/​measureable and thereby created an analytic landscape permit-
ting areas of disagreement to be pinpointed.10

The paradigm of death

The first analytic stage is to determine the preconditions of the argument or “paradigm” of
death: that set of assumptions that frame the analysis by clarifying its goals and boundar-
ies and stipulating the nature of what is being analyzed. Agreement on preconditions is
a prerequisite for further discussion. Many of the disagreements among scholars results
from their opposition to accepting one or more of the seven conditions that comprise the
death paradigm (Bernat 2013b):
1. “Death” is a nontechnical word that we use correctly in ordinary conversation to refer
to the cessation of the life of a previously living human being. The goal in an analy-
sis should be to make explicit the implicit meaning of “death” that we all accept in
our spoken and written usage but that has been made ambiguous by advances in life-​
support technology. The goal should not be to redefine “death” by contriving a new
and different sense than its consensual meaning. In this effort, “death” should not be
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346 Brain death and the definition of Death

overanalyzed to such a metaphysical depth that it is rendered devoid of its ordinary

meaning.
2. Death is a biological phenomenon. We all agree that life is a biological phenomenon;
thus its cessation also is fundamentally biological. Death therefore is an immutable,
objective, and inevitable biological fact and is not a social contrivance. An appropriate
biophilosophical analysis of the definition and criterion of death therefore solely con-
siders the ontology of death and not its normative aspects.
3. We restrict the analysis to the death of higher vertebrate species for whom death is
univocal. That is, we refer to the same phenomenon of “death” when we say our cousin
died as we do when we say our dog died. There is no biological justification for defining
death idiosyncratically only for humans. Of course, lower species, unicellular organ-
isms, and organ, tissue, and cellular component parts of organisms also can die but
those phenomena are not our focus here.
4. The term “death” should be applied directly and categorically only to organisms. All
living organisms must die and only living organisms can die. When we say “a person
died,” we refer to the death of the living organism that embodied the person, and do
not make the claim that their organism continues to live but no longer has the attri-
butes of personhood. Personhood is a psychological, religious, moral, and legal con-
cept that arguably may be lost in some cases of severe brain damage but that cannot
die except metaphorically, such as when the word is used in the expression “death of a
culture.”
5. A higher organism can reside in only one of two states, alive or dead: no organism
can be in both states simultaneously or in neither state. But because we lack the
technology to always correctly determine an organism’s life state at any given time,
we may only know with confidence in retrospect that death has occurred. Viewed
as sets in a Venn diagram, the only two possible states of an organism—​alive and
dead—​are mutually exclusive (nonoverlapping) and jointly exhaustive (no inter-
vening or other states).
6. Death is most accurately conceptualized as an event and not as a process. Because
there are only two mutually exclusive underlying states of an organism—​alive and
dead—​the transition from one state to the other, at least in theory, must be sudden
and discontinuous because there is no intervening state (Shewmon & Shewmon
2004). However, because of technical limitations, the event of death that marks
the transition from one state to the other may be determinable with confidence
only in retrospect. Death is conceptualized most accurately as the event separat-
ing the biological process of dying and the process of bodily disintegration (Bernat
et al. 1981).
7. Death is irreversible. All plausible concepts of death require its irreversibility. If the
event of death were reversible it would not be death but rather incipient dying that was
interrupted and reversed.
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The definition and criterion of death 347

Critiques of the paradigm of death

Most scholars concur that the goal of an analysis of death is to make explicit its consensual
meaning and not to contrive a new meaning and most analyses strive to accomplish that
goal. One analysis that does not is the “higher brain formulation” of death, advocated by
several scholars (Youngner & Bartlett 1983; Gervais 1986; Veatch 1993)  which defines
death as the loss of the uniquely human attributes of consciousness and cognition. This
formulation leads to diagnosing as dead patients in a vegetative state who breathe sponta-
neously and have spontaneous eye and limb movements. Rather than making explicit the
consensual meaning of death, this approach contrives a new definition because no society
on earth regards such people as dead or allows breathing people to be buried. This effort
also fails to respect the biological univocality of death across related species by creating a
unique standard applicable only to Homo sapiens. Such a formulation erects boundaries
where none exists in biology.
Some scholars reject the claim that death is primarily a biological phenomenon and
instead assert that death is a socially determined phenomenon that varies among cultures
(Veatch 1999). This claim seems to confound the ontological and normative issues sur-
round death. Obviously there are innumerable rich traditions within cultures and reli-
gions encompassing behaviors surrounding death and dying. But the full respect of these
traditions does not extend to the ontological question of when someone is dead. The nor-
mative aspects of death, including the subject of personal identity and morality, have been
thoroughly reviewed (DeGrazia 2011). Some scholars who champion this idea have made
the additional libertarian claim that respect for personal liberties should encompass the
rights of patients to be declared dead according to their personal beliefs about when one
is dead (Veatch 1999). As a public policy applied to clinical practice, however, it is hard to
imagine how this idea could be feasible.
A more substantive disagreement centers on whether a unitary concept of death for a
human being is possible or whether there must be two types of death: death of a human
organism and death of a person. Jeff McMahan (1995, 2002) argues that because human
beings are our persons and not simply our organisms, what counts most in a concept of
death is the death of the person. He advocates the creation of separate, dual accounts
of death for persons and for their embodied human organisms, and acknowledges that
this dichotomy represents a form of Cartesian mind–​body dualism. John Lizza (1999,
2005) has made a similar argument.
McMahan and Lizza reached their dualistic conclusions because their concept of person
is more expansive than merely one of a human organism endowed with certain attributes,
such as the concept of person and personhood that Gert, Culver, and I endorse (Bernat
et al. 1981). McMahan’s and Lizza’s idea of a person incorporates a soul or a spiritual ele-
ment that exists separately but in parallel with the bodily organism and therefore requires
a dual account of death.11
Lee and George (2008) and Shewmon (2010) have further developed the concept that
a person has both “animal and mental” components (“body–​self dualism”), and assert
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348 Brain death and the definition of Death

that the mental component cannot be produced merely from the animal component.
Shewmon (2010) elucidated this concept more explicitly: “Reflective self-​awareness, uni-
versal concept formation, abstract reasoning, and free will all have properties that tran-
scend spatiality and cannot in principle emerge from a complex electrochemical network.
They therefore derive from an immaterial principle, but nevertheless, one profoundly
oriented to operate in and through a body.” These scholars therefore deny the “reductive”
claim accepted by most cognitive neuroscientists that the mind is solely the product of the
brain without the necessity of an animating spiritual element (Pinker 1997; Koch 2012).
For our paradigm, Gert, Culver, and I require that human beings are only our human
organisms, that self-​awareness and other human behaviors are solely emergent functions
of the brain that do not derive from an immaterial principle, and therefore, human death
is the death of the human organism. This approach is consistent with three other elements
of the paradigm: (1) death is fundamentally a biological phenomenon; (2) only organisms
can die; and (3) the biologically univocal usage of the word death requires that it mean
the same thing for humans as for other higher animals such as dogs unimbued with souls.
We regard personhood as a set of psychosocial, legal, moral, and religious attributes of
human beings that arguably may be lost by severe brain injury or illness but cannot die
except metaphorically. In his monograph, Eric Olson (1997) more rigorously defends the
position that human beings are our organisms.
Linda Emanuel (1995) relies too heavily on metaphysics with her claim “there is no state
of death … to say ‘she is dead’ is meaningless because ‘she’ is not compatible with ‘dead.’ ”
The depth of Emanuel’s metaphysical abstraction of death cannot identify a definition or
criterion because it offers nothing to clarify the common usage of the term death. And
as an experienced physician, she obviously does not truly believe that there is no state
of death.
Amir Halevy and Baruch Brody (1993) claim that defining death is impossible because
an organism can reside in a transitional state between life and death that possesses fea-
tures of both states but is congruent with neither state. Using the mathematical model
of fuzzy logic, they postulate that whereas no organism can fully belong to both the sets
of living and dead organisms, because the sets represent mutually exclusive states, some
organisms can reside in a transitional state in which they have some features of each state
but do not fully belong to either the set of living or dead organisms.
Our argument against this position emphasizes the distinction between the ontology of
the life-​state of an organism and our ability to accurately determine that state. Because,
as a consequence of technical limitations, we may not be able to conclusively determine
at all times whether a given organism is alive or dead does not mean that it must reside
in a transitional state between alive and dead. The paradigm provides that all organisms
are either dead or alive, but, because of these technical limitations, we may not be able to
make the accurate determination of its life-​state in real time but only in retrospect. Future
technological advances will improve the accuracy and timeliness of this determination.
In their mathematical analysis of state discontinuities, Alan and Elisabeth Shewmon
(2004) settled the longstanding debate over whether death is best understood as an
 349

The definition and criterion of death 349

event or as a process.12 The Shewmons showed that death must be an event because
of the suddenness and discontinuity of the transition from the states of alive to dead,
given the absence of an intervening state. They agreed that we may not always be able
to identify the precise time of the event, and we may be able to identify it only in
retrospect because of technical limitations. Everyone agrees that the biological phe-
nomena of dying before death and of bodily disintegration after death are processes.
Most scholars, including the Shewmons, now agree with us that death is best viewed
as the event separating the process of dying from the process of bodily disintegration
(Bernat et al. 1981).
The neurologist-​philosopher Winston Chiong rejected the idea that death must be
defined before analyzing criteria to measure it (Chiong 2005, 2014). He cited Wittgenstein’s
argument that some common terms, such as games, cannot have uniform definitions that
are based on the possession of an essential meaning shared by all members of the set
because all members of the set in question do not share an essential characteristic. Rather
than communally sharing an essential characteristic, members of the set are related to
each other in various other ways. Chiong claims that death is such a word. He argues that
searching for the essence of the meaning of the word death from which to establish its
definition is futile because there are no conditions that are both necessary and sufficient
for death. He further maintained that defining death is an unnecessary step to provide
a coherent argument supporting the whole-​brain criterion of death. He concluded that
our paradigm–​definition–​criterion–​test sequential analytic method therefore should be
rejected.
My late colleague, Bernard Gert, refuted Chiong’s criticism, arguing that Chiong mis-
understood the correct meaning of a definition by accepting a discredited essentialist
concept of a definition (Gert 2006). The effort to choose a definition of death is not to
make explicit the implicit essence of the concept of death but rather to make explicit the
meaning implicit in our consensual and ordinary use of the nontechnical word death.
Gert further pointed out that, given this proper intent of definition, Chiong, perhaps
unknowingly, also relied on a definition of death—​though one more diffuse than ours—​
in his defense of the whole-​brain criterion of death. Therefore, Chiong’s argument reject-
ing definition constituted an invalid criticism of our paradigm–​definition–​criterion–​test
method of analysis that requires starting with what is ordinarily meant by the term death
before choosing its criterion.13
A number of commentators have reported cases of “near-​death” experiences to sup-
port their claim that death is not irreversible because, as their experience shows, some
people can return from being dead. The physiological explanation of these personal
narratives is the presence of acute encephalopathies that occur during critical illness
from marked disturbances in brain metabolism (Parnia & Fenwick 2002). Patients with
“near-​death” experiences were rescued from death while incipiently dying but were not
dead and therefore did not return from the dead. Despite the poignancy and sincerity
of these subjective accounts (Alexander 2012), they do not negate the axiom that death
is irreversible.
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350 Brain death and the definition of Death

The definition of death

The goal of divining the definition of death is to make explicit the meaning of death that is
implicit in the way we use the word death in our everyday conversation but that has been
obscured by technological advances of physiological organ support. Several putative defi-
nitions are unacceptable. The most conservative definition that requires the cessation of
all cellular functioning is unnecessarily conservative because some cells can be kept alive
in tissue culture and entire organs can be transplanted into other people allowing these
cells to continue living long after a person has died. Some religious people regard death
as the moment during dying at which the soul departs from the body. This definition of
death is unacceptable because, as it constitutes a religious belief, is not shared universally.
But more importantly, this definition does not represent the ordinary meaning of the
word death implicit in our consensual usage of the term. Finally, it cannot yield a measur-
able criterion.
One plausible and intuitively acceptable definition of death is the irreversible cessation
of all organ functions, usually as a consequence of the irreversible cessation of systemic
circulation. The irreversible cessation of systemic circulation is an established criterion
of death, featured in death statutes such as the UDDA as discussed previously. No one
questions whether the irreversible cessation of all organ functions is sufficient for death;
the essential question is whether it is necessary. Scholars supporting a definition focusing
on the organism’s unity and the interrelatedness of its component parts conclude that the
irreversible cessation of all organ functions is unnecessary for death therefore this defini-
tion is unnecessarily conservative.
Brain-​based approaches to the definition of death center on the concepts of the loss of
the interrelatedness of the component parts of the organism and the loss of wholeness
and coherent unity of the organism. They emphasize the critical distinction between the
continued life of parts of the organism as a consequence of technological support and the
continued life of the organism itself. It addresses the relationship between the whole and
its parts and their ontological meaning.14 The definition encompassing these ideas that
has enjoyed the greatest staying power is that death is the cessation of functioning of the
organism as a whole.
The organism as a whole, as first proposed a century ago by the biologist Jacques Loeb
(1916), is not congruent with the whole organism, that is, the sum of the parts of the
organism. Rather, the organism as a whole refers to those functions that are greater than
the sum of the parts of organism, that reflect its unity and wholeness, and that serve the
continued life and health of the organism, even at the expense of some of its parts. These
features now are referred to as the emergent functions of the organism.
Emergent functions are characteristics of a whole that cannot be reduced or localized
to any of its component parts but emerge spontaneously when the parts operate in their
normal ensemble (Mahner & Bunge 1997, pp.29–​30). Emergent functions are hierarchi-
cal. Tissues have emergent functions not reducible to their constituent cells and organs
have emergent functions not reducible to their constituent tissues. In the context of the
definition of death, the emergent functions of the organism are those that comprise its
 351

The definition and criterion of death 351

unity and wholeness. Biological theorists have shown that an organism’s emergent func-
tions are complex phenomena that are difficult to model or predict merely by studying its
isolated parts (Clayton & Kauffman 2006).
Bonelli and colleagues offered a conceptual analysis of the role of the cessation of the
organism as a whole in death (Bonelli et al. 2009). They stated that all life forms possess an
intrinsic unity characterized by four criteria: (1) dynamics, or signs of life, such as metabo-
lism, regeneration, growth, and propagation; (2) integration, the requirement that the life
process derives from the mutual interaction of its component parts; (3) coordination, the
requirement that the interaction of the component parts is maintained within a certain
order; and (4) immanency, the requirement that the preceding characteristics originate
from and are intrinsic to the life form. They identified four criteria that make a life form
an integrated, unified, whole organism: (1) completion, the requirement that an organism
is not a component part of another living entity but is itself an intrinsically independent
and completed whole; (2) indivisibility, the condition of intrinsic unity that no organism
can be divided into more than one living organism; and, if such a division occurs and
the organism survives, the completed organism must reside in one of the divided parts;
(3) self-​reference or auto-​finality, the characteristic that the observable life processes and
functions of the component parts serve the self-​preservation of the whole, even at the
expense of the survival of its parts, because the health and survival of the living whole
is the primary end in itself; and (4) identity, the circumstance that, despite incremental
changes in form and the loss or gain of certain component parts (that even could eventu-
ally result in the exchange of all component atoms), the living being remains one and the
same throughout life (Bonelli et al. 2009). My Dartmouth colleague, Andrew Huang, and
I currently are critiquing and expanding upon Bonelli and colleagues’ formulation.

The criterion of death

The criterion of death must satisfy the definition of death as the cessation of functioning
of the organism as a whole by being both necessary and sufficient for death. The principal
scholarly disagreement over the criterion of death is between those who hold that the
functions of the organism as a whole are operated solely by the brain and those who hold
that these functions are operated jointly by the brain and other body parts. Scholars who
hold the first position consider irreversible cessation of brain function as a criterion of
death whereas scholars who hold the second position require the irreversible cessation of
function of all organs, a condition that can be satisfied only by the irreversible cessation
of circulation and respiration.
Some of the numerous functions of the organism as a whole are more critical than
others for the organism’s life and health. The exact set of functions whose loss is both
necessary and sufficient for death remains a topic of debate. Nearly all scholars agree that
conscious awareness is an ineffable, emergent function of higher animals that counts as
a critical function of the organism as a whole. Similarly, the systems controlling circula-
tion, respiration, fluid–​electrolyte balance, movement, and temperature regulation count
as critical functions because the organism’s health and life depend on them. Most of the
352  3

352 Brain death and the definition of Death

critical functions of the organism as a whole can be classified as control and executive
functions.
Advocates of “brain death” hold that because most of the critical functions of the organ-
ism as a whole are executed by the brain, irreversible cessation of brain functions elimi-
nates these critical functions and is death (Korein 1978, 1997). Bonelli and colleagues
stated this position most rigorously, arguing that with irreversible cessation of clinical
brain functions (“brain death”), the organism has lost (1)  immanency, because its life
processes no longer arise from itself but result from external intensive care support;
(2)  auto-​finality, because whatever control over the component organ subsystem parts
that remains now is directed at the level of the surviving parts and no longer at the whole;
(3) self-​reference, because the continued functioning of its parts no longer supports to
the function of the whole; and (4) completeness and indivisibility, because its separate
component parts and subsystems no longer belong to each other and no longer constitute
a whole. Once an organism has irreversibly lost its totality, completion, indivisibility, self-​
reference, and identity, it no longer functions as a whole and is dead (Bonelli et al. 2009).
Brain criterion advocates disagree to some extent on the question of exactly which ele-
ments of the brain’s functioning must cease to be sufficient for death. Higher-​brain crite-
rion advocates require the cessation only of the functions of the cerebral hemispheres and
thalami because those structures underlie conscious awareness and the cognitive func-
tions that are the unique characteristics of the human being and whose cessation is death
(Veatch 1975; Gervais 1986). The higher-​brain criterion remains popular in the academy
but has not been accepted by any medical society or jurisdiction in the world. The fail-
ure of its acceptance despite decades of argument is because, rather than trying to make
explicit the implicit definition of death that has been obscured by technology, the higher-​
brain criterion is a radical redefinition of death. The evidence for this conclusion is that
applying it wrongly labels many patients in coma or vegetative states as dead, despite the
fact that they are considered as alive by societies throughout the world.
Brainstem formulation advocates require only the cessation of functions of the brain-
stem, arguing that the brainstem controls respiration, circulation, and consciousness, and
serves as a through-​station for nearly all hemispheric input and output. Further, the clini-
cal tests determining “brain death” examine mostly for brainstem functions (Pallis 1995).
But by not requiring the absence of hemispheric functioning, it permits the unlikely but
possible case of false-​positive death determination if awareness were retained despite the
loss of other brainstem functions. The brainstem criterion and the whole-​brain criterion
have similar sets of bedside tests but it has been accepted as a criterion of death only by
the United Kingdom and a few other countries.
The prevailing whole-​brain criterion of death has been accepted in nearly all juris-
dictions except those that accept the brainstem criterion. The whole-​brain criterion
acknowledges that the hemispheres, thalami, hypothalami, and brainstem all contribute
to the critical functions of the organism as a whole, hence the clinical functions con-
trolled by each of these parts of the brain must be abolished for death. But, despite its
categorical name, the whole-​brain criterion does not require the cessation of all brain
 35

The definition and criterion of death 353

neurons, only a critical number and array (currently unknown) that conduct the clini-
cal functions of the brain underlying the critical functions of the organism as a whole
(Bernat 1998, 2002).
An assessment of the physiological state of the “brain dead” patient shows the contrast
between the technologically maintained and continued life of many component parts of
the organism despite the death of the human organism itself. “Brain death” advocates do
not deny that much of the human organism remains alive because of technological sup-
port, but assert that the body on the ventilator has died because of irreversible cessation
of the clinical brain functions serving the organism as a whole.
Scholars who reject any brain criterion embrace the circulation–​respiration criterion.
Alan Shewmon, the intellectual leader of this group, accepts the definition of death as the
cessation of function of the organism as a whole (Shewmon 2010). However, he rejects
any brain criterion because he argues that many functions of the organism as a whole are
operated by the spinal cord and other organs and tissues outside the brain (Shewmon
2001, 2004). Further, he cites cases of “chronic brain death” in whom people declared
brain dead have been treated with circulatory and respiratory support of ventilators and
other therapies to allow their visceral organs to be perfused and oxygenated successfully
for months (Shewmon 1998) or, in one remarkable case, for 16 years (Repertinger et al.
2006). He argues that it is simply counterintuitive to the concept of death that people could
have circulation and visceral organ function maintained for long periods, go through
puberty, or gestate fetuses during this treatment, as have been reported. Shewmon and
other advocates of the circulatory–​respiratory criterion claim that the definition of death
therefore is not fulfilled in typical brain death, and instead, death requires the irrevers-
ible cessation of circulation of oxygenated blood to all organs (Shewmon 2001, 2009).
Brain death advocates counter that the definition of death is fulfilled in “brain death” and
that the criterion of irreversible cessation of circulation and respiration, while sufficient
for death, is not necessary. In a paper in preparation, my colleague Andrew Huang and
I rebut Shewmon’s claim.

The circulatory criterion of death

The alternative to the whole-​brain criterion of death is the circulatory–​respiratory crite-
rion of death, often shortened to the circulatory criterion. Cessation of systemic circula-
tion was the traditional criterion of death prior to the 1950s when technology rendered
death no longer a unitary phenomenon. It remains a valid criterion of death in the over-
whelming number of cases in which cardiopulmonary resuscitation will not be attempted
(or had been attempted and failed) and in which mechanical ventilation will not be per-
formed. Cessation of systemic circulation also causes cessation of brain circulation that
leads to fulfillment of the brain criterion of death. If circulation ceases by cardiac arrest
or respiration ceases by respiratory arrest and medical intervention is omitted, the mutual
interdependence of vital functions leads immediately to their complete cessation. Thus,
the traditional unitary concept of death remains valid in cases in which no resuscitative
intervention takes place.
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354 Brain death and the definition of Death

Although everyone agrees that the irreversible cessation of systemic circulation is suf-
ficient for death, the current controversy over the circulatory criterion surrounds the
question of how long physicians must wait to declare death once circulation (and respira-
tion) have ceased. In cases of circulatory–​respiratory death determination in which organ
donation is not being performed, this question is usually inconsequential. Physicians
examine the patient, determine the absence of breathing, heartbeat, responsiveness, and
pupillary light reflexes, and simply declare death at that moment. There is no need to
hurry and physicians usually conduct a leisurely examination without concern about tim-
ing. Death is declared at the completion of the examination.
In cases in which the patient is an organ donor, however, circulatory–​respiratory death
determination is an entirely different situation. Here, death determination must be per-
formed as rapidly as possible to minimize warm ischemic damage to the organs to be
transplanted. Conducting a timely death determination in the organ transplantation
donor raises a knotty question:  what is the shortest time interval after circulation and
respiration have ceased after which physicians can declare death? This seemingly straight-
forward question has led to considerable controversy and, although a few guidelines have
emerged, remains unresolved.
Many hospitals around the world have established programs of organ donation after
the circulatory determination of death (DCDD), known formerly as nonbeating organ
donation or donation after cardiac death (Bernat et al. 2006). In “controlled” DCDD as
practiced in the United States and Canada, in which the donor is usually a patient with
profound brain damage on a ventilator in an intensive care unit, family members or other
lawful surrogates order withdrawal of life-​sustaining therapy (the mechanical ventilator) to
allow the patient to die and also consent for organ donation after death has been declared,
presumably representing the wishes of the patient. Once respiration and circulation stop
following endotracheal extubation, after a mandatory observation period to guarantee
that breathing and circulation will not restart spontaneously (“auto-​resuscitation”), the
patient is declared dead and rushed to the surgical suite for organ donation. An analogous
program of “uncontrolled” DCDD is practiced in some European countries, in which the
often previously healthy donor suffers a sudden cardiac arrest, undergoes CPR but cannot
be resuscitated, and is declared dead prior to organ donation (Munjal et al. 2013).
In death declaration of the controlled DCDD donor, the essential question centers on
how long respiration and circulation must be absent before death can be declared. This
interval varies from 2 minutes in the pioneering DCDD protocol at the University of
Pittsburgh Medical Center (DeVita & Snyder 1993), to 5 minutes as recommended by the
US Institute of Medicine (2000) which has been instituted by most US hospitals, to up to
20 minutes in some European countries. The principal requirement is that the duration
chosen must exceed the interval in which auto-​resuscitation can occur to be sure that cir-
culation cessation is permanent. This empirical question was addressed in a study of pub-
lished reports of auto-​resuscitation after circulatory cessation (Hornby et al. 2010). The
investigators found no cases at all of auto-​resuscitation to restored circulation after with-
drawal of mechanical ventilator therapy in the intensive care unit (a situation analogous
 35

The definition and criterion of death 355

to controlled DCDD) but many cases of auto-​resuscitation to restored circulation for up

to 7 minutes after CPR was stopped when it failed to restore heartbeat (a situation analo-
gous to uncontrolled DCDD). Therefore, the problem of auto-​resuscitation represents a
greater concern in uncontrolled than in controlled DCDD (Bernat 2010b).
Even if commentators were to agree on the auto-​resuscitation issue, however, there
remains disagreement over whether the controlled DCDD donor is even dead at the
moment of death declaration in most DCDD protocols. Critics claim that at 2–​5 minutes
after circulatory cessation, there remains the possibility that CPR could succeed in restor-
ing heartbeat and circulation—​even though it will not be performed because of a preex-
isting do-​not-​resuscitate (DNR) order—​and that this potential circulatory reversibility
proves that the donor was not dead at the moment death was declared because it is not
manifestly irreversible (Miller and Truog 2008; Marquis 2010). Analyzing this criticism
requires making two related distinctions: (1) between the biological concept of death and
the medical standards for death determination, and (2) between the irreversible cessation
of circulatory and respiratory functions and the permanent cessation of those functions
(Bernat 2010a).15
Irreversible cessation of a function means that, once stopped, it cannot be restored using
available technology. Permanent cessation of a function means that it will not be restored
because, once stopped, because it will neither restart spontaneously (auto-​resuscitate) nor
will physicians attempt to restart it because of a DNR order. The prospective DCDD organ
donor on whom death is declared after 5 minutes of ceased circulation and breathing, and
for whom resuscitative effort will not be attempted because of a DNR order, has achieved
permanent but not yet necessarily irreversible cessation of circulation and respiration
(Bernat 2010a). But is the DCDD donor dead at that moment?
The medical practice of death determination using the circulatory criterion has tradi-
tionally followed the permanent cessation standard. When a physician declares a patient
dead who has lost heartbeat, circulation, and respiration, the physician requires only the
permanent cessation of those vital functions. In the setting of a DNR order, no attempt
is made to resuscitate and there is no requirement for physicians to prove that the cessa-
tion is irreversible because permanent cessation is sufficient. For example, patients who
are expected to die of an untreatable terminal disease who then stop breathing and lose
heartbeat are immediately declared dead after a brief examination. There is no require-
ment for physicians declaring death to first prove that the patient’s cessation of circula-
tion and respiration is irreversible or to postpone declaring death for a sufficient time to
assure that it is irreversible. In non-​donation instances of circulatory death determina-
tion in whom CPR will not be performed, the medical consultants to the United States
President’s Commission, in Defining Death (1981, p.162), required “persistent cessation
of functions during an appropriate period of observation” that is equivalent to the perma-
nent cessation concept.
However, because all plausible biological concepts of death require that it is an irre-
versible state, there exists noncongruence between the biological concept of death
requiring irreversible cessation of the circulatory–​respiratory functions and the medical
356  3

356 Brain death and the definition of Death

determination of death requiring only the permanent cessation of those functions. Thus,
the answer to the question of whether the DCDD donor is dead at the moment death is
ordinarily declared in DCDD protocols is “yes” by the medical standard of permanent
cessation but “no” by the biological standard that requires irreversibility. The permanence
standard to determining death has been accepted implicitly in all controlled DCDD pro-
tocols, explicitly by one medical society (American Academy of Pediatrics 2013), and
was recommended by an expert panel advising DCDD programs on standardizing policy
for circulatory death determination in organ donors (Bernat et al. 2010, 2014). Further
scholarly and public policy debate among organ donation stakeholders should clarify if
the clinical standard of permanent cessation of circulation and respiration also should
pertain to death determination in the setting of organ donation (Bernat 2013a).

Future directions
The futures of brain death and the definition of death remain intertwined. The societal
consensus accepting brain death as human death, although described by one critic as
“superficial and fragile” (Youngner 1992), has endured for nearly half a century. One
knowledgeable commentator accurately summarized the state of brain death in the devel-
oped world as “well settled but still unresolved” (Capron 2001). It has been settled to the
extent that societies have enacted more or less uniform laws permitting physicians to use
brain death as a determination of death. But it remains unresolved to the extent that its
opponents validly identify weaknesses in its rationale causing them to reject it and requir-
ing a stronger conceptual defense. As an advocate of brain death, I believe that its most
coherent biophilosophical justification is that the definition of death should be based on
the cessation of functioning of the organism as a whole. But more work needs to be done
to fill in conceptual gaps in the present foundation—​particularly in the criteria of the
organism as a whole—​that are necessary to more rigorously establish this rationale. My
Dartmouth colleague, Andrew Huang, and I are presently constructing such an argument.
In any analysis of the definition of death or the determination of brain or circulatory
death, it is essential to separate the social desirability and instrumental value of organ
donation (Citerio et al. 2016) from conceptual and policy questions about death determi-
nation. Independent of its utilitarian value, the determination of death must be biologi-
cally accurate and the definition of death must be philosophically plausible and coherent.
Public policies may permit certain agreed upon practical compromises to assure that
medical practices involving organ donation and death determination are workable and
socially acceptable. But these adjustments must be understood by physicians, accepted by
the public, and operationalized into optimal practices of informed consent for the deter-
minations of both brain death and circulatory death, particularly in the context of organ
donation. Current informed consent practices in organ donation appear to be suboptimal
for both brain death (Iltis 2015) and circulatory death (Overby et al. 2015).
It is in this regard that the noncongruence between the medical standards for death
determination and the biological concept of death must be fully appreciated. Medical
 357

Future directions 357

standards permit physicians to declare death at an earlier moment than the biological
concept would otherwise allow. Primarily for social reasons, physicians routinely declare
death when a person’s vital functions have ceased permanently but at a time before these
functions have ceased irreversibly (Bernat 2013a). As public policy, it is desirable for our
society to rely on accepted medical standards for death determination in both organ
donors and nondonors even though medical standards may not achieve the biologi-
cal standard of death. Stakeholders in organ donation and death determination need to
debate and accept a standard that they conclude is optimal for society. I advocate the per-
manent cessation standard that is implicit in all DCDD protocols and therefore appears
to have achieved widespread acceptance.
An unresolved public policy question remains the extent to which moral or religious
beliefs and personal preferences should influence the medical standards that physicians
will apply in one’s own death determination. This issue has arisen most frequently in
the context of brain death but also could be raised in circulatory death determination
for organ donors. The tension present here is between respect for personal liberties
and the authority of medical practices and societal laws. As is true in most such con-
troversies, differing opinions about the location of the equilibrium point of this ten-
sion result from individual differences in political philosophies, for example, between
communitarianism and libertarianism. A successful public policy needs to identify an
equilibrium point that adequately provides individual liberty rights but does not lead
to social chaos.
Most people intuit the desirability of having uniform standards of brain and circulatory
death determination—​whatever they may be—​across countries and societies (Choi et al.
2008). Yet, variability in medical practices remains the norm, even in the United States
where expert guidelines on brain death determination have been in effect for over two
decades (Greer et al. 2016). To some extent, this variability results from physicians who
remain unaware of or who refuse to comply with national standards and from hospitals
not enforcing them (Bernat 2008b). Achieving international standardization will be even
more difficult because it must accommodate varying societal mores, religious beliefs, and
medical practice variations (Wahlster et al. 2015). A few medical societies and the World
Health Organization are currently working to try to develop such uniform standards but
it presents a formidable undertaking.
Given the survey data documenting a stubbornly persistent and widespread level of
ignorance about brain death (Siminoff et al. 2004), most people agree that there is a need
to improve public and professional education on concepts and practices of death deter-
mination. Medical professionals need to increase their sophistication about the definition
of death and their knowledge of the concept and determination of brain death. Among
other goals, greater sophistication and knowledge will clarify the true level of support for
the concept of brain death in the medical community that has been hard to assess accu-
rately with current surveys. Better public education should include journalists who write
articles on brain death in the popular press that educate (or mislead) the public and mold
public opinion.
358  3

358 Brain death and the definition of Death

Finally, there remain gaps in the scientific understanding of incipient dying and death
which, once filled, can inform the development of medical standards for death deter-
mination. For example, we know relatively little about the natural history and precise
time course of how cessation of systemic circulation leads to hypoxic-​ischemic neuronal
damage and brain death, particularly, at what moment all brain functions cease and the
point when brain death occurs. Although preliminary observational studies have made
an important contribution to understanding this common phenomenon (Munshi et al.
2015), more such studies need to be conducted.

Notes
1. In their landmark 1959 article from the Claude Bernard Hospital in Paris, Mollaret and Goulon
reported 23 cases of patients with utter coma, apnea, EEG electrocerebral silence, and total brain
necrosis at autopsy (Mollaret & Goulon 1959). They coined the term le coma dépassé (which Prof.
Goluon translated into English as “irreversible or irretrievable coma”) to describe their unprecedented
deep state of coma with no cognitive or vegetative functions (Wijdicks 2011). The article included
the clinical, electroencephalographic, and pathological features of what later would be called “brain
death.” Mollaret and Goulon also discussed ethical and philosophical issues including the boundaries
between life and death and the ethical duty of physicians to continue to support patients in that hope-
less state. Because of the comprehensiveness of their description and discussion, Mollaret and Goulon
are generally credited with describing the first cases of brain death although Lofstedt and von Reis had
done so briefly 3 years earlier (Diringer & Wijdicks 2001).
2. The report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of
Brain Death, misleadingly subtitled “A definition of irreversible coma,” first made the medical and legal
communities and the general public aware of the use of the absence of brain functions to determine
human death. Harvard anesthesiologist and research ethicist, Henry K. Beecher, chaired the commit-
tee. Other members included neurologists Raymond D. Adams, Derek Denny-​Brown, and Robert
Schwab; neurosurgeon William Sweet; transplant surgeon Joseph Murray; law professor William
Curran; historian of medicine Everett Mendelsohn; and five others (Wijdicks 2003). The purpose of the
Committee’s report was “to define irreversible coma as a new criterion of death” (Ad Hoc Committee
1968). The Ad Hoc Committee proposed the first examination criteria to certify brain death. These
tests have withstood the test of time and have not been altered significantly in the 49 years since they
were proposed. The four cardinal characteristics of the brain dead patient are: (1) unreceptiveness and
unresponsiveness; (2) no movements or breathing; (3) no reflexes, especially cranial nerve innervated
reflexes; and (4) flat EEG. The tests needed to be repeated after 24 hours to insure irreversibility. They
incorrectly predicted that if the medical community embraced this concept, no change in the law on
death statutes would be required. They correctly asserted that considering the permanent cessation of
all brain functions as death was implicit in the traditional concept of death.
3. The Harvard Medical School Ad Hoc Committee popularized the term “brain death.” This was an
unfortunate choice of terms because it misleadingly implied that only the brain was dead and that
there were two types of death: brain death and ordinary death. The misleading term “brain death”
has contributed to both public and professional persisting misunderstanding (Molinari 1982).
Committee member Murray anticipated this problem and wrote a memo to committee chairman
Beecher in which he pleaded: “The term ‘brain death’ should be eliminated. Death is what we are
talking about, and adding the adjective ‘brain’ implies some restriction on the term as if it were an
incomplete type of death…our charge is to define death…” (Giacomini 1997). But Beecher chose to
retain the term “brain death.”
 359

Future directions 359

4. When the Health Resources & Services Administration Division of Transplantation of the United
States Department of Health and Human Services empaneled an expert committee to determine
standards for the circulatory determination of death in DCDD organ donors, it explicitly and firmly
barred all membership to and influence from organ transplantation surgeons although these sur-
geons could have contributed useful technical information to the process. See Bernat et al. (2010) and
Bernat et al. (2014).
5. That Kansas became the first state in the United States to amend its death statute to incorporate brain
death has been attributed to the outsize influence of a Kansas neurosurgeon who was friendly with
state legislators and used his powers of personal persuasion to push through the bill (Kennedy 1971).
6. Ironically, Canadian provincial governments chose to ignore their federal council recommenda-
tion to adopt the model statute and, despite its clarity, did not incorporate the model statute into
provincial laws.
7. Despite the papal pronouncement, opponents of brain death remain within Roman Catholicism who
continue to assert that it is inconsistent with Roman Catholic, and even Christian, belief systems.
Most persistent in this area over the past 40  years has been Paul Byrne (Byrne et  al. 1979). Yet,
even before the Pope’s pronouncement, it was clear that Byrne’s opinion was marginalized within
Roman Catholic circles. The conservative Roman Catholic bioethics institute, the National Catholic
Bioethics Center (formerly called the Pope John Center), held that Byrne was incorrect and that
brain death was fully consistent with the teachings of Roman Catholicism (Furton 1999). Following
Pope John Paul’s endorsement of brain death in 2000, the Center predicted that the papal pronounce-
ment should quell the disagreement by Byrne and other critics on Roman Catholic religious grounds
(Furton 2002; Haas 2011).
8. The Orthodox rabbi-​scientist Moshe Tendler argues that brain death is compatible with Halacha
(historical-​traditional Jewish law) because it is the physiological equivalent of decapitation. In the
twelfth century, Maimonides asserted that a decapitated person was immediately dead and that tran-
sient muscle twitches observed in the decapitated body were not signs of life. Tendler and the phy-
sician-​talmudist Fred Rosner cite the Talmudic tract, discussed by Rashi, in which it is stated that
breathing, not heartbeat, is the primary sign of life. Therefore, brain death is human death according
to Jewish law (Rosner & Tendler 1989; Rosner 1999). But Orthodox rabbis and Talmudic scholars
David Bleich (1989) and Ahron Soloveichik (1979) reached the opposite conclusion. In emphasizing
the distinction between a sign of death and death itself, they explained that ancient rabbis consid-
ered the cessation of respiration as the cardinal sign of death because it implied a prior cessation of
heartbeat. They concluded that, according to Jewish law, physicians cannot determine death in the
presence of spontaneous heartbeat. Although only the strictest Orthodox sects consistently embrace
this position, it remains the official position in Israel though changes to the Brain Death Act in 2012
permitted brain death determination in some situations and thereafter, brain dead organ donation
increased substantially (Cohen et al. 2012). For learned commentaries on this continuing religious
dispute, see Halachic Organ Donor Society (https://​www.hods.org/​).
9. The follow-​up stories of McMath and Muñoz are instructive. As of February 2017, McMath appar-
ently remains supported on a ventilator somewhere in New Jersey as her mother and her attorneys
try to convince a California judge to reverse her death declaration citing affidavits submitted by
physicians who have examined her stating she is not dead (Winkfield v. Rosen 2015). It is difficult to
objectively know her true condition because, other than these affidavits, her current medical find-
ings are not accessible in the public record. In the Muñoz case, in response to a lawsuit filed by her
husband, a Texas judge ruled that she should be removed from the ventilator because the Texas law
requiring continued life-​sustaining therapy to brain-​damaged pregnant women for the benefit of the
fetus did not apply to dead women. Her ventilator treatment was then discontinued.
10. Portions of this section were adapted from Bernat (2013b), Bernat (2014b), and Bernat (in press).
360  3

360 Brain death and the definition of Death

11. See John Lizza’s (2009) anthology of articles relating personhood to death.
12. The classic debate over whether death is a process or an event was conducted in the pages of Science
by Morison (1971) and Kass (1971).
13. Chiong thereafter countered that Gert misunderstood and misrepresented his position. For the latest
chapter on this debate, see the point-​counterpoint in (Bernat 2014b) and Chiong (2014). My col-
league, Andrew Huang, and I respond further to Chiong in our manuscript in preparation.
14. Mereology is the branch of philosophy that analyzes the differences between the properties of a whole
and its parts and explores their ontological relationship. The principles of biological mereology hold
the key to understanding the concept of the organism as a whole. See Hovda (2009).
15. Portions of this section were adapted from Bernat (2014b).

References
Ad Hoc Committee (1968). A definition of irreversible coma. Report of the Ad Hoc Committee of the
Harvard Medical School to Examine the Definition of Brain Death. JAMA, 205, 337–​340.
Aita, K. (2009). Japan approves brain death to increase organ donors: will it work? The Lancet, 374,
1403–​1404.
Alexander, E. (2012). Proof of Heaven: A Neurosurgeon’s Journey into the Afterlife. New York: Simon &
Schuster.
American Academy of Pediatrics Committee on Bioethics (2013). Policy statement: ethical
controversies in organ donation after circulatory death. Pediatrics, 131, 1021–​1026.
Belkin, G.S. (2003). Brain death and the historical understanding of bioethics. Journal of the History of
Medicine and Allied Sciences, 58, 325–​361.
Bernat, J.L. (1998). A defense of the whole-​brain concept of death. Hastings Center Report, 28(2), 14–​23.
Bernat, J.L. (2002). The biophilosophical basis of whole-​brain death. Social Philosophy & Policy, 19,
324–​342.
Bernat, J.L. (2006). The whole-​brain concept of death remains optimum public policy. Journal of Law,
Medicine and Ethics, 34, 35–​43.
Bernat, J.L. (2008a). Ethical Issues in Neurology (3rd edn.). Philadelphia, PA: Lippincott Williams &
Wilkins.
Bernat, J.L. (2008b). How can we achieve uniformity in brain death determinations? Neurology, 70,
252–​253.
Bernat, J.L. (2010a). How the distinction between “irreversible” and “permanent” illuminates
circulatory-​respiratory death determination. Journal of Medicine and Philosophy, 35(3), 242–​255.
Bernat, J.L. (2010b). How autoresuscitation impacts death determination in organ donors. Critical Care
Medicine, 38, 1377–​1378.
Bernat, J.L. (2013a). On noncongruence between the concept and determination of death. Hastings
Center Report, 43(6), 25–​33.
Bernat, J.L. (2013b). The definition of death. In: Bernat, J.L. and Beresford, H.R. (Eds.) Ethical and Legal
Issues in Neurology. Handbook of Clinical Neurology (3rd Series, Volume 118), pp. 419–​435. (Series
Eds. Aminoff, M.J., Boller, F., and Swaab, D.F.). Edinburgh: Elsevier.
Bernat, J.L. (2013c). Controversies in defining and determining death in critical care. Nature Reviews
Neurology, 9, 164–​173.
Bernat, J.L. (2014a). Whither brain death? American Journal of Bioethics, 14(8): 3–​8.
 361

References 361

Bernat, J.L. (2014b). There can be agreement as to what constitutes human death. In: Caplan,
A.L. and Arp, R. (Eds.) Contemporary Debates in Bioethics, pp.377–​387, 397–​398. Chichester,
UK: Wiley-​Blackwell.
Bernat, J.L. (in press). Defining death. In: Moreman, C. (Ed.) Routledge Companion to Death and Dying.
London: Taylor & Francis/​Routledge.
Bernat, J.L., Culver, C.M., and Gert, B. (1981). On the definition and criterion of death. Annals of
Internal Medicine, 94, 389–​394.
Bernat, J.L., D’Alessandro, A.M., Port, F.K., et al. (2006). Report of a national conference on donation
after cardiac death. American Journal of Transplantation, 6, 281–​291.
Bernat, J.L., Capron, A.M., Bleck, T.P., et al. (2010). The circulatory-​respiratory determination of death
in organ donation. Critical Care Medicine, 38, 963–​970.
Bernat, J.L., Bleck, T.P., Blosser, S., et al. (2014). Circulatory death determination in uncontrolled organ
donors: a panel viewpoint. Annals of Emergency Medicine, 63, 384–​390.
Bleich, J.D. (1989). Of cerebral, respiratory and cardiac death. Tradition, 24(3), 44–​66.
Bonelli, R.M., Prat, E.H., and Bonelli, J. (2009). Philosophical considerations on brain death and the
concept of the organism as a whole. Psychiatria Danubina, 21, 3–​8.
Brock, D.W. (1999). The role of the public in public policy on the definition of death. In: Youngner, S.J.,
Arnold, R.M., and Schapiro, R. (Eds.) The Definition of Death: Contemporary Controversies, pp.293–​
307. Baltimore, MD: Johns Hopkins University Press.
Burkle, C.M., Schipper, A.M., and Wijdicks, E.F. (2011). Brain death and the courts. Neurology, 76,
837–​841.
Byrne, P.A., O’Reilly, S., and Quay, P.M. (1979). Brain death—​an opposing viewpoint. JAMA, 242,
1985–​1990.
Campbell, C.S. (1999). Fundamentals of life and death: Christian fundamentalism and medical science.
In: Youngner, S.J., Arnold, R.M., and Schapiro, R. (Eds.) The Definition of Death: Contemporary
Controversies, pp.194–​209. Baltimore, MD: John Hopkins University Press.
Capron, A.M. (2001). Brain death—​well settled yet still unresolved. New England Journal of Medicine,
344, 1244–​1246.
Capron, A.M. and Kass, L.R. (1972). A statutory definition of the standards for determining human
death: an appraisal and a proposal. University of Pennsylvania Law Review, 121, 87–​118.
Chiong, W. (2005). Brain death without definitions. Hastings Center Report, 35(6), 20–​30.
Chiong, W. (2014). There cannot be agreement as to what constitutes human death: Against definitions,
necessary and sufficient conditions, and determinate boundaries. In: Caplan, A.L. and Arp, R. (Eds.)
Contemporary Debates in Bioethics, pp.388–​396, 399–​400. Chichester, UK: Wiley Blackwell.
Choi, E.K., Fredland, V., Zachodni, C., Lammers, J.E., Bledsoe, P., and Helft, P.R. (2008). Brain death
revisited: the case for a national standard. Journal of Law, Medicine and Ethics, 36, 824–​836.
Citerio, G., Cypel, M., Dobb, D.J., et al. (2016). Organ donation in adults: a critical care perspective.
Intensive Care Medicine, 42, 305–​315.
Clayton, P. and Kauffman, S.A. (2006). On emergence, agency, and organization. Biology and
Philosophy, 21, 501–​521.
Cohen, J., Ashkenazi, T., Katvan, E., and Singer, P. (2012). Brain death determination in Israel: the
first two years experience following changes to the brain death law—​opportunities and challenges.
American Journal of Transplantation, 12, 2514–​2518.
Daoust, A. and Racine, E. (2014). Depictions of “brain death” in the media: medical and ethical
implications. Journal of Medical Ethics, 40, 253–​259.
DeGrazia, D. (2011). The definition of death. In: Stanford Encyclopedia of Philosophy. Available
from: http://​plato.stanford.edu/​entries/​death-​definition/​ [accessed February 11, 2015].
362  3

362 Brain death and the definition of Death

DeVita, M.A. and Snyder, J.V. (1993). Development of the University of Pittsburgh Medical Center
policy for the care of terminally ill patients who may become organ donors after death following the
removal of life support. Kennedy Institute of Ethics Journal, 3, 131–​143.
Diringer, M.N. and Wijdicks, E.F.M. (2001). Brain death in historical perspective. In: Widjicks, E.F.M.
(Ed.) Brain Death, pp.5–​27. New York: Oxford University Press.
Ecker, J.L. (2014). Death in pregnancy—​an American tragedy. New England Journal of Medicine, 370,
889–​891.
Emanuel, L.L. (1995). Re-​examining death: the asymptotic model and a bounded zone definition.
Hastings Center Report, 25(4), 27–​35.
Flamm, A.L., Smith, M.L., and Mayer, P.A. (2014). Family members’ requests to extend physiologic
support after declaration of brain death: a case series analysis and proposed guidelines for
management. Journal of Clinical Ethics, 25, 222–​237.
Fry-​Revere, S., Reher, T., and Ray, M. (2010). Death: a new legal perspective. Journal of Contemporary
Health Law and Policy, 27(1), 1–​75.
Furton, E.J. (1999). Reflections on the status of brain death. Ethics and Medics, 24(10), 2–​4.
Furton, E.J. (2002). Brain death, the soul, and organic life. National Catholic Bioethics Quarterly, 2,
455–​470.
Gardiner, D., Shemie, S., Manara, A., and Opdam, H. (2012). International perspective on the
diagnosis of death. British Journal of Anesthesia, 108 (S1), i14-​i28.
Gert, B. (2006). Matters of life and death. Hastings Center Report, 36(3), 4.
Gervais, K.G. (1986). Redefining Death. New Haven, CT: Yale University Press.
Giacomini, M. (1997). A change of heart and a change of mind? Technology and the redefinition of
death in 1968. Social Sciences in Medicine, 44, 1465–​1482.
Gostin, L.O. (2014). Legal and ethical responsibilities following brain death: the McMath and Muñoz
cases. JAMA, 311, 903–​904.
Greer, D.M., Wang, H.W., Robinson, J.D., Varelas, P.N., Henderson, G.V., and Wijdicks, E.F.M. (2016).
Variability of brain death policies in the United States. Neurology, 73, 213–​218.
Haas, J.M. (2011). Catholic teaching regarding the legitimacy of neurological criteria for the
determination of death. National Catholic Bioethics Quarterly, 11(2), 279–​299.
Halevy, A. and Brody, B. (1993). Brain death: reconciling definitions, criteria, and tests. Annals of
Internal Medicine, 119, 519–​525.
Hornby, K., Hornby, L., and Shemie, S.D. (2010). A systematic review of autoresuscitation after cardiac
arrest. Critical Care Medicine, 38, 1246–​1253.
Hovda, P. (2009). What is classical mereology? Journal of Philosophical Logic, 38(1), 55–​82.
Iltis, A.S. (2015). Organ donation, brain death and the family: valid informed consent. Journal of Law,
Medicine and Ethics, 43(2), 369–​382.
Institute of Medicine (2000). Non-​Heart-​Beating Organ Transplantation: Practice and Protocols.
Washington, DC: National Academy Press.
Jain, S. and Maheshawari, M.C. (1995). Brain death—​the Indian perspective. In: Machado, C. (Ed.)
Brain Death, pp.261–​263. Amsterdam: Elsevier.
Joffe, A. (2010). Are recent defences of the brain death concept adequate? Bioethics, 24(2), 47–​53.
Joffe, A., Carcillo, J., Anton, N., et al. (2011). Donation after cardiocirculatory death: a call for a
moratorium pending full public disclosure and fully informed consent. Philosophy, Ethics, and
Humanities in Medicine, 6, 17.
Kass, L. (1971). Death as an event: a commentary on Robert Morison. Science. 173. 698–​702.
Kennedy, I.M. (1971). The Kansas statute on death—​an appraisal. New England Journal of Medicine,
285, 946–​950.
 36

References 363

Koch, C. (2012). Consciousness: Confessions of a Romantic Reductionist. Cambridge, MA: MIT Press.

Korein, J. (1978). The problem of brain death: development and history. Annals of the New York
Academy of Sciences, 315, 19–​38.
Korein, J. (1997). Ontogenesis of the brain in the human organism: definitions of life and death of the
human being and person. Advances in Bioethics 2: 1–​74.
Law Reform Commission of Canada (1981). Criteria for the Determination of Death. Ottawa, ON: Law
Reform Commission of Canada.
Lee, P. and George, R.P. (2008). Body–​Self Dualism in Contemporary Ethics and Politics.
New York: Cambridge University Press.
Lewis, A., Varelas, P., and Greer, D. (2016). Prolonging support after brain death: when families ask for
more. Neurocritical Care, 24(3), 481–​487.
Lizza, J.P. (1999). Defining death for persons and human organisms. Theoretical Medicine and Bioethics,
20, 439–​453.
Lizza, J.P. (2005). Potentiality, irreversibility, and death. Journal of Medicine and Philosophy, 30, 45–​64.
Lizza, J.P. (2009). Defining the Beginning and End of Life. Readings on Personal Identity and Bioethics.
Baltimore, MD: Johns Hopkins University Press.
Lock, M. (1995). Contesting the natural in Japan: moral dilemmas and technologies of dying. Culture,
Medicine and Psychiatry, 19, 1–​38.
Lock, M. (2002). Twice Dead: Organ Transplants and the Reinvention of Death. Berkeley, CA: University
of California Press.
Loeb, J. (1916). The Organism as a Whole. New York: GP Putnam’s Sons.
McMahan, J. (1995). The metaphysics of brain death. Bioethics, 9(2), 91–​126.
McMahan, J. (2002). The Ethics of Killing: Problems at the Margins of Life. New York: Oxford
University Press.
Magnus, D.C., Wilfond, B.S., and Caplan, A.L. (2014). Accepting brain death. New England Journal of
Medicine, 370, 891–​894.
Mahner, M. and Bunge, M. (1997). Foundations of Biophilosophy. Berlin: Springer-​Verlag.
Marquis, D. (2010). Are DCD donors dead? Hastings Center Report, 40(3), 24–​31.
Miles, S. (1999). Death in a technological and pluralistic culture. In: Youngner, S.J., Arnold, R.M., and
Schapiro, R. (Eds.) The Definition of Death: Contemporary Controversies, pp.311–​318. Baltimore,
MD: Johns Hopkins University Press.
Miller, A.C., Ziad-​Miller, A., and Elamin, E.M. (2014). Brain death and Islam: the interface of religion,
culture, history, law, and modern medicine. Chest, 146, 1092–​1101.
Miller, F.G. and Truog, R.D. (2008). Rethinking the ethics of vital organ donations. Hastings Center
Report, 38(6), 38–​46.
Molinari, G.F. (1982). Brain death, irreversible coma, and words doctors use. Neurology, 32, 400–​402.
Mollaret, P. and Goulon, M. (1959). Le coma dépassé (mémoire préliminaire). Révue Neurologique,
101, 3–​15.
Morison, R.S. (1971). Death: process or event? Science, 173, 694–​698.
Munjal, K.G., Wall, S.P., Goldfrank, L.R., Gilbert, A., Kaufman, B.J., and Dubler, N.N. (2013). A
rationale in support of uncontrolled donation after circulatory determination of death. Hastings
Center Report, 43(1), 19–​26.
Munshi, L., Dhanini, S., Shemie, S.D., Hornby, L., Gore, G., and Shahin, J. (2015). Predicting time to
death after withdrawal of life-​sustaining therapy. Intensive Care Medicine, 41, 1014–​1028.
Nair-​Collins, M. (2015). Taking science seriously in the debate on death and organ transplantation.
Hastings Center Report, 45(6), 38–​48.
364  3

364 Brain death and the definition of Death

Nakagawa, T.A., Ashwal, S., Mathur, M., et al. (2011). Guidelines for the determination of brain death
in infants and children: an update of the 1987 Task Force recommendations. Critical Care Medicine,
39, 2139–​2155.
Olick, R.S. (1991). Brain death, religious freedom, and public policy: New Jersey’s landmark legislative
initiative. Kennedy Institute of Ethics Journal, 4, 275–​288.
Olick, R.S., Braun, E.A., and Potash, J. (2009). Accommodating religious and moral objections to
neurological death. Journal of Clinical Ethics, 20, 183–​191.
Olson, E.T. (1997). The identity of organisms. In: The Human Animal: Personal Identity Without
Psychology, pp.131–​135. New York: Oxford University Press.
Orr, R.D. and Genesen, L.B. (1997). Requests for inappropriate treatment based on religious beliefs.
Journal of Medical Ethics, 23, 142–​147.
Overby, K.J., Weinstein, M.S., and Fiester, A. (2015). Addressing consent issues in donation after
circulatory determination of death. American Journal of Bioethics, 15(8), 3–​9.
Padela, A.I., Arozullah, A., and Moosa, E. (2013). Brain death in Islamic ethico-​legal
deliberation: challenges for applied Islamic bioethics. Bioethics, 27, 132–​139.
Pallis, C. (1995). ABC of Brainstem Death (2nd edn.). London: British Medical Journal Publishers.
Parnia, S. and Fenwick, P. (2002). Near death experiences in cardiac arrest: visions of a dying brain or
visions of a new science of consciousness. Resuscitation, 52, 9–​11.
Pernick, M.S. (1999). Brain death in a cultural context: the reconstruction of death 1967–​1981.
In: Youngner, S.J., Arnold, R.M., and Schapiro, R. (Eds.) The Definition of Death: Contemporary
Controversies, pp.3–​33. Baltimore, MD: Johns Hopkins University Press.
Pinker, S. (1997). How the Mind Works. New York: W.W. Norton & Co.
Pontifical Academy of Sciences (2007). The Signs of Death. Scripta Varia 110. Vatican City: Pontifical
Academy of Sciences.
Pope John Paul II (2000, August 29). Address of the Holy Father John Paul II to the 18th International
Congress of the Transplantation Society, August 29, Rome. http://​www.vatican.va/​holy_​father/​john_​
paul_​ii/​speeches/​2000/​jul-​sep/​documents/​hf_​jp-​ii_​spe_​20000829_​transplants_​en.html [accessed
June 4, 2012].
Pope, T.M. (2014). Legal briefing: brain death and total brain failure. Journal of Clinical Ethics, 25(3),
245–​257.
President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and
Behavioral Research (1981). Defining Death. Medical, Ethical, and Legal Issues in the Determination
of Death. Washington, DC: US Government Printing Office.
President’s Council on Bioethics (2008). Controversies in the Determination of Death: A White Paper by
the President’s Council on Bioethics. Washington, DC: US Government Printing Office.
Racine, E., Amaram, R., Seidler, M., Karczuska, M., and Illes, J. (2008). Media coverage of the
persistent vegetative state and end-​of-​life decision-​making. Neurology, 71, 1027–​1032.
Repertinger, S., Fitzgibbons, W.P., Omojola, M.F., and Brumback, R.A. (2006). Long survival following
bacterial meningitis-​associated brain destruction. Journal of Child Neurology, 21, 591–​595.
Rodriguez-​Arias, D., Tortosa, J.C., Burant, C.J., Aubert, P., Aulisio, M.P., and Youngner, S.J. (2013).
One or two types of death? Attitudes of health professionals towards brain death and donation after
circulatory death in three countries. Medicine, Health Care and Philosophy, 16, 457–​467.
Rosner, F. (1999). The definition of death in Jewish law. In: Youngner, S.J., Arnold, R.M., and Schapiro,
R. (Eds.) The Definition of Death: Contemporary Controversies, pp.210–​221. Baltimore, MD: Johns
Hopkins University Press.
Rosner, F. and Tendler, M.D. (1989). Definition of death in Judaism. Journal of Halacha and
Contemporary Society, 17, 14–​31.
 365

References 365

Shah, S.K. and Miller, F.G. (2010). Can we handle the truth? Legal fictions in the determination of
death. American Journal of Law & Medicine, 36, 540–​585.
Shewmon, D.A. (1998). Chronic “brain death:” meta-​analysis and conceptual consequences. Neurology,
51, 1538–​1545.
Shewmon, D.A. (2001). The brain and somatic integration: insights into the standard biological
rationale for equating “brain death” with death. Journal of Medicine and Philosophy, 26, 457–​478.
Shewmon, D.A. (2004). The “critical organ” for the organism as a whole: lessons from the lowly spinal
cord. Advances in Experimental Medicine and Biology, 550, 23–​42.
Shewmon, D.A. (2009). Brain death: can it be resuscitated? Hastings Center Report, 39(2), 18–​24.
Shewmon, D.A. (2010). Constructing the death elephant: a synthetic paradigm shift for the definition,
criteria, and tests for death. Journal of Medicine and Philosophy, 35, 256–​298.
Shewmon, D.A. and Shewmon, E.S. (2004). The semiotics of death and its medical implications.
Advances in Experimental Medicine and Biology, 550, 89–​114.
Siminoff, L.A., Burant, C., and Youngner, S.J. (2004). Death and organ procurement: public beliefs and
attitudes. Kennedy Institute for Ethics Journal, 14, 217–​234.
Soloveichik, A. (1979). The Halakhic definition of death. In: Rosner, F. and Bleich, J.D. (Eds.) Jewish
Bioethics, pp.296–​302. New York: Sanhedrin Press.
Spike, J. and Greenlaw, J. (1995). Ethics consultation: persistent brain death and religion: must a person
believe in death to die? Journal of Law, Medicine and Ethics, 23, 291–​294.
Taylor, R.M. (1997). Reexamining the definition and criterion of death. Seminars in Neurology, 17,
265–​270.
Truog, R.D. (1997). Is it time to abandon brain death? Hastings Center Report, 27(1), 29–​37.
Veatch, R.M. (1975). The whole brain-​oriented concept of death: an outmoded philosophical
formulation. Journal of Thanatology, 3, 13–​30.
Veatch, R.M. (1993). The impending collapse of the whole-​brain definition of death. Hastings Center
Report, 23(4), 18–​24.
Veatch, R.M. (1999). The conscience clause: how much individual choice in defining death can
our society tolerate? In: Youngner SJ, Arnold RM and Schapiro R (eds). The Definition of
Death: Contemporary Controversies. Baltimore: Johns Hopkins University Press: 137–​160.
Veith, F.J., Fein, J.M., Tendler, M.D., et al. (1977a). Brain death I. A status report of medical and ethical
considerations. JAMA, 238, 1651–​1655.
Veith, F.J., Fein, J.M., Tendler, M.D., et al. (1977b). Brain death II. A status report of legal
considerations. JAMA, 238, 1744–​1748.
Wahlster, S., Wijdicks, E.F., Patel, P.V., et al. (2015). Brain death declaration: practices and perceptions
worldwide. Neurology, 84, 1870–​1879.
Wijdicks, E.F.M. (2002). Brain death worldwide. Accepted fact but no global consensus in diagnostic
criteria. Neurology, 58, 20–​25.
Wijdicks, E.F.M. (2003). The neurologist and the Harvard criteria for brain death. Neurology, 61,
970–​976.
Wijdicks, E.F.M. (2011). Brain Death (2nd edn.). New York: Oxford University Press.
Wijdicks, E.F., Varelas, P.N., Gronseth, G.S., and Greer, D.M. (2010). American Academy of Neurology.
Evidence-​based guideline update: determining brain death in adults: report of the Quality Standards
Subcommittee of the American Academy of Neurology. Neurology, 74, 1911–​1918.
Winkfield v. Rosen. First Amended Complaint for Damages for Medical Malpractice, Case No. Rg
15760730, Superior Court of the State of California for the County of Alameda, filed November
4, 2015.
36  3

366 Brain death and the definition of Death

Yaqub, B.A. and Al-​Deeb, S.M. (1996). Brain death: current status in Saudi Arabia. Saudi Medical
Journal, 17, 5–​10.
Youngner, S.J. (1992). Defining death: a superficial and fragile consensus. Archives of Neurology, 49,
570–​572.
Youngner, S.J. and Bartlett, E.T. (1983). Human death and high technology: the failure of the whole
brain formulations. Annals of Internal Medicine, 99, 252–​258.
 367

Part III

Social, legal, and regulatory

frameworks: Lessons
of the past guide policy
for the future
368
 369

Chapter 19

Minors and incompetent adults: A tale

of two populations
Vasiliki Rahimzadeh, Karine Sénécal,
Erika Kleiderman, and Bartha M. Knoppers

Introduction
Biomedical research enables improvements in diagnosis and treatment of human dis-
eases, and participation in research is the cornerstone of such medical progress. Indeed,
the scholarly beginnings of the bioethics field are often attributed to human rights ques-
tions concerning the ethics of human participation in research, and which have since
influenced every biomedical field from pediatrics (Diekema 2006) to aging (Kim et al.
2001), and genomics (Knoppers 2013) to neurology (Choudhury et al. 2014). The com-
pletion of the Human Genome Project in 2003 brought about paradigmatic shifts in the
nature and conduct of biomedical research. This shift toward data-​intensive science is evi-
dent in the ways that analysis, exchange, and reporting now occur increasingly in virtual
(e.g., the cloud commons (Stein et al. 2015)) rather than physical spaces.
The participation of humans in research remains nevertheless a central consideration in
bioethics, and an increasingly complex area for policy development as research becomes
more data intensive and data driven. This is particularly true for the participation of cat-
egorically vulnerable populations in biomedical research—​such as minors and incom-
petent adults—​who warrant special protections against potential rights violations and
exposure to undue risk or, to undue exclusion and deprivation of the benefits of research.
In this chapter, we provide both a retrospective and prospective analysis of research
involving these two populations with a special focus on the data-​intensive sciences such
as genomics and its related “omics” disciplines. In doing so, our analysis adopts what we
term “reverse vulnerability” as one lens through which to examine the ethical intersec-
tionalities between both populations in an effort to better complement governance strate-
gies to the contemporary realities of data-​intensive science and data sharing.
The first and second parts of this chapter provide a policy overview of research participa-
tion and the protection of minors and incompetent adults living with dementia. We com-
ment on the practical and theoretical implications of reverse vulnerability to an emerging
area of contemporary policy development: international data sharing. A reinvigorated
370  3

370 Minors and incompetent adults

discussion of research participation involving minors and patients living with dementia
necessarily precedes, in our view, policy-​making for sharing research data.
Historically, the parens patriae doctrine was the first to legitimize the legal status of
vulnerable persons and the State’s obligation to protect them. This legal doctrine stipu-
lates that the government acts as a guardian of all persons legally incapable of acting on
their own, even in the absence of specific legislation (Griffith 1991). Such State powers
are protective of both property and personal interests, and are usually exercised by the
courts. Both children and incompetent adults are legally presumed to be unable to make
decisions concerning their health, welfare, or involvement in research. It was not until the
Nuremberg Code in 1947, and later the Declaration of Helsinki in 1964, that the interests of
minors and incompetent adults were specifically addressed in medical research.
Ethical principles outlined in the Nuremberg Code emphasized protection through
exclusion, while the Declaration endorsed their inclusion albeit with special protections.
Most countries recognize parents or family members as primary decision-​making author-
ities for minors and incompetent adults. Surprisingly, however, neither the 1989 United
Nations (UN) Convention on the Rights of the Child, nor the 2006 UN Convention on
the Rights of Persons with Disabilities (the latter encompassing incompetent adults such
as “those living” with dementia) explicitly addresses their inclusion in research.
From these historically protective stances toward vulnerable populations in research,
international ethics norms evolved to adopt more promotional approaches. The European
Clinical Trials Directive is but one example that testifies to this evolution, which positively
mandates the inclusion of children and incompetent adults in clinical trials in Europe
(European Parliament & the Council of the European Union 2014, s. 32(1)).
Table 19.1 summarizes the Directive, as well as other international ethics guidelines
with specific mention of research involving vulnerable persons.
International ethics guidelines promote the inclusion of incompetent adults in research
as for minors, provided certain special protections. The benefits, either direct or indi-
rect, as a result of their participation justify such inclusion in part, to say nothing of the
fact that certain diseases belong to these groups exclusively. Furthermore, improved stan-
dards of care for conditions earlier or later in life may not otherwise emerge without the
participation of these populations. Data-​intensive research involving vulnerable groups,
we argue, must reconcile protective and promotional stances to make way for realistic
and proportional risk analysis and governance. Only then can we facilitate, rather than
obstruct, a future of open science required to advance (personalized) medicine for minors
and patients living with dementia, among others.

Children and minors
The history of children in biomedical research has been (paradoxically) marked by both
grave human rights abuses as well as groundbreaking clinical progress. Their participation
in research has, in turn, long raised ethical concerns. An era of over-​protectionism ensued
in the wake of research abuses involving children such as those at the Willowbrook State
  371
Table 19.1  International ethics guidelines on the participation of vulnerable persons in medical research

International conven- Participation of legally incompetent persons in research Ethical rationale

tion/​guidelines/​policy
World Medical Article 13: All vulnerable groups should receive specifically Article 20: Medical research with a vulnerable group is only
Association (WMA) considered protection justified if the research is responsive to the health needs or
Declaration of Article 28: For a potential research subject who is incapable of priorities of this group and the research cannot be carried out
Helsinki (2013) giving informed consent, the physician must seek informed con- in a non-​vulnerable group. In addition, this group should stand
Ethical Principles for sent from the legally authorised representative. These individuals to benefit from the knowledge, practices or interventions that
Medical Research must not be included in a research study that has no likelihood result from the research.
Involving Human of benefit for them unless it is intended to promote the health
Subjects of the group represented by the potential subject, the research
cannot instead be performed with persons capable of providing
informed consent, and the research entails only minimal risk and
minimal burden.

Council for Guideline 15: Research involving vulnerable persons Commentary on Guideline 15:
International When vulnerable individuals and groups are considered for … It is important to recognize that vulnerability involves not
Organizations of recruitment in research, researchers and research ethics commit- only the ability to provide initial consent to participate in
Medical Sciences tees must ensure that specific protections are in place to safe- research, but also aspects of the ongoing participation in
(CIOMS) (2016) guard the rights and welfare of these individuals and groups in research studies. In some cases, persons are vulnerable because
International Ethical the conduct of the research. they are relatively (or absolutely) incapable of protecting their
Guidelines for own interests. This may occur when persons have relative
Health-​related or absolute impairments in decisional capacity, education,
Research Involving resources, strength, or other attributes needed to protect their
Humans own interests. In other cases, persons can also be vulnerable
because some feature of the circumstances (temporary or per-
manent) in which they live makes it less likely that others will be
vigilant about, or sensitive to, their interests.

(continued)
 372
Table 19.1  Continued

International conven- Participation of legally incompetent persons in research Ethical rationale

tion/​guidelines/​policy
United Nations Article 7: Persons without the capacity to consent Article 8: Respect for human vulnerability and personal
Declaration In accordance with domestic law, special protection is to integrity
on Bioethics be given to persons who do not have the capacity to con- In applying and advancing scientific knowledge, medical prac-
and Human sent: (a) authorization for research and medical practice should tice and associated technologies, human vulnerability should
Rights (2005) be obtained in accordance with the best interest of the person be taken into account. Individuals and groups of special vulner-
[Articles 7–​8] concerned and in accordance with domestic law. However, the ability should be protected and the personal integrity of such
person concerned should be involved to the greatest extent pos- individuals respected.
sible in the decision-​making process of consent, as well as that
of withdrawing consent; (b) research should only be carried out
for his or her direct health benefit, subject to the authorization
and the protective conditions prescribed by law, and if there is
no research alternative of comparable effectiveness with research
participants able to consent. Research which does not have
potential direct health benefit should only be undertaken by
way of exception, with the utmost restraint, exposing the person
only to a minimal risk and minimal burden and, if the research is
expected to contribute to the health benefit of other persons in
the same category, subject to the conditions prescribed by law
and compatible with the protection of the individual’s human
rights. Refusal of such persons to take part in research should be
respected.
 37

Children and minors 373

School, Staten Island, New York City, between the late 1950s and early 1970s (Diekema
2006). While the motivation for a protectionist approach was well intentioned, such poli-
cies resulted in children’s near exclusion from biomedical research generally. The con-
sequences of which resulted in a dearth of pediatric-​specific therapies (Fernandez et al.
2003), felt even today as standards of care derived from clinical trial findings are often
extrapolated from studies in adults.
Children and adolescents are not miniature adults, but differ both physiologically and
psychologically. Thus, pediatric research is essential to developing treatments that are
safe and effective for children and adolescents, specifically. Advances in pediatric health
research improve the way we understand child and adolescent health, disease, and devel-
opment, and how these are influenced by factors such as genetics and the environment.
Classical tensions related to the involvement of children as vulnerable participants in
research are synthesized in Table 19.2, and include how researchers determine the appro-
priate level of protection, the extent of parental authority and surrogate decision-​making,
and gauge the developing autonomy of minors. Transformative biotechnologies such as
next-​generation sequencing instantiate these classic tensions, but also shape new chal-
lenges around their responsible deployment and applications in the clinic.

Inclusion
Today, the need to include children and adolescents in research is recognized by inter-
national guidelines such as the United Nations Educational, Scientific and Cultural
Organisation (UNESCO) Declaration on the Human Genome and Human Rights pub-
lished in 1997 (s. 5(e)) and 2005 (s. 7), the Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines for Health-​Related Research
Involving Humans (2016, s. 3, 17), and the Council of Europe Convention on Human
Rights and Biomedicine (1997, s. 17(1)(ii)(iii)) and its Additional Protocol (2005, s. 15(1)(i)
(ii)). Indeed, such guidelines generally indicate that vulnerable persons, such as minors,
should be included in research when it is justifiable, when their rights are protected, and
when their safety and well-​being have been considered.
Overall, minors can be involved in pediatric research when the research cannot be car-
ried out on adults (World Medical Association (WMA) 2013, s. 20); parental consent, as
well as the minor’s assent (when possible) has been obtained; and the research involves
minimal risk. There is a stronger justification for their inclusion when direct clinical ben-
efit is anticipated (World Medical Association (WMA) 1964, s. 17; Council of Europe
1997, s. 17(1)(ii)(2), 2005, s. 15(2); UNESCO 1997, s. 5(e), 2005, s. 7(b); CIOMS 2002, s.
8–​9; CIOMS 2016, s. 17). Other guidelines formulate differently their position that “the
interventions and procedures should be studied in adults first [. . .], unless the necessary
data cannot be obtained without participation of children or adolescents; and the risks
must be minimized and no more than minimal.” However, “when the social value of the
studies with such research interventions and procedures is compelling, and these studies
cannot be conducted in adults, a research ethics committee may permit a minor increase
above minimal risk” (CIOMS, 2016, s. 17).
374

Table 19.2  International guidelines for the participation of minors in biomedical research

Guideline Relevant clause

Council for Guideline 17
International Children and adolescents must be included in health-​related research
Organizations of unless a good scientific reason justifies their exclusion. [T]‌heir distinctive
Medical Sciences physiologies and emotional development may also place children and
(CIOMS) (2016) adolescents at increased risk of being harmed in the conduct of research.
International Ethical Moreover, without appropriate support, they may not be able to protect
Guidelines for Health-​ their own interests due to their evolving capacity to give informed
related Research consent. Specific protections to safeguard children’s rights and welfare in
Involving Humans the research are therefore necessary.
◆ Before undertaking research involving children and adolescents, the
researcher and the research ethics committee must ensure:
• A parent or a legally authorized representative of the child or ado-
lescent has given permission; and
• The agreement (assent) of the child or adolescent has been
obtained in keeping with the child’s or adolescent’s capacity,
after having been provided with adequate information about the
research tailored to the child’s or adolescent’s level of maturity.
◆ If children reach the legal age of maturity during the research, their
consent to continued participation should be obtained.
◆ In general, the refusal of a child or adolescent to participate or con-
tinue in the research must be respected, unless, in exceptional circum-
stances, research participation is considered the best medical option
for a child or adolescent.
◆ For research interventions or procedures that have the potential to
benefit children or adolescents, the risks must be minimized and out-
weighed by the prospect of potential individual benefit.
◆ For research interventions or procedures that have no potential indi-
vidual benefits for participants, two conditions apply:
• The interventions and procedures should be studied in adults first,
when these interventions and procedures target conditions that
affect adults as well as children and adolescents, unless the neces-
sary data cannot be obtained without participation of children or
adolescents; and
• The risks must be minimized and no more than minimal.
◆ When the social value of the studies with such research interventions
and procedures is compelling, and these studies cannot be conducted
in adults, a research ethics committee may permit a minor increase
above minimal risk.

United Nations Article 12

Human Rights 1. State Parties shall assure to the child who is capable of forming his
Office of the High or her own views the right to express those views freely in all matters
Commissioner (1989) affecting the child, the views of the child being given due weight in
United Nations accordance with the age and maturity of the child.
Convention on the 2. For this purpose, the child shall in particular be provided the oppor-
Rights of the Child tunity to be heard in any judicial and administrative proceedings
affecting the child, either directly, or through a representative or an
appropriate body, in a manner consistent with the procedural rules of
national law.
 375

Children and minors 375

Consent
As children do not have the legal capacity to consent to their own participation in
research, international norms generally state that parental consent or permission of the
authorized legal representative is required (WMA 2013, s. 28; Council of Europe 1997,
s. 6.2, 17(1)(iv), 2005, s. 15(1)(ii); CIOMS 2016, s. 17; UNESCO 2005, s. 7), and that the
best interests of the child should be considered in this decision (UNESCO 2003, 2005).
They furthermore stipulate what information should appear in the consent form so as
to ensure parental consent is fully informed (e.g., the goal and nature of the research,
the potential risks and benefits, the right to withdraw, the protection of privacy and
confidentiality, the compensation for participation) (Council of Europe 1997, s. 5, 2005,
s. 13(2); UNESCO 2005, s. 6(2)). Some guidelines also set more technical requirements,
such as adapting consent language in line with the capacity of parents (Council of
Europe 2005, s. 13(1); UNESCO 2005, s. 6(2)). Although required, the scope of parental
consent can be controversial in particular research contexts. Longitudinal cohort stud-
ies or pediatric biobanking testify to this, where consent to research participation is a
continuous process that may span a lifetime.
Not only should consent be ongoing throughout the research project, but it should be
renewed if significant changes are made to the research protocol (Council of Europe 2005,
s. 24(2)). In addition, the CIOMS also states that, “if children reach the legal age of matu-
rity during the research, their consent to continued participation should be obtained”
(CIOMS 2016, s. 17). The likelihood requiring reconsent are perhaps greatest for longi-
tudinal studies, where child participants eventually reach the age of majority while still
enrolled in the study. A minor’s capacity to consent can thus evolve over time, and during
the course of the research. As a result, this may necessitate the re-​contact of minors once
they reach the age of majority, or once they become legally capable of deciding for them-
selves (Knoppers et al. 2016).

Assent of the child
In addition to parental or legal representative consent, applicable norms and policies
surrounding the involvement of children in research consider the emerging maturity
of a child, even if children do not have the legal capacity to consent. The 1998 inter-
national Convention on the Rights of the Child recognizes a child’s right to be heard in
decision-​making despite their inability to consent. Specifically, “[a]‌child who is capable
of forming his or her own views [has] the right to express those views freely in all matters
affecting the child, the views of the child being given due weight in accordance with the
age and maturity of the child” (United Nations General Assembly 1989, s. 12(1)). Thus,
it is equally important for the researcher to obtain the assent of a child who has the
capacity to participate at this level prior to inclusion in research (WMA 2013, s. 28–​29;
Council of Europe 1997, s. 6(2), 2005, s. 15(1)(iv); CIOMS 2016, s. 17, 2008, s. 13–​14;
UNESCO 2003, s. 8(b)(c), 2005, s. 7(a)). Since 1964, the WMA has adopted this posi-
tion in the Declaration of Helsinki (2013, s. 29), as well as the CIOMS (2016, s. 17),
376

376 Minors and incompetent adults

the Council of Europe in the Convention on Biomedicine (1997, s. 6(2)) and its Additional
Protocol (2005).
Despite recognizing the child’s assent dependent on age and maturity, this concept is
not uniformly defined or determined across clinical contexts. The UNESCO Universal
Declaration on Bioethics and Human Rights defines assent as the duty to involve a person
who is unable to express consent “[…] to the greatest extent possible in the decision-​
making process of consent, as well as that of withdrawing consent” (2005, s. 7(a)). The
International Bioethics Committee of UNESCO identifies the circumstances in which
this involvement should occur in their Report on Consent: individuals unable to consent
“[…] should be involved in the decision-​making process according to their age, maturity,
and/​or degree of capacity to consent” (2008, s. 164).
In addition to the absence of strict criteria, determining a child’s capacity can also vary
according to the quality or quantity of information given, the research environment, or
the relationship with the researcher or the research team. A change in any of these con-
textual factors could have a significant effect on the child’s capacity as a result, which
may occur at any point throughout the course of a research project. As with consent,
assent is a continuous process that may need to be reconfirmed throughout the duration
of the research, especially in the case of longitudinal studies and, more increasingly with
genomic data sharing that spans years or decades.

Dissent of the child
All norms governing pediatric research state that the opposition of a child to participate
in research (dissent of the child) should be respected (WMA 2013, s. 29; Council of
Europe 1997, s. 6(2), 2005, s. 15(1)(iv); CIOMS 2016, s. 17, 2008, s. 13–​14; UNESCO
2003, s. 8(b)(c)), even if parental consent has been obtained. Most international norms,
however, do not provide further guidance on how to formally acknowledge the child’s
dissent. Dissent typically requires a minor to possess the same level of capacity that is
needed for assent. Thus, if the child is too young, too immature, or unable to understand
the nature of the research, his or her dissent may be overridden. The CIOMS (2002), for
example, outlines that the dissent of a minor must be respected, unless, in exceptional
circumstances, research participation is considered the best medical option for a child
or adolescent (s. 17). The return of genetic/​genomic results and incidental findings with
next-​generation sequencing puts these issues of consent/​assent and dissent into sharp
relief, and will be discussed in depth in the following section (“Return of results and
incidental findings”).

Return of results and incidental findings

The focus on the return of results and incidental findings in the pediatric context dovetail
on the increasing use of next-​generation sequencing in the clinic. At the international
level, the 2014 P3G (Public Population Project in Genomics and Society) international
Statement on the Return of Whole-​Genome Sequencing Results in Paediatric Research,
 37

Incompetent adults 377

in consideration of the child’s best interests, holds that the potential to return inciden-
tal findings should be addressed at the time that informed consent is obtained (i.e.,
the decision to return results or not should be agreed upon in advance) (Knoppers et
al. 2014a). Incidental findings that are “scientifically valid, clinically useful, and reveal
conditions that are preventable and actionable during childhood should be offered”
(Knoppers et al. 2014a, p.5), while those that relate to an adult-​onset disorder should not
be returned, so as to preserve the child’s future autonomy and decision-​making ability.
The Statement also confirms that the views of the child or adolescent should be consid-
ered at the time of consent/​assent based on his or her age and maturity (Knoppers et al.
2014a), reinforcing the need to respect the child’s evolving decision-​making capacities.
In sum, a framework addressing pediatric research exists at the international level. The
principles and guidance, however, typically stem from research ethics norms applicable
in the clinical setting, and which are not always applicable in the data-​intensive research
context typified by genomics. The norms included here underscore the need to include
children in research, but do not provide specific guidance on how to manage the evolving
maturity of children and their capacity to consent to research. While it has been estab-
lished that the pediatric population should neither be excluded from medical research
nor considered therapeutic orphans (Shirkey 1968, 1999; Rieder & Hazardous Substances
Committee 2011), amending these international norms to address contemporary ethical
uncertainties, namely in the data-​intensive sciences and genomics, is warranted.
Guidance is furthermore lacking with respect to how these uncertainties in the data-
intensive sciences relate to incompetent adults living with dementia. Such persons’ inabil-
ity to consent to research participation is an ethical intersectionality they share with
children and minors. We explore this intersectionality, which we define as “reverse vul-
nerability” in further depth in the next section (“Incompetent adults”).

Incompetent adults
As the global population ages, so too has there been a steady increase in dementia and
dementia-​related diseases across high-​, middle-​, and low-​income countries (Brookmeyer
et al. 2007). With nearly 7.7 million new cases per year (World Health Organization
2012, 2016), there is considerable clinical demand (Fox & Petersen 2013; Ngandu et al.
2015) and political pressure for innovative research with curative goals (Department of
Health & Prime Minister’s Office 2013; Canadian Institutes of Health Research 2014).
Timely diagnosis, health-​related quality of life, and innovation in new therapies for
patients living with dementia, however, are markedly lacking. Advances in genomics
hold great promise toward improving patient outcomes through drug discovery, eluci-
dating risk reduction strategies, and slowing disease progression. To realize this prom-
ise, research priorities, data governance mechanisms, and alternative frameworks for
consent are needed. In particular, collaboration between dementia research and care,
and improvement in the accessibility of genomic and health data should be promoted
378

378 Minors and incompetent adults

across borders. Respect for persons and data protections for patients living with dementia
have both emerged as ethical priorities in turn. Perhaps more acute than in the pediatric
context, the scope of decision-​making authority among legally authorized representa-
tives is increasingly becoming a barrier to the sharing of incompetent adults’ research
data.

Inclusion
Similar to minors, the inclusion of incompetent adults living with dementia in research
is protected under international conventions and guidelines summarized in Table 19.3.
While these conventions and guidelines acknowledge that incompetent adults warrant
special protections in research—​and some explicitly identify living with dementia as a
hallmark scenario of vulnerability in adults—​the guidelines differ in their management
of vulnerability and types of research permissible as determined by level of risk. For
example, the Declaration of Helsinki stipulates that research with vulnerable populations
is “only justified if the research is responsive to the health needs or priorities of this group”
(WMA 2013, s. 20) while the CIOMS guidelines outline a set of criteria for determining
ethically appropriate participation (2016, s. 17). The UNESCO Declaration on Bioethics
and Human Rights (2005) is unique in this regard in two ways. First, it invokes concepts of
both minimal risk as well as minimal burden in rationalizing the participation of vulner-
able groups. Second, the human rights orientation of these guidelines marry the concepts
of personal integrity and best interests standards upon which the decision to participate
in research should be based for groups such as incompetent adults. Legally authorized
representatives (LARs) are the primary shareholders of these best interests on behalf of
incompetent adults, as well as for minors.

Legally authorized representatives

One emerging area of comparative policy interest relates to the scope of substitute
decision-​making authority to share research data derived from research with incompe-
tent adults living with dementia. Markedly lacking in the consensus guidelines compared
here is which individuals are eligible to serve as appropriate substitute decision-​makers
for incompetent adults in the research context. The limited guidance available has drawn
primarily from the clinical context to date. For the purposes of care decisions, the substi-
tute is often legally determined through the appointment of a LAR in most jurisdictions.
One study found, however, that court-​recognized LARs may in fact impede participation
in dementia research in some European countries (Galeotti et al. 2012). Similar debates
as to who may serve as LARs and the extent of their authority are underway in the United
States (Derse & Spellecy 2015; Yarborough 2015)  and Canada (Wildeman et  al. 2013),
where scholars are interrogating whether policies should “expand the concept of durable
power of attorney for health care to include research participation to facilitate substituted
judgments” (Taylor et al. 2015, p.64).
 379

Incompetent adults 379

Table 19.3  International guidelines for the participation of incompetent adults living

with dementia in biomedical research

Guideline Relevant clause

Council for Guideline 16: Research involving adults incapable of giving
International informed consent
Organizations of Adults who are not capable of giving informed consent must be included
Medical Sciences in health-​related research unless a good scientific reason justifies their
(CIOMS) (2016) exclusion. As adults who are not capable of giving informed consent
International Ethical have distinctive physiologies and health needs, they merit special
Guidelines for Health-​ consideration by researchers and research ethics committees. At the
related Research same time, they may not be able to protect their own interests due to
Involving Humans their lack of capacity to provide informed consent. Specific protections
to safeguard the rights and welfare of these persons in research are
therefore necessary.
Before undertaking research with adults who are not capable of giving
informed consent, the researcher and the research ethics committee must
ensure that:
◆ A legally authorized representative of the person who is incapable
of giving informed consent has given permission and this permission
takes account of the participant’s previously formed preferences and
values (if any); and
◆ Assent of the subject has been obtained to the extent of that person’s
capacity, after having been provided with adequate information about
the research at the level of the subject’s capacity for understanding
this information.
If participants become capable of giving informed consent during the
research, their consent to continued participation must be obtained.
In general, a potential participant’s refusal to enrol in the research must
be respected, unless, in exceptional circumstances, research participation
is considered the best available medical option for an individual who is
incapable of giving informed consent.
If participants have made advance directives for participation in research
while fully capable of giving informed consent, the directives should
be respected. For research interventions or procedures that have the
potential to benefit adults who are incapable of giving informed consent,
the risks must be minimized and outweighed by the prospect of potential
individual benefit.
For research interventions or procedures that have no potential individual
benefits for participants, two conditions apply:
◆ The interventions and procedures should be studied first in persons
who can give consent when these interventions and procedures target
conditions that affect persons who are not capable of giving informed
consent as well as those who are capable, unless the necessary data
cannot be obtained without participation of persons who are inca-
pable of giving informed consent; and
◆ The risks must be minimized and no more than minimal
When the social value of the studies with such research interventions
and procedures is compelling, and these studies cannot be conducted
in persons who can give informed consent, a research ethics committee
may permit a minor increase above minimal risk.

(continued)
380

380 Minors and incompetent adults

Table 19.3  Continued

Guideline Relevant clause

Commentary on Guideline 16
[…]A person may be incapable to give informed consent for a variety
of reasons (for example, dementia, some psychiatric conditions and
accidents). Persons can become capable of giving informed consent after
a certain period, or they can be incapable to decide whether they should
be treated for a certain disease but capable to decide whether they want
to enjoy a meal. This illustrates that a lack of decisional capacity is time-​,
task-​ and context-​specific

Political Declaration 12(j) Harnessing of scientific research and expertise and realizing the
and Madrid potential of technology to focus on, inter alia, the individual, social
International Plan and health implications of ageing, in particular in developing
of Action on Ageing countries;
(United Nations Second 75(e) Encourage, at all levels, arrangements and incentives to mobilize
World Assembly on commercial enterprises, especially pharmaceutical enterprises,
Ageing 2002) to invest in research aimed at finding remedies that can be pro-
vided at affordable prices for diseases that particularly afflict
older persons in developing countries and invite the World Health
Organization to consider improving partnerships between the pub-
lic and private sectors in the area of health research
86(b) Develop, where appropriate, effective strategies to increase the
level of quality assessment and diagnosis of Alzheimer’s and
related disorders at an early stage. Research on these disorders
should be undertaken on a multidisciplinary basis that meets the
needs of the patient, health professionals and carers;
United Nations Article 7
Principles for Older Older persons should remain integrated in society, participate actively
Persons (United Nations in the formulation and implementation of policies that directly affect
General Assembly 1991) their well-​being and share their knowledge and skills with younger
generations.
Article 8
Older persons should be able to seek and develop opportunities for ser-
vice to the community and to serve as volunteers in positions appropriate
to their interests and capabilities.

Consent, assent, and dissent

The ethical significance of assent is, as in the case of children, transferable to research with
incompetent adults (Black et al. 2010). Mild to moderate cognitive and memory-​impaired
adults have been shown to meaningfully engage in discussions of research participation
with researchers and their substitute decision-​makers (Kim et al. 2004, 2011; Karlawish
2008). These studies importantly substantiate the involvement of such persons in research
participation decisions as their abilities will allow. In incompetent adults living with
dementia, their cognitive decline can be gradual, sudden, or episodic in accordance with
 381

Examining ethical intersectionality in practice 381

the severity of their disease. Decision-​making capacity may therefore be task, time, and
context dependent.
Taken together, these decisional capacities should be evaluated on a continuous basis,
and a LAR identified early in the dementia trajectory. According to the conventions and
guidelines outlined in Table 19.3, adults living with dementia who are deemed incompe-
tent should be granted the opportunity to assent or dissent to participation in research
before becoming incompetent. A LAR may override a decision in cases where the partici-
pant has not stated an express wish to be involved in research, or when their participation
would constitute greater than minimal risk. Like for children, the best interests standard
varies considerably by jurisdiction and in how it is invoked to justify one’s inclusion or
exclusion from research, particularly if no direct clinical benefit is anticipated. The United
Nations Convention on the Rights of Persons with Disabilities (2008) safeguards the right to
engage in political, social, and cultural life, which could be interpreted to include partici-
pation in research as an exercise of civic engagement. The Convention protects the rights
to dignity, autonomy, independence, and participation in society. We argue that deci-
sion-​making associated with the type(s) of research participation, as well as the sharing of
research data should be considered extensions of the latter participatory right protected
under the Convention.

Examining ethical intersectionality in practice: Return

of results and incidental findings in Canada
The Canadian College of Medical Genetics (CCMG) implicitly adopted the ethical inter-
sectionalities of context, time, and task described herein between minors and incompe-
tent adults in its position on the return of results (Boycott et al. 2015). Although the
CCMG guidelines were drafted for application in clinical settings, they are useful for con-
sideration in the research context as well. This is increasingly true as genomics/​genetic
research informs evidence-​based practices, for example, and more firmly integrates into
routine clinical care, diagnostics, and personalized therapies.
The CCMG Professional and Ethical Guidelines (Boycott et  al. 2015)  establish two
responsibilities for the return of actionable results when they involve incompetent adults:
◆ Ensure the patient’s best interest and appropriate level of understanding when convey-
ing information to patients.
◆ Disclose all clinically relevant information to patients unless specifically instructed not
to do so by the patient.
The decision to return results and incidental findings is often tailored to one of five cir-
cumstances that typify the involvement of vulnerable persons in genetic research. Figure
19.1 provides an overview of these five circumstances, and the corresponding guide-
line concerning the return of results. Based on the CCMG guidelines, results should be
returned when incompetent adults have expressed wishes to this effect, or if the results
are medically actionable for the patient in line with their best interest as is the case with
children and minors.
382

382 Minors and incompetent adults

Researchers are also implicated in the fulfillment of a participant’s best interest, particu-
larly when they express prior wishes related to the return of results/​incidental findings
or participation in research generally. As Figure 19.1 illustrates, participants’ wishes may
be unknown. In this case, researchers along with substitute decision-​makers are charged
with determining the appropriateness of returning results based on the clinical action-
ability of the result and the participant’s best interest(s).

Figure 19.1  CCMG guidelines for return of results and incidental findings for children and
incompetent adults in research.
 38

Summary 383

Challenges related to feasibility of re-​contact for the disclosure of medically action-

able incidental findings remain a challenge, as is true for disclosure to child participants
and their parents, yet for different reasons. Incompetent adults lose “task” capacity that
prevents them from altering previously stated preferences. In contrast, the feasibility
challenges associated with re-​contacting minors centers on the fact that minors gain task
capacity to make decisions to participate in research, which may be considerably different
from their parents’ original consent. In addition to the familiar (or sometimes legal) chal-
lenges associated with identifying a LAR, Canadian guidelines are furthermore compli-
cated by provincial differences in LAR policies (see, for example, Thorogood et al. 2016).

Summary
As illustrated in this chapter, minors and incompetent adults are considered situationally
vulnerable within a research context. It is as a result of this vulnerability that special pro-
tections in research are justified. The nuances of such vulnerability, however, have impor-
tant implications for laying a responsible governance framework for sharing research
data involving both minors and incompetent adults living with dementia. Lange and col-
leagues have introduced the “situationality concept” for nuancing the typology of vulner-
ability that patients with dementia, and other vulnerable groups with limited cognitive
capacity may experience (Lange et al. 2013). It aligns furthermore with the framing of
vulnerability in the CIOMS (2016) guidelines: “[o]‌ne widely accepted criterion of vulner-
ability is limited capacity to consent or decline to consent to research participation” (com-
mentary, s. 15). The limitations to capacity can be task, time, or context specific. In this
way, the situational vulnerability that emerges from an inability to consent to research is
a useful ethical intersectionality upon which a policy for genomic data sharing involving
minors and incompetent adults living with dementia can build. Both populations share
task-​oriented deficiencies in their capacity to make research participation decisions, but
differ in time-​and context-​oriented capacities. The decisional capacities of these two pop-
ulations and their substitute decision-​makers, as well as the special ethical protections the
research community affords them, differ in their temporal and contextual specificities.
Each component of capacity—​time, task, and context—​will be next compared for minors
and incompetent adults living with dementia, respectively.
First, the situational vulnerability of minors with respect to decision-​making in
research is inversely related to their burgeoning autonomy. The convergence point
heralding the end of minors’ situational vulnerability and societal recognition of their
decision-​making ability is legally benchmarked upon reaching the age of majority.
Whereas minors mature out of their situational vulnerability that arises from a tem-
porary inability to consent to research (and in many cases clinical care), incompetent
adults living with dementia can regress into situational vulnerability commensurate with
their cognitive decline. The authors define this phenomenon “reverse vulnerability,” a
compelling ethical consideration when charting the ethics of responsible genomic and
health-​related data sharing.
384

384 Minors and incompetent adults

Second, in the case of minors, parents are charged with deciding whether, and to what
extent, to share their child’s genomic data. Research suggests parents make this decision
in line with their understanding of informational risks that data sharing poses for their
children today, as they mature into adults, as well as their altruistic intentions to support
further research through secondary data use.
Third, the ethical significance of task-​related capacity can be directly compared between
persons living with dementia and minors. That is, the cognitive tasks associated with pro-
viding informed consent to research require the same facilities and reasoning regardless
of whether an incompetent adult person with dementia or a minor makes this decision.
To make a decision to participate in research, a number of task-​specific capacities are
required. These include that prospective participants understand the nature and purpose
of the investigation, they acknowledge the roles and activities necessary to participate,
and they appreciate the immediate and future implications of their participation. Singh
(2007), however, proposes a shift in the ethical weight researchers should attribute the
task-​specific capacities of vulnerable groups such as children and incompetent adults.
She emphasizes the communicative process, rather than a strictly comprehension-​
oriented definition of task-​specific capacity is relevant both to clinical and research
decision-​making:
Children’s task-​specific capacities defy their characterization as vulnerable, incapacitated patients
who are fully dependent on surrogate decision-​makers … children must have the capacity to dis-
cuss their understanding of diagnosis and treatment. This understanding need not be correct to
be interesting and informative; therefore the capacity is specific to the task of communication, as
opposed to understanding. (Singh 2007, p.S36)

Finally, surrogate decision-​makers charged with ensuring the best interests of minors and
incompetent adults are motivated by different decisional outcomes. These differences can
provide some clarity to the contextual distinction in decision-​making capacities between
the two populations. Parents make decisions on behalf of their child temporarily, and
with an overarching motivation to protect as a means of fostering independency in the
future. Care providers or other legally authorized representatives also make decisions
with a chiefly protective aim, yet do so as an exercise of managing the incompetent adult’s
gradual dependency on others.

Sharing research data: A dual imperative framework

Ethics governance of sharing research data involving minors and incompetent adults
can draw from the ethical intersectionalities that arise from their shared sources of
vulnerability to fulfill dual imperatives in the biomedical research endeavor. The first
imperative is a scientific one, in which the sharing of research data is required to ade-
quately power statistical associations between genetics and human etiologies of disease,
and to provide care for particular health needs at all stages of life. The second impera-
tive is an ethical one, in which only through sharing research data can the benefits of
new scientific knowledge offset the anticipated risks. Knoppers and others have written
 385

References 385

elsewhere extensively on the human rights underpinnings of this second ethical imper-
ative (Knoppers et al. 2014b). International support for data sharing resulted in the
founding of which the Global Alliance for Genomics and Health, and adoption of its
Framework for the Responsible Sharing of Genomic and Health-​Related Data (Knoppers
2014). Founded on the right of all citizens to benefit from scientific progress (General
Assembly of the United Nations 1948, s. 47), the Framework promotes a positive obliga-
tion on governments to act in respect of this right. For minors and incompetent adults
who require LARs to act on their behalf, data sharing for research that is in their interest
should be encouraged in light of their specific needs. A proportionate risk analysis that
is based on the possible occurrence of real risks and the actual probability of their occur-
rence argues in favor of their inclusion in international data sharing initiatives. In line
with the human rights foundations upon which the Global Alliance was founded, this
chapter contends that the ethical intersectionalities between children and incompetent
adults helps orient research and data governance that is better tailored to the contempo-
rary challenges facing them in the post-​genomic era. Policy collaboration and empirical
policy research are needed if vulnerable populations are to continue benefiting from the
fruits of scientific progress made possible through concerted data sharing efforts.

Acknowledgments
The authors wish to thank the Vanier Canada Graduate Scholarship (CIHR), the Canada
Research Chair in Law and Medicine, Ministère de l’Économie, de la Science et de
l’Innovation du Québec, PSR-SIIRI-850 (Canada), the Fond de Recherche du Québec-
Santé, and the Québec Network of Applied Genetic Medicine (RMGA) for their funding
support. The excerpt from Article 12 was reproduced from “Convention on the Rights of
the Child,” by United Nations Human Rights Office of the High Commissioner, © 1989/​
1990 United Nations. Reprinted with the permission of the United Nations.

References
Black, B.S., Rabins, P.V., Sugarman, J., and Karlawish, J.H. (2010). Seeking assent and respecting
dissent in dementia research. American Journal of Geriatric Psychiatry, 18(1), 77–​85.
Boycott, K., Hartley, T., Adam, S., et al. (2015). The clinical application of genome-​wide sequencing for
monogenic diseases in Canada: position statement of the Canadian College of Medical Geneticists.
Journal of Medical Genetics, 52(7), 431–​7.
Brookmeyer, R., Johnson, E., Ziegler-​Graham, K., and Arrighi, H.M. (2007). Forecasting the global
burden of Alzheimer’s disease: forecasting the global burden. Alzheimer’s & Dementia, 3(3), 186–​191.
Canadian Institutes of Health Research (2014). Second Global Dementia Legacy Event Harnessing the
Power of Discoveries: Maximizing Academia-​Industry Synergies. Ottawa, ON: Canadian Institutes of
Health Research.
Choudhury, S., Fishman, J.R., McGowan, M.L., and Juengst, E.T. (2014). Big data, open science and
the brain: lessons learned from genomics. Frontiers in Human Neuroscience, 8, 239.
Council for International Organizations of Medical Sciences (CIOMS) and the World Health
Organization (WHO) (2016). International Ethical Guidelines for Health-​Related Research Involving
Humans. Geneva, Switzerland: COMS.
386

386 Minors and incompetent adults

Council of Europe (1997). Convention on Human Rights and Biomedicine. Oviedo, Spain: Council of
Europe.
Council of Europe (2005). Additional Protocol to the Convention on Human Rights and Biomedicine,
concerning Biomedical Research. Strasbourg, France: Council of Europe.
Department of Health and Prime Minister’s Office (2013). G8 Dementia Summit Agreement.
London: Department of Health.
Derse, A. and Spellecy, R. (2015). Ethical and regulatory considerations regarding enrollment of
incompetent adults in more than minimal risk research as compared with children. American
Journal of Bioethics, 15(10), 68–​69.
Diekema, D.S. (2006). Conducting ethical research in pediatrics: a brief historical overview and review
of pediatric regulations. Journal of Pediatrics, 149(Suppl. 1), S3–​11.
European Parliament and the Council of the European Union (2014). EU Clinical Trials Directive
2001/​20/​EC., L 269(September 2000), 1–​15.
Fernandez, C., Kodish, E., and Weijer, C. (2003). Informing study participants of research results: an
ethical imperative. IRB: Ethics & Human Research, 25(3),12–​9.
Fox, N.C. and Petersen, R.C. (2013). The G8 Dementia Research Summit –​a starter for eight? The
Lancet, 382(9909), 1968–​1969.
Galeotti, F., Vanacore, N., Gainotti, S., et al. (2012). How legislation on decisional capacity can
negatively affect the feasibility of clinical trials in patients with dementia. Drugs & Aging, 29(8),
607–​14.
General Assembly of the United Nations (1948). Universal Declaration of Human Rights. Paris: UN
General Assembly.
Griffith, D.B. (1991). The best interests standard: a comparison of the state’s parens patriae authority
and judicial oversight in best interests determinations for children and incompetent patients. Issues
in Law and Medicine, 7(3), 283–​338.
Karlawish, J. (2008). Measuring decision-​making capacity in cognitively impaired individuals.
Neurosignals, 16(1), 91–​98.
Kim, S.Y.H., Caine, E.D., Currier, G.W., Leibovici, A., and Ryan, J.M. (2001). Assessing the
competence of persons with Alzheimer’s disease in providing informed consent for participation in
research. American Journal of Psychiatry, 158(5), 712–​717.
Kim, S.Y.H., Appelbaum, P.S., Jeste, D.V., and Olin, J.T. (2004). Proxy and surrogate consent in
geriatric neuropsychiatric research: update and recommendations. American Journal of Psychiatry,
161(5), 797–​806.
Kim, S.Y.H., Karlawish, J.H., Kim, H.M., Wall, I.F., Bozoki, A.C., and Appelbaum, P.S. (2011).
Preservation of the capacity to appoint a proxy decision maker: implications for dementia research.
Archives of General Psychiatry, 68(2), 214–​20.
Knoppers, B.M. (2013). Genomics: from persons to populations and back again. Genome,
56(10), 537–​9.
Knoppers, B.M. (2014a). Framework for responsible sharing of genomic and health-​related data. The
HUGO Journal, 8(1), 3.
Knoppers, B.M., Avard, D., Sénécal, K., and Zawati, M.H. (2014b). Return of whole-​genome
sequencing results in paediatric research: a statement of the P3G international paediatrics platform.
European Journal of Human Genetics, 22(1), 3–​5.
Knoppers, B.M., Harris, J.R., Budin-​Ljøsne, I., and Dove, E.S. (2014c). A human rights approach
to an international code of conduct for genomic and clinical data sharing. Human Genetics, 133,
895–​903.
Knoppers, B.M., Sénécal, K., Boisjoli, J., et al. (2016). Recontacting pediatric research participants for
consent when they reach the age of majority. IRB: Ethics & Human Research, 38(6)
 387

References 387

Lange, M.M., Rogers, W., and Dodds, S. (2013). Vulnerability in research ethics: a way forward.
Bioethics, 27(6), 333–​40.
Ngandu, T., Lehtisalo, J., Solomon, A., et al. (2015). A 2 year multidomain intervention of diet,
exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive
decline in at-​risk elderly people (FINGER): a randomised controlled trial. The Lancet, 385(9984),
2255–​2263.
Rieder, M.J. and Hazardous Substances Committee (2011). Drug research and treatment for children
in Canada: a challenge. Paediatrics & Child Health, 16(9), 560–​561.
Shirkey, H. (1968). Editorial comment: therapeutic orphans. Journal of Pediatrics, 72(1), 119–​120.
Shirkey, H. (1999). Editorial comment: therapeutic orphans. Pediatrics, 104(Supplement 3), 583–​584.
Singh, I. (2007). Capacity and competence in children as research participants. EMBO Reports,
8(Special Issue), S35–​S39.
Stein, L.D., Knoppers, B.M., Campbell, P., Getz, G., and Korbel, J.O. (2015). Data analysis: create a
cloud commons. Nature, 523(7559), 149–​151.
Taylor, H.A., Kuwana, E., and Wilfond, B.S. (2015). Is it ethical to enroll cognitively impaired adults in
research that is more than minimal risk with no prospect of benefit? American Journal of Bioethics,
15(10), 64–​65.
Thorogood, A., Deschênes St-Pierre, C., and Knoppers, B. M. (2016). Substitute consent to data
sharing: a way forward for international dementia research? Oxford Journal of Law and Biosciences,
Available from: 1–26. http://doi.org/10.1093/jlb/lsw063.
United Nations Educational, Scientific and Cultural Organisation (UNESCO) (1997). Universal
Declaration on the Human Genome and Human Rights. Paris, France:UNESCO.
United Nations Educational, Scientific and Cultural Organisation (UNESCO) (2003). International
Declaration on Human Genetic Data. Paris, France:UNESCO.
United Nations Educational, Scientific and Cultural Organisation (UNESCO) (2005). Universal
Declaration on Bioethics and Human Rights. Paris, France:UNESCO.
United Nations Educational, Scientific and Cultural Organisation (UNESCO) (2008). International
Bioethics Committee, Report of the International Bioethics Committee of UNESCO (IBC) on Consent.
Paris, France:UNESCO.
United Nations General Assembly (1989). United Nations Convention on the Rights of the Child (UN
Document A/​RES/​44/​25). New York: United Nations.
United Nations General Assembly (1991). United Nations Principles for Older Persons, Resolution 46/​91
(UN Document A/​RES/​46/​91). New York: United Nations.
United Nations Second World Assembly on Ageing (2002). Political Declaration and Madrid
International Plan of Action on Ageing. New York: United Nations.
Wildeman, S., Dunn, L.B., and Onyemelukwe, C. (2013). Incapacity in Canada: review of laws and
policies on research involving decisionally impaired adults. American Journal of Geriatric Psychiatry,
21(4), 314–​325.
World Health Organization (2012). Dementia: A Public Health Priority. Geneva: World Health
Organization.
World Health Organization (2016). Dementia Fact Sheet. Available from: http://​www.who.int/​
mediacentre/​factsheets/​fs362/​en/​ [accessed February 21, 2017].
World Medical Association (2013). Declaration of Helsinki: Ethical Principles for Medical Research
Involving Human Subjects. Amended by the 64 General Assembly, Fotaleza, Brazil. World Medical
Association.
Yarborough, M. (2015). Inconsistent approaches to research involving cognitively impaired
adults: why the broad view of substituted judgment is our best guide. American Journal of Bioethics,
15(10), 66–​67.
38

Chapter 20

Behavioral and brain-​based research

on free moral agency: Threatening
or empowering?
Eric Racine and Veljko Dubljević

Ipsa scientia potestas est [Knowledge is power].

(Francis Bacon 1597)

Introduction
The belief that people are free human beings, able to undertake actions based on will
and desires, is central to much explanation of human behavior and to a broad set of
social practices such as law, ethics, and politics. Indeed, threats to human freedom1
and the ability to act according to individual beliefs and preferences can lead to seri-
ous conflict and is still the object of struggles of oppressed linguistic, ethnic, religious,
and racial minorities throughout the world. It is often stated that there is nothing more
precious than a person’s freedom and this is well reflected in national constitutions
where political freedoms and rights serve as the foundations of social and political
orders. One of the iconic figures of the fight for human freedom in the twentieth cen-
tury, Nelson Mandela, put forth in his famous discourse “No Easy Walk to Freedom”
in 1953 to the African National Congress, in the context of the fight against the regime
of apartheid that “[t]‌o overthrow oppression has been sanctioned by humanity and is
the highest aspiration of every free man” (Mandela 2011). In a similar mind-​frame,
the influential moral and political thinking of the Enlightenment stressed that free-
dom was intrinsic to the definition of humans as social and political beings such that,
in the words of Rousseau, humans had an intrinsic motivation to safeguard freedom
because freedom defines human beings to the point of representing a duty to uphold
this freedom for themselves and for others (Rousseau 1992).2 In a nutshell, freedom
has long been considered intrinsic to what people value in individual and collective
life and constitutes a precondition for the enjoyment of many goods. Accordingly, the
desire to be free has propelled democratic revolutions and social movements through-
out history.
 389

Introduction 389

In contrast to this deep commitment to human freedom in the humanities and in society,
and its omnipresence in individual life, domestic affairs, and international relationships,
neuroscience has been heralded as a game-​changing field which will radically change
how individuals view themselves, including their beliefs in human freedom. Such changes
have been captured under the concept of a neuroscience revolution (Wolpe 2002), the
idea that neuroscience could reveal another view of humankind which potentially contra-
dicts ordinary, non-​scientifically informed views of ourselves. The claim is enormous, as
the reader can easily guess. If freedom is a kind of illusion and human beings are ready to
fight and even die in its name, are they then lured and wronging themselves in pursuing
such a quasi-​sacred good?
If the interpretation of some famous studies and neuroscientists is taken seriously, it
would seem to be the case. Starting with the research of Libet in the 1980s (Libet et al.
1982, 1983), a stream of studies has been interpreted to suggest that free will—​a basic
descriptor of human freedom that we will come back to in “Behavioral and brain-​based
research as a threat to free moral agency”—​does not exist. Perhaps human beings have at
best some veto power allowing them to stop an action or thought already initiated by the
brain but nothing much more (Libet et al. 1983). Others have argued that perhaps free
will is simply an illusion (Wegner 2002), albeit a useful illusion which allows us to make
sense of agency, but nevertheless an ill-​founded concept, a concept that does not carve
nature at its joints. Perhaps human beings just simply do not have any kind of freedom,
and beliefs in freedom are supported by quirky metaphysics (Haggard, cited in Smith
2011). All these claims merit closer scrutiny, but they set an enormous challenge to the
vast array of social practices that rely on some fundamental beliefs in human freedom.
Adding to the importance of these interpretations of neuroscience research is the fact that
the disqualification of human freedom by neuroscience has become lore in as much as,
for example, the media has conveyed repeatedly that the existence of human freedom has
been invalidated based, for example, on Libet and colleagues’ famous study (Racine et al.
2016). Greene and Cohen have proposed that social practices such as ethics and law be
extensively revised to reflect challenges to human freedom (Greene & Cohen 2004).
In this chapter, we examine some of the basic claims that challenge beliefs in free moral
agency,3 an expression we propose to encompass different abilities4 of the moral agent
often captured with different concepts such as free will, freedom, and autonomy. (These
concepts are often included in the single term of freedom, broadly understood, as already
suggested.) We strive to provide a generous understanding of the underlying points of
views suggesting, for example, that decisions are not made consciously and voluntarily
but are actually predetermined by prior brain activity, as revealed by, for example, readi-
ness potentials. Other research has challenged how conscious and accurate human beings
actually are in making choices and decisions which are believed to be free but are actually
influenced by a host of implicit, nonconscious mechanisms (Bargh & Chartrand 1999).
Although there are methodological caveats to what has been published in neuroscience
with respect to this issue (e.g., about Libet’s research which we and others have scrutinized
(Dubljević 2013; Saigle et al. 2015)), this chapter looks at this problem from a conceptual
390

390 Behavioral and brain-based research on free moral agency

and normative standpoint without engaging in a detailed methodological review of such

claims. It assumes that some of the results of this research hold as true or at least can be
taken as a basis for a discussion about different aspects of free moral agency.
In this respect, we review threats to different aspects of free moral agency and from
various angles: some neuroscience experiments seem to threaten basic tenets about the
ability to choose; social psychology seems to dispute freedom by providing environmen-
tal constraints in which a person is enacting choices; and research into microbiota and
unconscious bias could be considered as an attack to autonomy. However, by having a
second look at some of the interpretations of these results taken as a threat to free moral
agency, we find that they have relied on ill-​founded assumptions about moral agency and
its relationship to empirical knowledge, such as the knowledge yielded by the behavioral
and brain sciences. Accordingly, in the second part of the chapter—​based on pragmatist
theories of voluntary action and the concept of “contextualized autonomy” (Racine &
Dubljević 2016; Racine et al. 2017) as well as recent work in social psychology which
both stress the dynamic nature of moral agency—​we reconsider a common objectivist
and essential stance toward free moral agency and an equally common dichotomist inter-
pretation of the fact–​value (is–​ought) tension which are at the center of these problem-
atic interpretations. In contrast, we propose that knowledge can empower moral agents
granted that there is, first, a genuine first-​person experience and intersubjective recogni-
tion of the abilities captured within the concept of free moral agency. Second, the value of
the experience of free moral agency is not jeopardized by the existence of third-​person,
behavioral, and brain-​based research about free moral agency, but the understanding of
this experience can actually be retooled and enriched by such knowledge provided that the
fact–​value dichotomy is reconsidered to reflect a more moderate tension or continuum.

Behavioral and brain-​based research as a threat to free moral

agency
The contribution of behavioral and brain research to the understanding of moral agency
(e.g., moral reasoning and behavior from the point of view of the protagonist) has brought
to light several domains of activity where moral agents are less free than they are thought
to be. As can be imagined, disentangling the actual perception of this capacity for agency
versus how it works in reality, with all cognitive biases and biases in self-​interpretation at
stake, is a complex undertaking and beyond the scope of this chapter. Hence, it is impor-
tant to first introduce, even if only in broad strokes, what we have in mind when referring
to the related concepts of free will, freedom, and autonomy (see Figure 20.1).
For the purposes of this paper, free will describes a basic ability to envision different
options and choose among them. More often than not, the actual physical ability of enact-
ing these choices is not part of the analysis of free will, although we do think that an
analysis of free will without these considerations neglects an important component of
the actual complexity of making choices in real-​world contexts. Freedom is a more sub-
stantive term that describes and alludes to more concrete possibilities of enacting one’s
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Behavioral and brain-based research as a threat to free moral agency 391

Autonomy, self-determination, self-regulation

Ability to make free decisions which meet additional criteria
such as following’s from one’s values and principles, being
clearly initiated by the moral agent, and resulting from a
deliberate effort of appreciating competing options.

Freedom, liberty
Ability to choose and benefit from
circumstances allowing the enactment of
one’s choice without coercion.

Free will
Basic ability to envision
options and choose
between them.

Figure 20.1 Key components of free moral agency: free will, freedom, autonomy.*

* This figure presents three sets of concepts commonly used to describe different components of free moral agency,
but does not put forth a model of free moral agency per se. The hierarchical relationship reflects that free will is
usually implied by freedom and freedom is usually implied by autonomy.

choices and preferences, often protected through specific rights in legal parlance such as
freedom of association, freedom of speech, and freedom of religion. For example, whereas
free will may be considered paradoxically to exist even if a choice cannot be enacted, this
usually does not hold true of freedom that entails the actual circumstances allowing the
exercise of one’s freedom. Otherwise said, free will alludes to a more basic ability than
freedom that captures more concrete aspects of choices and decisions. Now the concept
of autonomy, and related concepts like self-​determination and self-​regulation, designates
an even higher-​level or more specific ability to choose or decide as a result of deliberation
and reflection. Usually, there is an emphasis on the fact that the individual came to this or
that choice or decision on his or her own, or that this choice reflects deeply held principles
and values, although this criterion of authenticity is not univocal. According to these
distinctions, the mere act of voting under circumstances where this act is not hindered or
coerced could be an act of freedom, but it may not be autonomous if the choice to vote for
such-​and-​such candidate has not been the result of a certain kind of deliberate apprecia-
tion of the options available, their implications and consequences, and their alignment
with one’s convictions. And simply having a basic ability to envision options and choose
(having free will) would not entail that a person has the freedom to actually carry out this
choice. For instance, women have the same basic ability to choose according to their pref-
erence among options of government as men, but historically did not have the freedom to
actually carry out this choice. Women have only relatively recently been empowered with
the right to vote, and there are still places where women do not enjoy political freedom.
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392 Behavioral and brain-based research on free moral agency

Autonomy requires freedom, which itself requires free will, but free will does not nec-
essarily entail freedom, and freedom does not necessarily lead to autonomy. In our view,
these concepts—​distinguished for the sake of clarity here—​are interwoven in discussions
about the impact and relevance of behavioral and brain sciences on agency.5 Furthermore,
moral agency is much more than the free or autonomous aspects of attitudes and behavior
of the moral agent. For example, personality and responsibility represent other central
aspects of moral agency although we do not focus on them in this chapter.
Again, as readers may have already envisioned, there are different kinds of claims that
can be made about the impact of behavioral and brain sciences on free moral agency.
A moderate claim could be that what is learned about behavior, decision-​making pro-
cesses, including non-​conscious processes influencing human psychology, can inform
how behavior is understood, including the kinds of actions described as being free. For
example, an understanding of voting behavior that would exhibit an engagement of the
amygdala, a structure potentially considered “the perceptual or evaluative tool by which
the perceivers form their impressions” (Rule et al. 2010, p.354), does not mean that all
voting behavior is under the control of the amygdala. Different accounts of relational
autonomy have always integrated such moderate claims to revisit standard accounts of
autonomy that originally paid little attention to determinants of choice (Mackenzie &
Stoljar 2000). However, a stronger type of claim could capture statements and interpreta-
tions that suggest that revealing the existence of neurobiological mechanisms underlying
a behavior, a decision-​making process or the like, would lead to the conclusion that the
phenomenon is outside the purview of free moral agency. In other words, the behavior
or decision could be considered un-​free, determined, lacking any control by the agent,
being completely implicit and inaccessible to conscious awareness in ways that the agent
cannot do anything about how he or she behaves, thinks, or reacts. By and large, the first,
moderate claims are common in most everyday interpretations of what behavioral and
brain sciences mean for human action. However, stronger claims are not uncommon and
are often debated in the media because of their incredible (if true) and sensational impli-
cations (Racine et al. 2016). In the following sections, we illustrate how findings from the
behavioral and brain sciences have been interpreted as challenging different aspects of
free moral agency, notably (1) self-​determined action integral to autonomy, (2) conscious
volition involved in free will, (3) conscious control of action required for freedom, and
(4) the sense of self required for autonomous decision making. These are by no means the
only challenges that behavioral and brain sciences have brought to free moral agency or
agency more generally, and we acknowledge that we can only provide an overview to the
reader here.

Self-​determined action versus action determined by others

The ability to direct one’s attitudes and behaviors and orient one’s conduct is instrumental
to the concept of autonomy; autonomy entails an ability to come to decide for oneself
what is the best course of action or the right decision. However, before the advent of
contemporary discussions of the behavioral and brain sciences and moral agency, social
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Behavioral and brain-based research as a threat to free moral agency 393

psychology formulated a threat to the understanding of free moral agency because it

exhibited serious social constraints on decisions and behaviors. Otherwise said, it put
into question the putative prerequisites for free action and showed that human beings are
less free than they are thought to be and more dependent on others, thus challenging the
common understandings of free moral agency. Some key findings challenged autonomy,
notably the observation of operative deference to the wishes of other individuals (e.g.,
obedience to authority—​see Milgram (1974)) or of the group (e.g., conformity—​see Bond
(2005)). These are then the types of social influences (see Cialdini & Goldstein 2004) that
we briefly review here.
In Milgram’s classical experiment on obedience, subjects were made to believe that they
are about to take part in a study of memory and learning, and each of them has been
assigned the role of a teacher (Milgram 1974). The subject would then be paired with a
learner, who is actually aware of the true nature of the experiment and is, in fact, a col-
laborator of the experimenter. For every error of the learner, the teacher was instructed
to administer increasingly higher electric shocks, supposedly to facilitate and motivate
learning (Nissani 1990). Once the presumed shock level reached a certain point, the
strapped learner appeared to suffer pain and demanded to be set free, while the experi-
menter, if asked, insisted that the experiment was safe and that the teacher should con-
tinue (Milgram 1974). Contrary to expectations, which were that ordinary people would
reject authority when confronted with a choice between hurting others and being obedi-
ent, 65% of subjects continued with the delivery of electric shocks up to the very highest
levels (Nissani 1990). This experiment, and the research that followed it, had profound
implications for the understanding of voluntary action and moral responsibility. In
Milgram’s words, “[t]‌he essence of obedience consists in the fact that a person comes to
view himself as the instrument for carrying out another person’s wishes, and he therefore
no longer sees himself as responsible for his actions” (Milgram 1974, p.7).
However, actions and beliefs are not only influenced by powerful individuals, but they
are also fundamentally shaped by more common group pressures. Psychologists have
long been interested in the effects of group pressure on changes in the beliefs, actions,
and even perceptual experiences of individuals. Starting from classical studies of Asch
(1955) on effects of group pressure on judgments of perception of the length of drawn
lines, psychologists have convincingly demonstrated the effects of conformity and pin-
pointed different social influence processes (see Cialdini & Goldstein 2004). Normative
influences, for instance, may stem from the motive to please others and avoid negative
sanctions, and they appear to be stronger when participants make public responses and
are face-​to-​face with the majority (Bond 2005). Informational influences, on the other
hand, may stem from the motive to reach accurate judgments, and appear to be stronger
when individuals are faced with a difficult task and are less confident in their initial judg-
ment (Baron et al. 1996). Belonging to a collectivist or individualist culture further affects
the degree of conformity. Bond and Smith compared 134 studies in a meta-​analysis and
concluded that residents of collectivist countries are more likely to conform than people
from individualistic countries (Bond & Smith 1996). This effect might be caused by the
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394 Behavioral and brain-based research on free moral agency

difference in meaning that different cultures assign to the concept of nonconformity—​it

might be interpreted alternatively as representing deviance or uniqueness (Cialdini &
Goldstein 2004).
Neuroscience has recently contributed to the research on conformity with func-
tional and structural imaging. On the functional side, evidence has been found for
the involvement of the posterior medial frontal cortex in conformity (Izuma 2013).
In terms of structural differences, greater gray matter volume is observed in the
orbitofrontal cortex of people with high scores on tendency to conform (Campbell-​
Meiklejohn et al. 2012).6 All in all, susceptibility to outside social influences has been
firmly established by empirical data, and along with the psychological literature on
moral development (e.g., Gilligan 1993), it has served as a backdrop for philosophers
who reject the underlying assumptions (nonrelationality, value-​neutrality, and hier-
archical self-​control) of traditional conceptions of autonomy and free moral agency
(Benson 1990).

Conscious volition versus free and determined volition

In spite of the challenge from the behavioral sciences, the full-​fledged debate on free moral
agency, in particular on free will, later intersected with neuroscience with the emergence
of studies that looked into the neural basis of volition. A series of experiments conducted
by Benjamin Libet in the 1980s attempted to examine the physiological basis of spon-
taneous choice. Libet and colleagues investigated the readiness potential, that is, brain
activation prior to the initiation of a conscious and deliberate action. By using electroen-
cephalography, which measures electric activity of neurons, they established the existence
of a readiness potential prior to the subjects’ own consciousness of having made a deci-
sion. In other words, the brain was shown to be active before the subjects were aware of
their desire to initiate an action. It is beyond this chapter to review the methodological
and epistemological issues that challenge Libet and colleagues’ initial conclusions (Mele
2009), but these experiments led them to propose that
[O]‌ther relatively “spontaneous” voluntary acts, performed without conscious deliberation or plan-
ning, may also be initiated by cerebral activities proceeding unconsciously. These considerations
would appear to introduce certain constraints on the potential of the individual to exert conscious
initiation and control over his [this person’s] voluntary acts. (Libet et al. 1983, p.641)

Libet did grant that there:

[W]‌ould remain at least two types of conditions in which conscious control could be operative.
(1) There could be a conscious ‘veto’ that aborts the performance even of the type of ‘spontaneous’
self-​initiated act undress study here [ … ]. (2) In those voluntary actions that are not ‘spontaneous’
and quickly performed, that is, in those in which conscious deliberation (or whether to act or of
what alternative choice of action to take) precedes the act, the possibilities for conscious initiation
and control would not be excluded by the present evidence. (Libet et al. 1983, p.641)

Libet’s experiments led to diametrically opposed interpretations, with few siding with his
own original middle-​ground interpretation (Saigle et  al. 2015). These conclusions and
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Behavioral and brain-based research as a threat to free moral agency 395

interpretations are often taken to have significant implications. Based on Libet’s initial
findings and subsequent research, researchers have claimed that free will is simply an illu-
sion (Wegner 2002). Others have followed Libet’s lead to undertake a series of studies on
the automaticity and unconscious components of behavior (Haggard et al. 2004; Haggard
2005, 2011; Smith 2011) and have concluded that free will does not exist because human
behavior is essentially determined. A commentary in Nature Neuroscience (about a paper
which has supposedly shown that the brain activity was initiated seconds before a deci-
sion) well reflects this strong eliminativist interpretation:
The conscious decision to push the button was made about a second before the actual act but the
team discovered that a pattern of brain activity seemed to predict that decision by as many as seven
seconds. Long before the subjects were even aware of making a choice, it seems, their brains had
already decided. As humans, we like to think that decisions are under conscious control —​that we
have free will. Philosophers have debated that concept for centuries, and now Haynes and other
experimental neuroscientists are raising a new challenge. They argue that consciousness of a deci-
sion may be a mere biochemical afterthought, with no influence whatsoever on a person’s actions.
According to this logic, they say, free will is an illusion. “We feel we choose, but we don’t,” says
Patrick Haggard, a neuroscientist at University College London. (Smith 2011, p.24)

Conscious control of action versus unconscious influence on action

Another aspect of free moral agency which has been questioned in behavioral and brain
research is the ability for control over action, notably conscious control. The growing
literature on implicit biases—​a type of negative social attitudes that seem to guide most
overt behavior—​has been described as challenging traditional notions of freedom because
it directly puts to light influences that appear to be beyond conscious control of action,
and this kind of control is presumed in most understandings of freedom.
Negative social attitudes can be implicit and subtle (e.g., unconscious prejudice) or
explicit and blatant (e.g., overt discrimination). Subtle or implicit social attitudes are
not displayed openly—​the individual appears to be unbiased and even might consider
herself to be unbiased, whereas blatant biases are not denied—​they are displayed for
the world to see, and announce an individual’s displeasure with someone or something
(Keene 2011). Hate crimes are a perfect example of explicit bias—​harm is caused to an
individual due to the fact that this other individual is of a different race, gender, sexual
orientation, or social status. The dislike or prejudice against the victim is openly dis-
played and often motivated by the belief that it is justified, with no regard for the victim
(Fiske 2010). Implicit biases on the other hand, are an example of subtle and particularly
insidious social attitudes. They describe unconscious and automatic prejudiced judg-
ments, which often lead to social behavior that the individual might not be aware of
(Brownstein 2016).
Many categories of implicit bias have been empirically studied, including race, age,
gender, and ethnicity and other categories that fit more explicit negative social atti-
tudes. However, the most important and well-​known research has focused on attitudes
toward members of racial and ethnic minorities or socially stigmatized groups, or both
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396 Behavioral and brain-based research on free moral agency

(see Brownstein 2016). Many studies have showed that implicit biases can affect social
judgment and behavior independently from the subject’s explicit attitudes. These uncon-
scious and automatic influences, such as implicit racial bias, may be revealed on indi-
rect measures of attitudes (e.g., sequential priming or the Implicit Association Test—​see
Brownstein (2016)). The growing research on implicit biases has many upshots, from
chilling (e.g., biases in police shootings of unarmed men of African origin), very practical
(e.g., the well-​documented propensity of employers to prefer in-​group candidates in job
searches), to the more philosophical (e.g., how can a judgment be trusted once implicit
biased are acknowledged?).
The most important implications of implicit biases in the context of our discussion
stems from the fact that they stand in stark contrast to controlled cognitive processes.
Namely, mental causation is an important theme in many conceptions of free moral
agency—​freely willed actions are viewed as actions that are derived from a person’s con-
scious thoughts, whereas actions derived from the unconscious are viewed are unfree
(Baumeister & Monroe 2014). Thus, research into implicit attitudes and the range of
effects they have on judgment and behavior put the understanding of free moral agency
into question. This is exacerbated by data from social psychology and neuroscience,
which shows that prejudices and biases toward out-​group members are widespread and
persist in contemporary society (see Amodio 2014). The issue is whether automaticized
behaviors related to, say, sexism, should be thought of as under control of the person in
question. If they unfold in the absence of explicit reasoning, should individuals holding
such attitudes be responsible for them, and for the judgments and behaviors influenced
by their biases? Since there can be unawareness of the impact of a great many cogni-
tive states on behavior, this may lead to a global skepticism about moral responsibility
(Holroyd 2012). However, beyond the global issues of denying moral responsibility, the
fact that implicit biases are pervasive introduces additional constraints to free moral
agency and even forces us to consider ongoing, previously unreflected responsibility in
two ways: responsibility for having implicit attitudes and responsibility for the behavioral
expression of implicit attitudes (Faucher 2016).

Sense of self versus conglomerate of divergent wills

Another challenge to the understanding of free moral agency has come from surpris-
ing observations that the microorganisms living in the abdomen seem to affect many
decisions considered to be those of the moral agent. Ownership of action has a complex
relationship with free moral agency (e.g., a crime for which someone could be responsible
could then be disowned), but there is at least a minimal sense by which a moral agent is
someone who is the cause and the initiator of his or her actions. Recent research has called
into question this sense of being a free and autonomous self.
In the last decade or so, there has been a growing recognition of the synergetic relation-
ships between the gut microbiota comprising 1013–​1014 microorganisms and the nervous
system, that is, the gut–​brain axis (Neufeld & Foster 2009; Cryan & Dinan 2012). The
importance of the commensal microbiota for the development of the immune system and
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Behavioral and brain-based research as a threat to free moral agency 397

mucosal tissues has long been known to immunologists and even before to some vision-
ary scientists like Bernard, Darwin, James, Pavlov, and Lange (Cryan & Dinan 2012).
However, the behavioral and brain sciences have witnessed a plethora of findings sug-
gesting that not only disease states but also, so to speak, ordinary behavior is under the
influence of the microbiota (Neufeld & Foster 2009). The mechanisms through which this
action occurs are being explored (Cryan & Dinan 2012) but include the possible contri-
bution of the gut commensals in the synthesis of neurotransmitters and other microbial
mediators. These mediators then impact homeostasis in the central nervous system, acti-
vation of the hypothalamic–​pituitary–​adrenal axis (HPA) or stress axis, neuroimmune
response, and neurogenesis by affecting the vagus nerve, involved in the parasympathetic
regulation of many organs, or crossing directly the blood–​brain barrier (Sherwin et al.
2016), although other mechanisms could be at stake (Cryan & Dinan 2012).
One of the most intensively investigated areas of brain–​gut interaction concerns stress
response and the activity of the HPA axis in which several key observations have showed
clear interactions between the central nervous system and the gut. For example, maternal
separation (a stressor) in rhesus monkeys is associated with changes in the HPA axis but
also affects temporarily the composition of the gut microbiota (Cryan & Dinan 2012).
Long-​term effects have also been found in rats and physical stressors (physical restraint)
lead to changes in gut microbiota composition and reciprocally, stress response also
appears to be modulated by microbiota profile (Cryan & Dinan 2012). A few years ago,
a set of landmark studies suggested that the development of the immune system in mice
led to the normalization of the HPA axis. For example, adult germ-​free mice showed
an exaggerated stress response in comparison to control animals (Sudo et al. 2004). The
same study showed that colonization of the mice at 6 weeks (early adulthood) reversed
this effect but not in adulthood (8 weeks of life). Additionally, the function of the intes-
tinal barrier can be changed subsequent to stress exposure and can be reversed by the
use of some probiotics (Cryan & Dinan 2012). In addition to effects on the HPA axis, a
series of observations have suggested implications of gut composition and function on
memory, mood, and visceral pain perception (Cryan & Dinan 2012). Of great potential
clinical significance, neurodevelopmental disorders such as autism are associated with gut
dysfunction, although the relationship (causal or correlational) is unclear given that diet
and food intake (as well as use of antibiotics) can differ in individuals affected by autism
(Cryan & Dinan 2012). An association between certain psychiatric conditions (e.g., mood
disorders) and gastrointestinal disorders (e.g., irritable bowel syndrome) has also long
been observed (Neufeld & Foster 2009).
In different headquarters, microbiome7 research is now considered a genuine chal-
lenge to the existence of the self, let alone the self which is free to choose. Kramer
and Bressan (2015), describe human beings as superorganisms where the organisms
constituting the microbiota would have interests of their own, “which need not coin-
cide with ours” (p.464). For example, some behaviors of mammals could be dictated
by the interests of microorganisms to use their hosts to perpetuate their existence.
Rats inflected with toxoplasma lose their fear of cats; the toxoplasma is then able to
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398 Behavioral and brain-based research on free moral agency

reproduce sexually instead of asexually in the cat’s intestine, thereby suggesting that
the behaviors of these mammals are instrumentalized by toxoplasma. Similarly, food
cravings and other behaviors and choices of humans could be directed by microor-
ganisms, and could potentially run counter to long-​term health and autonomously
deliberated interests. Morar and Beever reviewed such microbiome research and
conclude that it is “producing a radically new understanding of ‘individual’ organ-
isms” (Morar & Beever 2016, p.39). In a nutshell, the human individual should be
more aptly viewed as a “community, but also in recognizing the ways that agency
and autonomy are additionally impacted by microbial interactions” (Morar & Beever
2016, p.40). Accordingly, they criticize standard accounts of autonomy (e.g., moral
agents as having a capacity for self-​sufficient, self-​determined decisions, i.e., a capac-
ity defined in abstract terms without much understanding or appreciation of deter-
minants of choice) for not taking into account evidence from the biological and
environmental sciences indicating that autonomy is influenced by a host of factors.
They even fault the relational account of autonomy, which was developed explicitly
to incorporate insights on social determinants of choice, as incomplete “to the extent
that it overlooks this deep biological interconnectedness between human individuals
and other organisms” (Morar & Beever 2016, p.41). However, the authors go further
and claim that there is “no reason not to jettison the concept” [of autonomy] “if a
suitable normative replacement for the value that autonomy has traditionally upheld
can be identified” (Morar & Beever 2016, p.42). Otherwise said, microbiome research
and brain–​gut interaction radically put into question the understanding of free moral
agency.
To conclude our analysis of threats stemming from behavioral and brain sciences,
different claims have been made to the effect that they bear significant implications
for the understanding of free (moral) agency. If different strands of research are to
be believed, individuals are not free in the sense that they are considered to be. On
the contrary, certain decisions would be heavily influenced by social determinants of
choice, preparatory brain activity such as the readiness potential and neuronal activity
preceding action, implicit biases, and as discovered more recently, the activity of the
microbiota. These insights have been interpreted as threats to free moral agency and
its different facets such as the capacities for self-​determined action, conscious volition,
conscious control of action, and the sense of self. In the next section of this chapter, we
discuss two challenges to these claims. First, we highlight their objectivist and essential-
ist assumption toward abilities relevant for free moral agency. Second, we point to their
misplaced devaluation of the normative principle of autonomy and human freedom,
which stresses the value of free moral agency. We propose that a concept of “contextual-
ized autonomy” (e.g., Racine et al. 2017)—​which relies on a recognition that autonomy
is a set of agential abilities (see also Dubljević 2013) exercised in context and originat-
ing in the experience of the agent—​can integrate the useful insights they describe while
avoiding these two pitfalls.
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Behavioral and brain-based research as empowerment 399

Behavioral and brain-​based research as empowerment

Strong interpretations of research in different domains of the behavioral and brain
sciences suggest that they explain away autonomy, freedom, and free will, and/​or sug-
gest that the insights provided by those concepts are wrong-​headed and misleading,
perhaps even simply useless from a scientific perspective. But, keeping in mind the
importance of free moral agency in human affairs, can these concepts be dismissed as
some propose (Wegner 2002)? Interestingly, some of those who more staunchly oppose
such eliminativism have tended to argue that nothing could be actually learned from
behavioral and brain science. For example, the behaviorist and legal scholar, Steven
Morse, argues that the strong eliminativist interpretations rely on a “brain overclaim
syndrome”. According to this view, the behavioral and brain sciences bear no impact
for the law because of the genuine value of beliefs in responsibility and autonomous
decisions. Morse advances that the law is unconcerned by metaphysical discussions
about free will, this concept being entirely abstract and barely relevant for law since the
law defaults to folk psychological attribution of presumed autonomy and responsibil-
ity (Morse 2006, 2008).
More promising are middle-​ground views that tend to give some credence to the
importance of the behavioral and brain sciences but nevertheless frame the contribu-
tion of the behavioral and brain sciences as perhaps not a threat, but a challenge to free
moral agency. For example, Felsen and Reiner have proposed that a standard model of
autonomy—​defined on the three criteria of (1) having a hierarchy of desires (reflexivity),
(2)  rationality, and (3)  freedom from external influences—​is to some extent inconsis-
tent with evidence emerging from behavioral and brain research, notably because of the
implicit mechanisms and biases to which human decision making is prone (Felsen &
Reiner 2011). Regarding the third criterion, which is key to our discussion, the authors
identify both internally generated influences to decisions and external influences to deci-
sions, and focus on the latter. Rightfully, they stress that influences on decisions could be
both detrimental and beneficial to the moral agent. Interestingly, they also note the pos-
sible interactions between external and internal influences, notably that covert external
factors may become internalized and “indistinguishable from authentic internal sources”
(Felsen & Reiner 2011, p.10). Their conclusion is that “at least some of our decisions
do not appear to be as free from undue influence as the standard model of autonomy
requires” (Felsen & Reiner 2011, p.10). Otherwise said, the commonly assumed ability of
moral agents to truly deliberate and be completely free is unrealistic. Felsen and Reiner
resist concluding that moral agents cannot undertake autonomous actions and should
not be held responsible for their actions, and they thus open the door to more nuanced
positions between the extremes found in the literature. However, they do not elaborate
further on these promising ideas, including the synergies between internal and external
factors as well as how influences can actually empower moral agents to achieve their
goals, including those they choose voluntarily and autonomously.
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400 Behavioral and brain-based research on free moral agency

In our eyes, middle-​ground positions like Felsen and Reiner’s are hinting at the
genuine promises of the behavioral and brain sciences but fall short from overcoming
explicitly the conceptual barriers to the meaningful integration of behavioral and brain
science knowledge to the theoretical and practical understanding of free moral agency.
Indeed, the discussion remains burdened—​we argue—​by two common fallacies within
the view of abstracted free moral agency (Figure 20.2a): first, concerning an objec-
tivist and essentialist stance (dualist metaphysics separating starkly the realms of the
subjective and the objective) toward abilities relevant for free moral agency (e.g., free
will, freedom, and autonomy) and second, a misplaced devaluation of the normative
principles that stress the value of free moral agency (e.g., respect for autonomy, respect
for individual rights, and responsibilities) based on behavioral and brain science. We
explain these two tension points and provide a different view informed notably by prag-
matist theory and the concept of “contextualized autonomy” (Dubljević 2013; Racine
& Dubljević 2016; Racine et al. 2017). The first fallacy is resolved by the adoption of a
nonessentialist (nondualistic) metaphysics; the second by taking a distance from pos-
tulating a strong fact–​value (is–​ought) dichotomy and siding with a description of this
dichotomy as a tension which needs to be resolved in actual moral judgment (see Figure
20.2 for an overview).

(a)
Stance Assumptions Implications

Objectivist,
Free moral essentialist, and dualist Abstract free will, freedom, and autonomy:
agency as an metaphysics Neuroscience undermines the ability for free moral
ability to choose agency because the third-person perspective of
and act without neuroscience challenges the first-person experience
Strong fact–value of being able to choose and act upon the world
constraints or
dichotomy in moral according to those choice and preferences.
undue influence
judgment

(b)
Stance Assumptions Implications

Intersubjectivist, non- Contextualized free will, freedom, and autonomy:

Free moral essentialist, and non- Neuroscience does not necessarily undermine free
agency as an dualist metaphysics moral agency because the third-person perspective
ability to choose of neuroscience does not challenge the first-person
and act within experience of being able to choose and act upon the
Fact–value continuum
constraints or world according to those choices and preferences. It
in moral judgments and
influence(s) may actually empower and retool that ability.
behaviors

Figure 20.2  Two interpretations of the contribution of behavioral and brain science to the
understanding of free moral agency. (a) Dualist metaphysical interpretation of behavioral and
brain research on free moral agency. (b) Pragmatist interpretation of behavioral and brain
research on free moral agency.
 401

Behavioral and brain-based research as empowerment 401

Assumption 1: Objectivist, essentialist, dualist metaphysics

versus intersubjectivist, nonessentialist, and nondualist
metaphysics
A large proportion of the debates about the existence of free moral agency, notably about
free will but also autonomy, have been framed within an all-​or-​nothing discussion (Gert
& Duggan 1979; Müller & Walter 2010; Baumeister & Monroe 2014). Either a person
has free moral agency or not. The idea that there could be degrees of free will, freedom,
or autonomy is often evacuated to the profit of such a polarized debate (Müller & Walter
2010; Baumeister & Monroe 2014; Racine 2017). Moreover, the corollary assumption is
that concepts capturing free moral agency are considered essences that exist somewhat
independently of the subject such that their existence can be established for all human
beings in all different contexts. Yet this tendency seems to be a challenge for any moderate
interpretation of behavioral and brain sciences’ contribution to this discussion because
empirical evidence from the behavioral and brain sciences enters a debate where the only
two defendable options are extreme and without consideration for middle-​ground posi-
tions. For example, Morar and Beever (2016, p.14), when reviewing findings from micro-
biome research come to the troubled conclusion that the status of autonomy, as an ethical
principle, is jeopardized. However, this interpretation needlessly pits knowledge about
social and biological determinants of choice against the abilities of free moral agency.
Unfortunately, there is a long tradition of dualist metaphysics where the capacity to act
freely or autonomously is salvageable only if considered to be outside the realm of caus-
ally described social, biological, and so on phenomena (see Figure 20.2a). Consequently,
more knowledge about such phenomena appears to jeopardize the ability to be a free
moral agent; the more is learned about such determinants of choice, the less freedom or
autonomy there seems to remain. Even the more nuanced position of Felsen and Reiner
(2011) describes greater knowledge about determinants of choice to be a moderate threat
to beliefs about autonomy and freedom. However, it is not the actual scientific knowledge,
but the outdated dualist metaphysics that is implicit in sweeping interpretations which is
the source of the problem and needs to be considered and criticized.
Another starting point, consistent with pragmatist theory and the concept of contextu-
alized autonomy, is offered by first granting that the concept of free moral agency origi-
nates in experience and describes, in folk psychological parlance, the ability to choose
between actions and to reflect upon desirable outcomes to then orient them according to
interests (Figure 20.1). This was well described philosophically by Gert and Duggan who
called for a reformulation of free will as the ability to will or as a volitional ability (Gert
& Duggan 1979). They posit a positive account of free moral agency as an ability to per-
form certain desired actions thereby overcoming the common fallacy that the more that
is known about the causes of an action, the less that action seems free.8
Interestingly, some recent qualitative and social psychology research has shown that,
contrary to scholarship claiming that lay views rely on substance dualism or exemption
402

402 Behavioral and brain-based research on free moral agency

from the law of causality (Bargh 2008; Montague 2008), ordinary perspectives on free
will are consistent with a positive definition of freedom as a fluctuating ability to make
a choice, acting consistently with one’s desires, and being reasonably free of constraints
(Baumeister & Monroe 2014). The challenge of determinism to free will is unclear in
lay understandings of free will because being free is viewed as something positive rather
than simply as acting outside the realm of causes. These findings have been supported
by other studies that have looked at ordinary views on free will (Baumeister & Monroe
2014). Otherwise said, the concepts describing free moral agency designate a genuine
first-​person experience of free moral agency and serve as an interpretation of these abili-
ties. This sense of free and autonomous agency could be somewhat imperfectly described
and captured by folk terminology, and it could be tricked in different ways as described by
Wegner (2002), but it alludes to a real ability that humans have and robustly attribute to
each other through different established social practices reflected in everyday interactions
and also in social and legal norms.9 As Baumeister (2008, p. 15) writes:
Freedom and choice are woven deeply into the fabric of human relations and activities. If freedom
and choice are completely illusions—​if the outcome of every choice was inevitable all along—​why
must people agonize so over decisions? Why do they argue and strive so much for the right to
decide (that is, for power and liberty)? Why has so much political, economic, and social struggle
been aimed at increasing freedom if freedom is just an illusion?

This positive account of free moral agency as a set of abilities—​and which actually is silent
on the issue of its compatibility or incompatibly with determinism—​maps well with the
functions attributed to this concept in daily life. Every time we are able to fulfill basic or
complex actions, we are comforted in our sense of being capable of acting both freely or
autonomously, and, likewise, when we are frustrated in doing so, we experience resistance
to our will and intents. As William James proposed, the feeling of effort and goal-​focused
activity “play a role in strengthening the internal sense of the will’s capabilities” (Gray
2007, p.5). If this first-​person experience and existence of free moral agency is not first
recognized, then either a person falls into the trap of explaining away free moral agency
(e.g., hard determinism) or reverts to “panicky metaphysics” (Strawson 1962), in order to
account for the basic conditions of free moral agency such as free will. Clearly, the abil-
ity to act freely or autonomously can be jeopardized by a host of factors, but knowledge
about those factors can also facilitate the realization of intents and desires such that the
ability of human beings to act upon the world is not undermined by greater knowledge of
how choices are made. The fact that free moral agency has a subjective and experiential
dimension does not make it less real; and understanding and explaining it through social,
psychological, or biological perspectives does not explain it away. As Dewey, the pre-
cursor of the concept of contextualized autonomy and free moral agency more broadly,
wrote: “we need freedom in and among actual events, not apart from them”10 (Dewey
1922, p.303)—​our ability to act upon the world is best understood as a capacity which
uses knowledge of personal, relational, social, biological, and environmental conditions
to actually enact goals and projects (Figure 20.1). The traditional opposition (based on
Kant’s work (Kant 1994)) between freedom and causality is spuriously generated by a
 403

Behavioral and brain-based research as empowerment 403

metaphysical view, which simply does not take into account seriously the basic subjective
and intersubjective experience of making free and autonomous, and sometimes less free
and autonomous, decisions. Acknowledging that this experience is the first foundation
for the actual existence of free moral agency prevents an interpretation that more knowl-
edge about its conditions actually somehow undermines this experience because the
all-​or-​none and essentialist objective nature of free moral agency is not posited; rather,
free moral agency describes agent-​dependent characteristics which can be diminished
or empowered. This is in line with the veto power interpretation of Libet: some deci-
sions might be unfree, but the power to choose at least some things cannot be reasonably
denied. Thus, empirical data gained about how different contexts can impede free moral
agency becomes valuable knowledge for the moral agent to try to overcome these barri-
ers or, if they are very difficult to surmount, to identify alternative remediation strategies
(e.g., changing the context instead of the agent). In discussions of contextual influences
on free moral agencies, studies similar to those that show that collectivist societies tend to
foster conformity whereas individualist societies tend to reinforce the value of personal
freedom and foster nonconformity, can be factored into the analysis of free moral agency.

Assumption 2: Strong fact–​value dichotomy (is–​ought fallacy)

versus the fact–​value continuum
One of the corollaries of strong interpretations of the behavioral and brain sciences is
that the ethical principles relying on the existence of the concepts of autonomy and free-
dom (e.g., respect for autonomy, protection of individual rights, and freedom) would be
imperiled because they rely on, at best, illusions or, perhaps worst, on flawed concepts
which are deficient. If, for example, free will or freedom does not exist, then they are, in a
sense, truly chimeras. And if this is the case, then such concepts should be expelled from
moral thinking to be replaced, likely, by concepts and principles compatible with a sci-
entific understanding of the world. An example of this move is Morar and Beever’s claim
that the normative value and force of autonomy are imperiled because the integrity of
autonomy is challenged by microbiome research which undermines both the traditional
and relational accounts of autonomy (Morar & Beever 2016). Similarly, Green and Cohen
(2004) contend that the legal system needs to be realigned with consequentialism based
on a deterministic view, allegedly supported by neuroscience. Otherwise said, behavioral
and brain science knowledge about different aspects of free moral agency would not only
alter how this ability is conceived of (epistemological revisionism) but actually challenge
its existence (ontological revisionism). It is true that a positivist or dichotomist interpre-
tation of the contribution of the behavioral and brain sciences does set the stage for such
a strong opposition between fact and value (Figure 20.2a), but it is by no means the only
possible epistemological stance (Figure 20.2b).
The claim that concepts describing free moral agency as free will, freedom, or autonomy
should be expelled from the discourse of ethics is based on a fallacious understanding
of the relationship between normative discourse (i.e., values, the “ought”) and descrip-
tive discourse (i.e., facts, the “is”). Claiming that knowing more about the factual aspects
40

404 Behavioral and brain-based research on free moral agency

undermines the normative force of autonomy is profoundly erroneous because it implies

that knowing more about the objective conditions of autonomy imperils not only the
existence of free moral agency but also its value and relevance.11 But, this would mean,
somehow, that what is experienced and valued would be qualitatively distinct from what
is known; experience could be invalidated by a scientific understanding of that world.
However, the capacity for human agency would be worthless if it would not have some
clear causality and logically, be describable according to the lenses of the behavioral and
brain sciences but also those of sociology, psychology, and biology, not to say of per-
sonal experience. For instance, much has been made of the fact that 65% of people fol-
low orders even when these orders are harmful and immoral. But what of the 35% that
refuse to do so? Also, it has to be noted that normative values empower certain behaviors,
specifically because they are reinforced by social influence. As Dewey commented about
liberty, a term he used to describe a richer account of free moral agency, “[w]‌hat men have
esteemed and fought for in the name of liberty is varied and complex—​but [it] certainly
has never been a metaphysical freedom of will” (Dewey 1922, p.304). Instead, Dewey pro-
posed that what matters with respect to free moral agency is the ability to carry out plans,
the ability to change them, and the power of the individual to be an actor in the course
of events. There is actually much evidence pointing to the psychological existence and
relevance of free moral agency.
Freedom and autonomy are valued because they describe a genuine ability to under-
take actions, ponder about options, and imagine actionable scenarios—​abilities which
can generate an immense sense of achievement when they lead to outcomes that help
individuals meet the challenges of daily lives and accomplish their intents (Peterson
et  al. 1995; Baumeister et  al. 1998; Baumeister 2008). Baumeister writes, rightfully in
our opinion, that “[l]‌aypersons may not understand the concept of free will in the same
way as philosophers and scientists, but they use ‘freedom’ to denote some psychological
phenomena that are powerful and important” (Baumeister 2008, p.15). Likewise, when
the ability for free moral agency is compromised or diminished, it generates alienation
(Habermas 1968), depressive feelings (Wegener et al. 2007), and apathy even in nonhu-
man animals (Seligman 1975). Furthermore, the presence of choice (freedom and auton-
omy versus no choice) has demonstrated impact on coping and stress (Glass et al. 1969,
cited in Baumeister 2008), as well as self-​motivation and healthy psychological develop-
ment (Ryan & Deci 2000, cited in Baumeister 2008). Self-​determination theory and evi-
dence supporting it, suggest that the ability to have intrinsic motivations and be able to
carry them out contributes to a sense of growth and fulfillment that foster psychological
well-​being and mental health (Ryan & Deci 2000). Likewise, when extrinsic motivations
are shared by the agents and can be meaningfully internalized, individuals experience
greater freedom or autonomy in action, even though the fulfillment of intrinsic moti-
vations contributes more to well-​being than extrinsic motivation (Ryan & Deci 2000).
However, feelings of alienation (i.e., not being able to enact one’s ability to will) can have
a negative impact on psychological well-​being. Accordingly, the existence of free moral
agency has clear support in common-​sense understandings of individual and social life as
 405

Conclusion 405

well as those of fields such as social psychology and sociology (where it is more customary
to speak of “empowerment”) (Perkins & Zimmerman 1995). Freedom presupposes hav-
ing mature powers of volition and the capacity of self-​control, but not that it is exercised
all the time (Dubljević 2013). Self-​control can be depleted and imperfect, but empiri-
cal research points toward the conclusion that it is undoubtedly present in most adults
(Baumeister et al. 1998; Moller et al. 2006; Vohs et al. 2008).12
Autonomy and free will find their value in experience. And better factual or scien-
tific understanding of the different aspects of free moral agency does not fundamen-
tally undermine the value attributed to them because knowledge does not change the
experience and exercise of free moral agency and its importance. Those claiming that
the behavioral and brain sciences could bring new insights to the understanding of free
moral agency are right, but they are wrong to conclude that ontological revisionism will
be a dominant trend or even should be the dominant trend. It is true that the abilities
described by the concepts of autonomy, freedom, and free will could be re-​described in
more accurate normative language. Pragmatist theory does grant and even encourage
the scientific reconstruction of the understanding of physical and psychological realities
(Racine 2013). However, as Dewey warned, contrary to the sweeping reductionism of
positivist and eliminativist neurophilosophy, “it will be a long time before anything of this
sort will be accomplished for human beings [in contrast to physics]. To expel traditional
meanings and replace them by ideas that are products of controlled inquiries is a slow
and painful process” (Dewey 1937, in Gouinlock 1994, p.48). Accordingly, we caution
against the desire to reduce the experience of free moral agency to more rigorous or philo-
sophical language if it leads to expelling important dimensions of the concept, as recent
research does suggest it would be the case if the thinking of the eliminativists is followed
(Monroe & Malle 2010). Meaningful contributions to the understanding of free moral
agency should be understandable through the lenses of different disciplines. Contribution
of diverse disciplines will likely provide enrichments and revisions to self-​understanding
and the understanding of other’s behaviors. It would indeed be strange if, like proposed by
Churchland (1981), the behavioral and brain sciences would systematically explain away
the phenomena initially triggering the scientific inquiries. There are cases of ontological
revisions (e.g., phlogiston in chemistry), but it might be more fruitful to expect that most
scientific discoveries in neuroscience and psychology will enrich the understanding of
common-​sense (folk psychological) concepts that currently have some traction in indi-
vidual and social life (e.g., law, ethics, and politics).

Conclusion
Neuroscience has been heralded as a game-​changing field for its impact on the under-
standing of free human agency. Research in diverse fields examining, for example, social
determinants of choice, brain activity preceding action, implicit biases, and more recently,
the microbiome and its impact on brain function and behavior have all been interpreted
as radically jeopardizing the existence of free moral agency. In this chapter we did not
406

406 Behavioral and brain-based research on free moral agency

scrutinize the scientific and methodological foundations for such claims, which we have
done elsewhere (Dubljević 2013; Saigle et  al. 2015). We tackled another set of issues
related to the conceptual and metaphysical assumptions underlying common interpreta-
tions of behavioral and brain science research. Much possible uptake of the behavioral and
brain sciences with respect to the understanding of free moral agency could be hindered
by strong dualistic metaphysical assumptions as well as dichotomous interpretations of
the fact–​value continuum. A  resolution can be found in pragmatist theory and recent
research in social psychology. These support the concept of contextualized autonomy that
recognizes explicitly that different aspects of free moral agency originate in a first-​person
experience of agency. Moreover, the value placed on the abilities captured by the con-
cept of free moral agency is not necessarily jeopardized by a factual understanding from
the behavioral and brain sciences. In fact, knowledge can also empower moral agency.
Behavioral and brain sciences provide us with important contributions and information
on how free moral agency is limited and could even be seen as a depletable resource.
However, scientific evidence can empower choices by teaching when to conserve limited
resources, and when to undertake or delay decisions.

Acknowledgments
Support for this work comes from the Social Sciences and Humanities Research Council
(Racine), the Fonds de recherche du Québec–​Santé for career awards (Racine), and the
Banting Postdoctoral Fellowships Programme (Dubljević). We extend our thanks to
members of the Neuroethics Research Unit for feedback on previous versions of this man-
uscript. Special thanks to Kaylee Sohng, Simon Rousseau-​Lesage, and Roxanne Caron for
editorial assistance in the preparation of this manuscript. Some parts of this chapter have
appeared previously in a short paper by the authors (Racine & Dubljević 2016).

Notes
1. We will introduce a finer-​grained distinction between free will, freedom, and autonomy (and their
synonyms), although “freedom” is often used as a generic term to describe these three different
aspects of free moral agency.
2. “Renoncer à sa liberté c’est renoncer à sa qualité d’homme, aux droits de l’humanité, même à ses
devoirs” (Rousseau 1992, p.34).
3. We also thereby acknowledge that there are many different aspects of agency (e.g., authenticity and
responsibility) which we do not tackle since our discussion deals with the issue of freedom in a
general sense and in the context of ethics, hence the qualifier “moral” used throughout even though
some of our points about free agency could be valid beyond the context of ethics.
4. We frequently use the term “abilities” to stress the active dimension of these concepts; the term
“capacities” has a more static connotation and reflects less clearly the context-​dependent and agent-​
dependent nature of these concepts. However, when the abilities are not engaged, we use “capacities.”
5. The concepts of autonomy, liberty, and free will have been used in different ways. Our conceptualiza-
tion does not obviate other uses. It is simply meant to clarify how we use these terms in this chapter.
The most important idea that is conveyed is the gradual expansion in the substantive commitments
from free will to autonomy. One of us (Dubljević 2013) has used a different designation of the three
 407

References 407

distinct levels (basic autonomy, free will, ideal of autonomy), but in this chapter we opted not to use
autonomy twice, so as not to confuse the reader.
6. The tendency to conform is a stable trait with observable neuroanatomical correlates. The upshot
is that not only do some people conform more than others, but that the neuroscience evidence
may actually predict who is more likely to conform and who is more likely to resist such external
influences.
7. In this chapter, we do not draw a strong distinction between the concepts of microbiome and
microbiota.
8. Gert and Duggan (1979, p.197) write:  “We are thus in agreement with Moore that the question
whether man has Free Will is best viewed as a question about whether he has a certain power (we
prefer to talk about ability) not as a question about whether what a man has willed to do was the
result of coercion.”
9. The fact that our abilities can be tricked or manipulated does not imply that we do not have them.
Otherwise, visual illusions would suffice to debunk the fact that we have the ability to see, and rely on
sight accurately, at least most of the time.
10. Dewey did not adopt the tripartite distinction (Figure 20.1) but stressed nevertheless how free will
was a limited ability (in contrast to actual freedom).
11. Consider an analogy with slavery: the lack of freedom experienced by slaves does not mean that they
lack appreciation or value of freedom, or that the right to be free has no meaning.
12. Vohs and colleagues equate self-​control and self-​regulation (which is the literal translation of the
word autonomy) and define it as “the self-​exerting control to override a prepotent response, with the
assumption that replacing a response with another is done to attain goals and conform to standards”
(Vohs et al. 2008, p.884). Moller and colleagues, in their self-​determination theory make the distinc-
tion between self-​control, which is ego-​depleting, and self-​regulation, which is not ego-​depleting
(Moller et al. 2006). “Ego depletion” refers to the phenomenon of diminished ability to enact self-​
regulation with repeated efforts, and neuroscience evidence supports the view that relevant capacities
for exertion of control exist (Berkman & Miller-​Ziegler 2013; Wagner & Heatherton 2013).

References
Amodio, D.M. (2014). The neuroscience of prejudice and stereotyping. Nature Reviews Neuroscience,
15(10), 670–​682.
Asch, S.E. (1955). Opinions and social pressure. Scientific American, 193(5), 33–​35.
Bargh, J.A. (2008). Free will is unnatural. In: Baer, J., Kaufman, J.C., and Baumeister, R.F. (Eds.) Are We
Free? Psychology and Free Will, pp.128–​154. New York: Oxford University Press.
Bargh, J.A. and Chartrand, T.L. (1999). On the unbearable automaticity of being. American
Psychologist, 54(7), 462–​479.
Baron, R.S., Vandello, J.A., and Brunsman, B. (1996). The forgotten variable in conformity
research: impact of task importance on social influence. Journal of Personality and Social Psychology,
71(5), 915–​927.
Baumeister, R.F. (2008). Free will in scientific psychology. Perspectives on Psychological Science,
3(1), 14–​19.
Baumeister, R.F. and Monroe, A.E. (2014). Recent research on free will: Conceptualizations, beliefs, and
processes. In: Zanna, M.P. and Olson, J.M. (Eds.) Advances in Experimental Social Psychology (Vol.
50), pp. 1–​52. Burlington, MA: Academic Press.
Baumeister, R.F., Bratslavsky, E., Muraven, M., and Tice, D.M. (1998). Ego depletion: is the active self a
limited resource? Journal of Personality and Social Psychology, 74(5), 1252–​1265.
408

408 Behavioral and brain-based research on free moral agency

Benson, P. (1990). Feminist second thoughts about free agency. Hypatia, 5(3), 47–​64.
Berkman, E.T. and Miller-​Ziegler, J.S. (2013). Imaging depletion: fMRI provides new insights into the
processes underlying ego depletion. Social Cognitive and Affective Neuroscience, 8(4), 359–​361.
Bond, R. (2005). Group size and conformity. Group Processes & Intergroup Relations, 8(4), 331–​354.
Bond, R. and Smith, P.B. (1996). Culture and conformity: a meta-​analysis of studies using Asch’s
(1952b, 1956) line judgement task. Psychological Bulletin, 119(1), 111–​137.
Brownstein, M. (2016). Implicit bias. The Stanford Encyclopedia of Philosophy. Available from: http://​
plato.stanford.edu/​archives/​spr2016/​entries/​implicit-​bias/​ [accessed March 30, 2016].
Campbell-​Meiklejohn, D.K., Kanai, R., Bahrami, B., et al. (2012). Structure of orbitofrontal cortex
predicts social influence. Current Biology, 22(4), R123–​R124.
Churchland, P.M. (1981). Eliminative materialism and the propositional attitudes. Journal of Philosophy,
77(2), 67–​90.
Cialdini, R.B. and Goldstein, N.J. (2004). Social influence: compliance and conformity. Annual Review
of Psychology, 55, 591–​621.
Cryan, J.F. and Dinan, T.G. (2012). Mind-​altering microorganisms: the impact of the gut microbiota on
brain and behaviour. Nature Reviews Neuroscience, 13(10), 701–​712.
Dewey, J. (1922). Human Nature and Conduct: An Introduction to Social Psychology. New York: Holt.
Dewey, J. (1937). An address delivered before the College of Physicians in St. Louis, April 21, 1937,
republished in Gouinlock, J. (Ed.) The Moral Writings of John Dewey, Revised Edition (Great Books
in Philosophy), pp.47–​55. Amhert, NY: Prometheus Books.
Dubljević, V. (2013). Autonomy in neuroethics: political and not metaphysical. American Journal of
Bioethics Neuroscience, 4(4), 44–​51.
Faucher, L. (2016). Revisionism and moral responsibility for implicit attitudes. In: Brownstein, M. and
Saul, J. (Eds.) Implicit Bias & Philosophy: Volume 2, Moral Responsibility, Structural Injustice, and
Ethics, pp.115–​144. Oxford: Oxford University Press.
Felsen, G. and Reiner, P.B. (2011). How the neuroscience of decision making informs our conception of
autonomy. American Journal of Bioethics Neuroscience, 2(3), 3–​14.
Fiske, S.T. (2010). Social Beings: Core Motives in Social Psychology. Hoboken, NJ: Wiley.
Gert, B. and Duggan, T.J. (1979). Free will as the ability to will. Noûs, 13(2), 197–​217.
Gilligan, C. (1993). In a Different Voice: Psychological Theory and Women’s Development. Cambridge,
MA: Harvard University Press.
Glass, D.C., Siger, J.E., and Friedman, L.N. (1969). Psychic cost of adaptation to an environmental
stressor. Journal of Personality and Social Psychology, 12(3), 200–​210.
Gray, M.T. (2007). Freedom and resistance: the phenomenal will in addiction. Nursing Philosophy,
8(1), 3–​15.
Greene, J.D. and Cohen, J. (2004). For the law, neuroscience changes nothing and everything.
Philosophical Transactions of the Royal Society B: Biological Sciences, 357(1451), 1117–​1785.
Habermas, J. (1968). Technik und Wissenschaft als „Ideologie.” Frankfurt am Main: Suhrkamp.
Haggard, P. (2005). Conscious intention and motor cognition. Trends in Cognitive Sciences, 9(6),
290–​295.
Haggard, P. (2011). Decision time for free will. Neuron, 69(3), 404–​406.
Haggard, P., Cartledge, P., Dafydd, M., and Oakley, D.A. (2004). Anomalous control: when ‘free-​will’ is
not conscious. Consciousness and Cognition, 13(3), 646–​654.
Holroyd, J. (2012). Responsibility for implicit bias. Journal of Social Philosophy, 43(3), 274–​306.
Izuma, K. (2013). The neural basis of social influence and attitude change. Current Opinion in
Neurobiology, 23(3), 456-​462.
Kant, E. (1994). Fondements de la métaphysique des mœurs. Paris: Delagrave.
 409

References 409

Keene, S. (2011). Social bias: prejudice, stereotyping, and discrimination. The Journal of Law
Enforcement, 1(3), 1–​5.
Kramer, P. and Bressan, P. (2015). Humans as superorganisms: how microbes, viruses, imprinted
genes, and other selfish entities shape our behavior. Perspectives on Psychological Science, 10(4),
464–​481.
Libet, B., Wright, E.W., and Gleason, C.A. (1982). Readiness-​potentials preceding unrestricted
‘spontaneous’ vs. pre-​planned voluntary acts. Electroencephalography and Clinical Neurophysiology,
54(3), 322–​335.
Libet, B., Gleason, C.A., Wright, E.W., and Pearl, D.K. (1983). Time of conscious intention to act in
relation to onset of cerebral activity (readiness-​potential). The unconscious initiation of a freely
voluntary act. Brain, 106(3), 623–​642.
MacKenzie, C. and Stoljar, N. (2000). Relational Autonomy: Feminist Perspectives on Automony, Agency,
and the Social Self. Oxford: Oxford University Press.
Mandela, N. (2011). Nelson Mandela by Himself: The Authorized Book of Quotations.
London: MacMillan.
Mele, A. (2009). Effective Intentions: The Power of Conscious Will. Oxford: Oxford University Press.
Milgram, S. (1974). Obedience to Authority. New York: Harper & Row.
Moller, A.C., Deci, E.L., and Ryan, R.M. (2006). Choice and ego-​depletion: the moderating role of
autonomy. Personality and Social Psychology Bulletin, 32(8), 1024–​1036.
Monroe, A.E. and Malle, B.F. (2010). From uncaused will to conscious choice: the need to study,
not speculate about people’s folk concept of free will. Review of Philosophy and Psychology, 1(2),
211–​224.
Montague, P.R. (2008). Free will. Current Biology, 18(14), R584–​R585.
Morar, N. and Beever, J. (2016). The porosity of autonomy: social and biological constitution of the
patient in biomedicine. American Journal of Bioethics, 16(2), 34–​45.
Morse, S. (2006). Brain overclaim syndrome and criminal responsibility: a diagnostic note. Ohio State
Journal of Criminal Law, 3, 397–​412.
Morse, S. (2008). Psychopathy and criminal responsibility. Neuroethics, 1(3), 205–​212.
Müller, S. and Walter, H. (2010). Reviewing autonomy: implications of the neurosciences and the free
will debate for the principle of respect for the patient’s autonomy. Cambridge Quarterly of Healthcare
Ethics, 19(2), 205–​217.
Neufeld, K.A. and Foster, J.A. (2009). Effects of gut microbiota on the brain: implications for psychiatry.
Journal of Psychiatry & Neuroscience, 34(3), 230–​231.
Nissani, M. (1990). A cognitive reinterpretation of Stanley Milgram’s observations on obedience to
authority. American Psychologist, 45(12), 1384–​1385.
Perkins, D.D. and Zimmerman, M.A. (1995). Empowerment theory, research, and application.
American Journal of Community Psychology, 23(5), 569–​579.
Peterson, C., Maier, S.F., and Seligman, M.E.P. (1995). Learned Helplessness: A Theory for the Age of
Personal Control. New York: Oxford University Press.
Racine, E. (2013). Pragmatism and the contribution of neuroscience to ethics. Essays in the Philosophy
of Humanism, 21(1), 13–​20.
Racine, E. (2017). A proposal for a scientifically-informed and instrumentalist account of free will and
voluntary action. Frontiers in Psychology, in press.
Racine, E. and Dubljević, V. (2016). Porous or contextualized autonomy? Knowledge can empower
autonomous moral agents. American Journal of Bioethics, 16(2), 48–​50.
Racine, E., Nguyen, V., Saigle, V., and Dubljević, V. (2016). Media portrayal of a landmark
neuroscience experiment on free will. Science and Engineering Ethics. Advance online publication.
doi:10.1007/​s11948-​016-​9845-​3
410

410 Behavioral and brain-based research on free moral agency

Racine, E., Aspler J., Forlini, C., and Chandler, J. (2017). Broadening the lenses on complementary and
alternative medicines in preclinical Alzheimer’s disease: Tensions between autonomy and contextual
determinants of choice. Kennedy Institute of Ethics Journal, 27(1), 1–41.
Rousseau, J.-​J. (1992). Du Contrat Social. Paris: GF-​Flammarion.
Rule, N.O., Freeman, J.B., Moran, J.M., Gabrieli, J.D., Adams, R.B., Jr., and Ambady, N. (2010).
Voting behavior is reflected in amygdala response across cultures. Social Cognitive and Affective
Neuroscience, 5(2–​3), 349–​355.
Ryan, R.M. and Deci, E.L. (2000). Self-​determination theory and the facilitation of intrinsic motivation,
social development, and well-​being. American Psychologist, 55(1), 68–​78.
Saigle, V., Dubljević, V., and Racine, E. (2015). The impact of a landmark paper on the concept of free
will: reconsidering the legacy of the Libet et al. EEG experiments. American Journal of Bioethics
Neuroscience, 6(4), 91.
Seligman, M.E.P. (1975). Helplessness: On Depression, Development, and Death. San Francisco, CA: W.H.
Freeman.
Sherwin, E., Rea, K., Dinan, T.G., and Cryan, J.F. (2016). A gut (microbiome) feeling about the brain.
Current Opinion in Gastroenterology, 32(2), 96–​102.
Smith, K. (2011). Neuroscience vs philosophy: taking aim at free will. Nature, 477(7362), 23–​25.
Strawson, P.F. (1962). Freedom and resentment. Proceedings of the British Academy, 48, 1–​25.
Sudo, N., Chida, Y., Aiba, Y., et al. (2004). Postnatal microbial colonization programs the
hypothalamic-​pituitary-​adrenal system for stress response in mice. The Journal of Physiology,
558(1), 263–​275.
Vohs, K.D., Baumeister, R.F., Schmeichel, B.J., Twenge, J.M., Nelson, N.M., and Tice, D.M. (2008).
Making choices impairs subsequent self-​control: a limited-​resource account of decision making,
self-​regulation, and active initiative. Journal of Personality and Social Psychology, 94(5), 883–​898.
Wagner, D.D. and Heatherton, T.F. (2013). Self-​regulatory depletion increases emotional reactivity in
the amygdala. Social Cognitive and Affective Neuroscience, 8(4), 410–​417.
Wegener, J.R., Ludlow, C.E., Olsen, A.J., Tortosa, M., and Wintch, P.H. (2007). Ego depletion: a
contributing factor of hopelessness depression. Intuition, 3, 12–​17.
Wegner, D. (2002). The Illusion of Conscious Will. Cambridge, MA: MIT Press.
Wolpe, P.R. (2002). The neuroscience revolution. The Hastings Center Report, 32(4), 8.
 41

Chapter 21

Cognitive enhancement of today may

be the normal of tomorrow
Fabrice Jotterand

Introduction
Contemporary debates on human enhancement often characterize the notion of enhance-
ment as morally troubling because it undermines some deeply held beliefs concerning
humanity and challenges what some deem as the appropriate use of biotechnologies to
serve human ends. Most techniques and procedures beyond therapeutic aims raise the
eyebrows of many concerned with the potential harmful implications of enhancement
technologies. Fewer people might oppose the enhancement of human physiological and
mental capacities if these techniques address specific diseases and disorders. If the goal of
any intervention is therapeutic, it falls under the purview of medicine. Beyond therapy,
where the aims of enhancement are not well defined, the moral landscape becomes less
clear. To say that human enhancement strives to the betterment of the human condition
or personal fulfillment does not make any normative claim robust enough to justify why
we ought to embrace any type of enhancement. In addition, enhancement is often gauged
against therapy to provide the backdrop necessary to discriminate what belongs to the
domain of medicine and healthcare as well as to provide conceptual clarity. However, the
conceptual distinction between therapy and enhancement has limitations that restrain
our ability to demarcate the types of enhancements that could indeed benefit some
individuals.
In light of these considerations, this chapter considers the use of cognitive enhancers
in healthy individuals with cognitive impairment caused by mental disability, that is, dis-
abled people with limited functioning but who are otherwise healthy and in a stable con-
dition. The use of cognitive enhancers in healthy individuals with cognitive impairment
illustrates the necessity to make more nuanced distinctions when examining the issue of
cognitive enhancement technologies in order to harness their potential clinical benefits
(Jotterand et al. 2015). The main objectives of this analysis are twofold: (1) to outline some
of the problems associated with the attempt to distinguish the concept of enhancement
from therapy. Both concepts assume that an understanding of health and normality is dif-
ficult to establish. I argue that these two concepts cannot be the basis for the assessment of
the use of cognitive enhancers in people with mental impairment because the restoration
of health or the attainment of normality cannot be realized in the case, for instance, of
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412 Cognitive enhancement of today may be the normal of tomorrow

people with cerebral palsy (permanent state); and (2) to show the relevance of the distinc-
tion between two types of enhancement in the attempt to demonstrate why the notion
of human enhancement, if it aims at the improvement of the quality of life of individuals
with mental impairments, might become part of the therapeutic language of tomorrow.
To this end, I introduce the concept of the clinical ideal to justify my claim about the use
of cognitive enhancers in the mentally impaired.
The first section of this chapter examines the various conceptualizations of enhance-
ment found in the literature, especially as outlined by Ruth Chadwick and Nicolas Agar.
These two scholars present helpful categorizations of enhancement that will provide the
basis for the development of the concept of the clinical ideal. Chadwick suggests four
approaches to enhancement helpful to understand how the concept is used in current
debates whereas Agar offers a valuable distinction between the objective ideal and the
anthropocentric ideal. In the second section, building on the work of Agar, I argue that
both ideals have limited clinical relevance and favor the clinical ideal, which allows for
the evaluation of the concept of enhancement in the context of clinical interventions. The
final section looks at the implications of the clinical ideal in relation to the use of cognitive
enhancers in the mentally impaired. I contend that the moral evaluation of enhancement
must take place within the context of the patient’s clinical condition and in relation to the
notion of quality of life.

Therapy and enhancement: Two evolving concepts

The pursuit of human enhancement through the transcending of human biological capa-
bilities can be traced back to the 17th century in the writings of philosophers such as
Francis Bacon (The New Atlantis, 1627), René Descartes (Discours de la méthode pour bien
conduire sa raison et chercher la vérité dans les sciences, 1637), and Marquis de Condorcet
(Esquisse d’un tableau historique des progrès de l’esprit humain, 1795) who suggested that
human nature can be improved. Descartes, for instance, in his Discourse on Method
(1637), advanced the idea that the human species can become master and possessor of
nature whereas de Condorcet considered the possibility of human enhancement asking
rhetorically:
[M]‌ay it not be expected that the human race will be meliorated by new discoveries in the sciences
and the arts, and, as an unavoidable consequence, in the means of individual and general prosper-
ity; by farther progress in the principles of conduct, and in moral practice; and lastly, by the real
improvement of our faculties, moral, intellectual and physical…? (de Condorcet 1795)

Contrary to the theoretical nature of these early reflections by Bacon, Descartes, and
de Condorcet, some of the contemporary conceptualizations of human enhancement
can be validated through use of specific technologies, either under development or
already implemented. In current discussions, enhancement usually “characterize[s]‌
interventions designed to improve human form or functioning beyond what is neces-
sary to sustain or restore good health” (Juengst 1998, p.29). Cognitive enhancement
encompasses “the amplification or extension of core capacities of the mind, using
 413

Therapy and enhancement: Two evolving concepts 413

augmentation or improvements of our information processing systems” (Sandberg

2011). These core capacities include information acquisition (perception), active
processing of information (attention), the ability to comprehend concepts and their
meaning (understanding), and the capacity to store and retrieve information (mem-
ory). Cognitive enhancement comprises two types of technologies:  (1)  psychophar-
maceutical enhancers (modafinil (Provigil®), dextroamphetamine, methylphenidate
(Ritalin®), fluoxetine (Prozac®), donepezil (Aricept®), and propranolol (Inderal®); and
(2) brain stimulation technologies (deep brain stimulation, transcranial direct current
stimulation, and transcranial magnetic stimulation). In both instances, these modali-
ties are used for therapeutic purposes, but when used in healthy subjects they may
have enhancement effects such as increased focus and concentration; enhanced mood,
memory, and learning; procedural learning tasks; motor learning; and visuomotor
coordination tasks (Morein-​Z amir et  al. 2007, 2008; Sandberg 2011; Houdsen et  al.
2011; Smith & Farah 2011; Gehring et al. 2012).
A closer look at how the concept of enhancement is used in the literature, however,
reveals a different interpretation of what it entails. Two analyses are worth considering,
the first by Ruth Chadwick and the second by Nicolas Agar. In her examination of the var-
ious interpretations of enhancement, Chadwick (2008) suggests four categories: (1) the
“beyond therapy” view (President’s Council on Bioethics 2003) holds the position that
any procedures beyond therapeutic interventions are considered a type of enhancement.
This interpretation, however, has deficiencies since some interventions might be viewed
as enhancement but might be partly therapeutic too. In other words, the challenge is not
only to define enhancement in relation to therapy. Therapy itself is likewise a difficult
concept to describe and to suggest that the intentions behind any intervention can deter-
mine whether that particular intervention is therapeutic does not provide the necessary
criteria to explain the difference between therapy and enhancement. (2) The additionality
view holds that enhancement is understood quantitatively and signifies that “to enhance
x is to add to, or exaggerate, or increase x in some respect.” But in this case, without being
“characteristic-​specific,” it is not possible to establish what counts as therapy or enhance-
ment. To enhance cannot be understood in generic terms but requires focusing on par-
ticular capacities for moral evaluation (Chadwick 2008, pp.28–​29). (3) The improvement
view (enhancement understood qualitatively) means that to enhance is to improve or to
make better. This view is not very useful because it does not provide the criteria neces-
sary to determine what is considered an improvement. Any knowledge of the goals and
intentions behind any request for improvement (i.e., enhancement) is contingent upon
qualitative judgments and therefore makes it difficult to assess from a moral standpoint.
(4) The umbrella view. Considering the challenges of the previous three approaches, this
view offers a venue to assess enhancement case by case since it considers various potential
changes: enhancement may be therapeutic (contra the “beyond therapy” view), enhance-
ment may not add anything (contra the additionality view); and enhancement may not
be an improvement (contra the improvement view) (See Table 21.1 for a side-​by-​side
comparison of different definitions of enhancement.)
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414 Cognitive enhancement of today may be the normal of tomorrow

Table 21.1  Comparative table for the definition of enhancement

Concepts Definitions Key features and challenges

Views (Chadwick)

Beyond therapy view Any procedures beyond thera- Some interventions might be viewed
peutic interventions are consid- partly as enhancement and partly as
ered a type of enhancement therapy
Additionality view Enhancement is understood Requires focus on specific capacities
quantitatively: To enhance x is to establish what defines therapy or
to add to, or exaggerate, or enhancement
increase x in some respect Requires focus on particular capaci-
ties for moral evaluation
Improvement view Enhancement is understood Does not provide the criteria neces-
qualitatively: To enhance is to sary to determine what is considered
improve or to make better an improvement
Contingent upon qualitative
judgments
Difficult to assess from a moral
standpoint
Umbrella view Enhancement is assessed case by Too generic and does not provide
case to determine its nature: a proper framework for conceptual
◆ Enhancement may be thera- clarity
peutic (contra the beyond
therapy view)
◆ Enhancement may not
add anything (contra the
additionality view)
◆ Enhancement may not be
an improvement (contra the
improvement view)
Ideals

Objective ideal (Agar) All things being equal, tech- Prudential value of enhancement
nologies that produce greater is based on the degree to which it
enhancements are intrinsically objectively enhances human capacity
more valuable than other tech- Requires setting objective standards
nologies that generate fewer to evaluate levels of enhanced
enhancement outcomes capacities
Anthropocentric ideal Enhancement is evaluated based Assigns value to enhancement
(Agar) on a balance between the instru- relative to human standards and
mental and intrinsic value of the whether or not an enhancement is
enhanced capacity beneficial to the recipient based on
standardized norms
Requires a normative framework
to determine how enhancement
advances the well-​being of the
human species within the normal
range of human capacities.
 415

Therapy and enhancement: Two evolving concepts 415

Table 21.1  Continued

Concepts Definitions Key features and challenges

Clinical ideal (Jotterand) Enhancement is evaluated Requires setting contextual standards
based on whether it enhances Necessitates the development of cri-
the physical, mental, and social teria to evaluate degrees of enhance-
capacities and the overall ment in relation to quality of life
quality of life of an individual
with mental impairment, where
the baseline is disabled, and in
the context of life (contextual
standards)

While Chadwick’s categorization of enhancement is helpful in many respects (espe-

cially the umbrella view), Nicholas Agar presents a more fruitful classification to define
human enhancement with regard to the focus of this chapter: the objective ideal and the
anthropocentric ideal. The objective ideal states “an enhancement has prudential value
commensurate with the degree to which it objectively enhances a human capacity.” In
other words, this approach holds that, all things being equal, technologies that produce
greater enhancements are intrinsically more valuable than other technologies that gener-
ate less enhancement outcomes. This position is favored by transhumanists since they
seek transcending our biological limitations, hence the maximization of human trans-
formation. On the other hand, the anthropocentric ideal states: “some enhancements of
greater objective magnitude are more prudentially valuable than enhancements of lesser
magnitude … or [it] assigns value to enhancement relative to human standards” (Agar
2014, pp.17, 27). This view asserts that the normal range of human capacities can be
determined and that an enhancement can be evaluated based on a balancing between the
instrumental and intrinsic value of the enhanced capacity. The enhancement of a human
capacity has more intrinsic value if “instantiating more valuable internal goods” (i.e., an
individual can directly benefit from enhancement only if that person enhances her/​him-
self) whereas it has more instrumental value if it produces qualitative and quantitative
superior external goods (goods that depends on social circumstances) (Agar 2014, p.29).
The objective ideal approach is a vision of enhancement supported by transhuman-
ism but is somewhat at the margin of reflections pertaining to the clinical setting
since it focuses on the radical enhancement of the human species. Transhumanists do
not seek to address disorders or illnesses as such but rather improve the condition of
the human species through technological means (posthumanity). Efforts to develop
enhancement technologies, on their account, should be geared toward transcending
the limitations of our brains and bodies as the survival of our species is closely linked
to a technological future.
The anthropocentric ideal approach represents a more promising conceptualization
with regard to the issue addressed in this chapter since enhancement is understood within
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416 Cognitive enhancement of today may be the normal of tomorrow

the context of personal benefits (internal goods) and social benefits (external goods).
Accordingly, the value of enhancement is not contingent upon an evaluative framework
that fosters the maximization of the enhancement of human capacities but rather on the
enhancement of the capacities of a particular individual based on his or her unique per-
sonal goals and values. However, according to Agar, the value of an enhancement is relative
to the degree of prudential value in relation to the objective degree of enhancement within
the normal range of human capacities. Beyond a certain point, he contends, enhancement
becomes highly hypothetical, if not unrealistic, because it lacks objectivity with regard to
its feasibility, and therefore its degree of prudential value decreases due to the uncertainty
of how individuals could potentially be affected negatively by specific enhancements.
The anthropocentric ideal offers a potential way to evaluate the use of cognitive enhanc-
ers in people with mental impairments. Contrary to the objective ideal approach, the
anthropocentric ideal specifically focuses on the established range of normal human
capacities to evaluate the prudential value of particular enhancing technologies. As Agar
puts it: “enhancement beyond human norms encompasses interventions whose purpose
is to boost levels of functioning beyond biological norms” (Agar 2014, p.19). Thus, he
assumes that the normal range of human capacities can be determined based on biologi-
cal attributes of normal functioning, a claim I will challenge in the next section.
While Agar’s distinction is valuable in many ways, I propose a third way of evaluating
enhancement, especially since the objective ideal and the anthropocentric ideal, in my
estimation, have limited clinical relevance. I am proposing what I call the clinical ideal
based on the conceptualization of diseases as clinical problems (Engelhardt 1984).

The clinical ideal and enhancements

Diseases as clinical problems
In order to explain what I mean by clinical ideal, I will turn first to the concept of dis-
ease. Elsewhere, in relation to prison medicine, I outline why describing diseases as clini-
cal problems (Engelhardt 1984) represents a more satisfactory account than descriptive
explanations such as the ones adopted by Christopher Boorse (1975, 1977) and Leon Kass
(1985) (Jotterand & Wangmo 2014).
Usually the term disease refers to a condition that is outside a set of functional stan-
dards within human biology. Boorse, for instance, states that the concept of disease can be
understood in relation to the notion of species-​typical levels of species-​typical functions
(Boorse 1975, 1977). Living organisms have an organization of biological functions that
Boorse defines according to the following four criteria:
1) the reference class is a natural class of organisms of uniform functional design; specially, an age
group of a sex of a species; 2) normal function of a part or process within members of the reference
class is a statistically typical contribution by it to their individual survival and reproduction; 3) a
disease is a type of internal state which is either an impairment of normal functional ability, i.e., a
reduction of one or more functional abilities below typical efficiency, or a limitation on functional
ability caused by environmental agents; 4) health is the absence of disease. (Boorse 1997, pp.7–​8)
 417

The clinical ideal and enhancements 417

These criteria characterize a framework based on biostatistical analysis that provides stan-
dards of normal functioning (or healthy states) for which any deviation constitutes a state
of disease. Kass likewise suggests that health, or the absence thereof, is based on biological
standards. Each species displays specific bodily functionalities that can be recognized or
determined by the specificities of its organism (Kass 1985).
Engelhardt, however, rejects the idea that diseased states can be established uniquely in
terms of species-​typical levels of species-​typical functions. The indeterminateness of the
forces of nature does not allow establishing a taxonomy of disease in relation to the func-
tional organization of the body (Engelhard 1996). In addition, a species, the human spe-
cies for instance, displays a range of characteristic polymorphisms that demands a specific
understanding of what we mean by human nature, its purpose, and its values, which in
turn justify the normality or abnormality of biological attributes (Engelhardt 1996). These
values operate in a proscriptive manner since they inform what behaviors and habits (e.g.,
smoking, unhealthy diet) affect a person’s health and therefore are considered detrimental
to a person’s health. In short, conceptualizations of health and disease are the result of a
complex interaction between values and norms, in addition to biological standards, that
qualify specific understandings of well-​being and human flourishing (Engelhardt 1996).
In contrast to a descriptive account of disease, Engelhardt suggests considering diseases
as clinical problems. The focus of clinical medicine is to address questions of pain, expec-
tations concerning human form and grace, physical aptitudes, and mental capacities inso-
far as they affect a person’s ability to achieve specific human goals and ends (Engelhardt
1984). This means that diseases are not considered as abnormalities outside the scope of
what is deemed species-​typical levels of species-​typical functions. Diseases, as clinical
problems, are contextualized based on the goals, ends, and notions of human flourishing
held by individuals suffering from incapacitating ailments.
Based on the above analysis, I would argue that enhancement cannot be understood
outside a normative framework and therefore without contextualizing enhancement in
relation to notions of human flourishing, goals, and ends debates will remain somewhat
entrenched in ideological positions rather than careful critical enquiry. In addition, as
I stated earlier, my goal is to examine the concept of enhancement within the clinical con-
text. To this end, I suggest that describing the notion of enhancement as a clinical ideal
allows disentangling enhancement from extreme applications such as transhumanism,
and from a narrow explanation based on a normal range of human capacities. In so doing,
I consider the possibility of enhancement as a means to address clinical problems rather
than as a way to promote the agenda of transcending the boundaries of human biology
to achieve a posthuman state. But in order to justify this claim, an important distinction
between two types of enhancement must be made as I show in what follows.

Enhancement #1 versus enhancement #2

Elsewhere I  make an important conceptual distinction between enhancement #1 and
enhancement #2 (Jotterand et al. 2015). Enhancement #1 is associated with the enhance-
ment of healthy people with no cognitive impairments. This means that these individuals
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418 Cognitive enhancement of today may be the normal of tomorrow

at baseline are nondisabled (normal function) and interventions in unhealthy individuals

within that group of people imply therapy if the goal is to restore baseline function whereas
in healthy individuals any intervention resulting in the enhancement of cognitive capaci-
ties is equated with enhancement #1. This is usually how people will find the distinction
between therapy and enhancement in the bioethics literature. Enhancement #2, however,
starts with a baseline disabled (limited function). These individuals are healthy but have
cognitive impairments that limit their ability to function normally in major life activities
(e.g., speaking, learning, communicating, interacting with others, caring, walking, sit-
ting, and standing). This patient population is affected by genetic disorders, illnesses, or
injuries that result in conditions such as cerebral palsy with accompanying developmental
delay. Therapeutic interventions are warranted if these people have other underlying con-
ditions that make them unhealthy but individuals who do not suffer from any ailment and
have cognitive impairments might benefit from cognitive enhancers (enhancement #2).
The distinction between enhancement #1 and enhancement #2 is critical to the main
argument presented in this chapter. Conceptually, it demonstrates that enhancement
ought not to be limited to issues related to a posthuman agenda but could, in principle,
become part of the therapeutic language of tomorrow under specific conditions. When
enhancement is associated with the idea of transcending the limitations of our brains
and bodies, it implies particular values and a vision of the human future that does not
capture the realities and frailties of this life in contrast to a potential enhanced existence
(posthuman condition). Such discourse relegates discussion about the clinical implica-
tions of enhancement to concerns about the current human condition, which is exactly
what the strongest proponents of transhumanism want to transcend. In their view, human
nature is improvable and can legitimately justify “reform[ing] ourselves and our nature
in accordance with human values and personal aspirations” (Bostrom 2005 p.205). This
perspective on the enhancement project does not include carefully any clinical aspects. It
polarizes the debate over enhancement in ways that do not consider how some enhance-
ments could actually be beneficial for the improvement of the quality of life of individ-
uals whose levels of functioning cannot be regained or achieved in comparison to the
nondisabled.

Clinical ideal
To reiterate Agar’s earlier distinction, the objective ideal argues that the prudential value
of enhancement is based on the degree to which it objectively enhances human capac-
ity and therefore adopts a position that demands a set of objective standards to evaluate
levels of enhanced capacities. On the other hand, the anthropocentric ideal assigns value
to enhancement relative to human standards, that is, whether or not it benefits the recipi-
ent of an enhancement based on standardized norms. This approach assumes a norma-
tive framework that determines how enhancement advances the well-​being of the human
species.
In contrast to these two ideals, the clinical ideal assigned value to enhancement if it
enhances the physical, mental, and social capacities and the overall quality of life of an
 419

Clinical ideal and mental impairment 419

individual with mental impairment (baseline disabled) in the context of life (contextual
standards). The clinical ideal facilitates the introduction of the notion of enhancement in
the clinical language without the need to contrast it or oppose it to the notion of therapy. It
limits its scope of considerations to the life of a particular individual whose quality of life
and well-​being could be improved by cognitive enhancers. Ordinarily, therapy refers to
the restoration, partial or complete, of the functions of an organism affected by a disease, a
disability, or an impairment using appropriate treatment. Therapy is a useful concept that
helps clinicians determine the scope of medical practice based on established baseline
criteria. In addition, the language of therapy implies an understanding of what a healthy
organism is, and the scope of normal functioning. But providing clear definitions and
conceptual clarity to notions such as health, normality, impairment, and abnormality has
been a notoriously difficult task. Notions of health and normality are concepts that have
evolved, and continue to do, as progress in the biomedical sciences constantly reshapes
the boundaries of what health is or what normal functioning for a biological organism
entails. Health determinants are a complex combination of environmental, social, educa-
tional, and biological factors and therefore the expectation to achieve a healthy status is in
constant flux. That said, the practice of medicine requires the establishment of standards
that will allow practitioners to help their patients achieve the optimization of functioning
established on standards of functionality within the boundaries of human biology.
On the other hand, enhancement #1 refers to the use of the power of biotechnologies
to transcend the normal scope of species-​typical human capacities to improve biological
abilities. Therapy is limited to the scope of medicine whereas enhancement #1 applies
to a different domain since its application focuses on healthy individuals who want to
enhance some capacities. Yet, the line of demarcation between what constitutes therapy
and enhancement respectively is increasingly fuzzy because some therapeutic interven-
tions, devices, or drugs have dual effects or, as I point out in this chapter, enhancement #2
could be employed in the context of individuals whose levels of capacities are not consis-
tent with being nondisabled.

Clinical ideal and mental impairment

Now that a general framework has been outlined as to the nature of the clinical ideal, we
need to delve further into its implications for the mentally impaired. The overall purpose
of the use of cognitive enhancers in individuals with cognitive impairment is to increase
their quality of life. Various factors should be considered in the evaluation of quality
of life in patients: (1) the nature of the illness and the side effects of treatment; (2) the
patient’s ability to perform basic everyday life activities such as walking, and preparing
meals; (3) the patient’s levels of independence, privacy, and dignity; and (4) the patient’s
experience of happiness, pleasure, pain, and suffering (Lo 2000 p.30). Typically, compe-
tent patients are able to communicate how they experience their own quality of life and
to make decisions with regard to treatment options, their length, and their possible ces-
sation. However, there are challenges to evaluate the quality of life of others either when
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420 Cognitive enhancement of today may be the normal of tomorrow

these individuals are not competent, if they cannot voice their option, or when clinicians
and family members make claims about the patient’s quality of life. Studies have shown
that there are discrepancies between how patients perceive their quality of life and what
others say about it, especially since patients learn how to cope with illness, find support
elsewhere, and in many instances remain positive about life in general and still find plea-
sure despite their situation (Lo 2000 p.30). Consequently, as Lo rightly states: “quality of
life judgments by others might be inaccurate and biased unless they reflect the patient’s
own assessment of quality of life” (Lo 2000 p.30).
Another important issue to consider is the quality of life of individuals with cogni-
tive impairments. Some authors argue that below a certain level of functionality con-
sidered essential for being a person, individuals cannot experience a meaningful quality
of life and consequently clinical interventions are futile. Others are concerned that such
evaluation of quality of life could lead to the contention that people who do not exhibit
attributes of personhood will be “eliminated” because such lives are deemed “not worth
living” (Schneiderman et al. 1990). The deep disagreement about the nature of the quality
of life of the mentally impaired epitomizes the challenge for its assessment in those who
are baseline disabled. So we need to be cognizant that ultimately the determination of the
quality of life by others remains problematic.
With these considerations in mind, I turn now specifically to the criteria outlining the
boundaries of the quality of life of the mentally impaired when potentially undergoing
cognitive enhancement. The specific aims of the use of cognitive enhancers in people
with mental disabilities include “increase[ing] functioning with a decrease in the need
for health care and daily assistance” and “increase[ing] the individual’s social capacity”
(Jotterand et  al. 2015  p.123). Social capacity refers to the ability to increase a person’s
ability to socialize and enter into relationships with others, which includes a broadening
of personal choices, self-​expression, and an optimization of how to engage in the world
(Jotterand et al. 2015). Disabled people with mild cognitive impairments who exhibit self-​
awareness could benefit from cognitive enhancers with regard to a stronger social lifestyle
and increased independence (Kittelsaa 2014). The case of the severely disabled is more
complex and requires a more nuanced examination.
To make a stronger argument in my analysis, I will use the case of Ashley (often referred
as the Pillow Angel Case). As far as I know, Ashley never underwent interventions
involving cognitive enhancers. This case exemplifies how the use of cognitive enhancers
could improve the quality of life of mentally impaired individuals such as children in a
“permanently unabled state” for which there is no treatment currently available but who
might benefit from enhancement technologies. Of course the assumption here is that
these techniques are safe and efficacious—​which I do not intend to assess in this chapter.
My goal is simply to look at enhancement #2 and the implications of its applications in
a real-​life case.

Case scenario: Ashley, born in 1997, was diagnosed at the age of 6½ with static encephalopathy, a
condition that keeps the brain of this patient population in a “permanent and unchanging state” and
 421

Clinical ideal and mental impairment 421

for which there is no treatment. This severe brain disorder kept Ashley “permanently unabled” men-
tally (age of an infant) while her body continued to grow normally. The parents, concerned with the
care of Ashley, made three requests to the Children’s Hospital and Regional Medical Center in Seattle,
Washington. They asked doctors to have Ashley undergo the following three procedures: (1) a hyster-
ectomy (to remove the uterus), (2) the removal of breast buds, and (3) a height attenuation to control
height and weight through hormone therapy. While alert and responsive to her surroundings Ashley
could not walk, sit up, grasp objects, use language or eat.

I will not analyze the case in terms of whether the doctors should proceed with the request
of the parents as other scholars have already examined this case in depth (Gunther &
Diekema 2006). Rather, my intention is to use the case of Ashley to raise the following
question: Does the (hypothetical) improvement of the quality of life of individuals such as
Ashley justify the use of cognitive enhancers?
To answer this question, it is essential to stress that context is crucial in our analysis.
The clinical ideal asserts that any enhancement that improves the quality of life of an
individual with a mental impairment is justified if it takes into account the particular situ-
ation of the person involved. This means that no general claims can be asserted as to the
widespread usage of cognitive enhancers and as to the moral obligation of their use in the
mentally impaired even if it has been proven that enhancers improve their overall quality
of life. The prudential value of enhancement is determined by how clinical procedures—​
the degree of enhancement—​meet realistic expectations set by the person caring for the
(incompetent) cognitively impaired individual proportionally to the improvement of the
quality of life, to the enhanced physical and mental functionality, and to the increased
social capacity. Such a framework does not require setting any threshold since its goal is
to promote the well-​being of the individual subjected to these enhancements.
There is always a danger in using graphics to represent questions of enhancement and
quality of life due to the difficulty in quantifying these concepts. However, the representa-
tion in Figure 21.1 might help visualize the concept of the clinical ideal.
The point here is to make a normative statement about the nature of enhancement with
regard to quality of life. Consider the y-​axis as representing quality of life on a scale of
0–​10 and the x-​axis as representing degrees of enhancement on a scale of 0–​10. In addi-
tion, consider this graphic as a visual aid used by the person deciding whether to allow the
use of cognitive enhancers in the mentally impaired under his/​her responsibility. While
I recognize that quantification of enhancement and quality of life are difficult to establish,
Figure 21.1 is a graphic representation of the relationship between degrees of enhance-
ment and degrees of quality of life. In an ideal scenario, the clinical ideal suggests that the
increased degree of quality of life must be equal or superior to the degree of increased
enhancement as indicated by the gray arrow. This means that quality of life should take
priority over enhancement to avoid an instrumentation of patients through technologi-
cal interventions. Unless enhancement technologies are safe, the focus should be on the
improvement of quality of life and not on increased capacities. In a nonideal scenario
(degree of enhancement higher than degree of quality of life—​see Figure 21.1) where the
improvement of quality of life of an individual requires extensive enhancements, each
42

422 Cognitive enhancement of today may be the normal of tomorrow

Clinical Ideal
10
9
8
7
Quality of Life

6
5
4
3
2
1
0
0 1 2 3 4 5 6 7 8 9 10
Degrees of Enhancement
Figure 21.1 Graphic representation of the relationship between degrees of enhancement and
degrees of quality of life. In an ideal scenario, the clinical ideal suggests that the increased degree
of quality of life must be equal or superior to the degree of increased enhancement as indicated
by the gray arrow.

case must be evaluated on its own facts using ethical guidelines that prevent the use of
enhancement technologies that objectify the patient and promote his or her welfare and
safety.
The clinical ideal does not necessitate setting a normal range of human capacities
because the patient population concerned has a baseline disabled that is outside the nor-
mal range of human abilities. Therefore, any moral assessment as to the acceptability of
an enhancement must be established on the subjective degree of improvement of qual-
ity of life. Furthermore, to protect and maximize the well-​being of the recipient of the
enhancement procedure, the degree of enhancement must be equal or superior to the
degree of improved quality of life. In other words, if the degree of enhancement in rela-
tion to a baseline disabled is 4, ideally the degree of quality of life should be deemed to be
4 or higher.
The individualist approach of the clinical ideal is represented in Figure 21.2. It shows
each individual starting at a different stage with regard to how quality of life is experi-
enced or expressed and that the degree of enhancement does not necessarily improve
well-​being.
In Figure 21.2, we have three individuals with mental impairment whose quality of life
has been determined to 2 at baseline disabled for person ◆, to 3 at baseline disabled for
person ■, and to 4 at baseline disabled for person ✕. The clinical ideal does not provide
a normative framework within specific parameters other than the fact that enhance-
ments that do not increase quality of life above baseline line should be dismissed. In
addition, quality of life is closely related to the condition of a particular person, how it
is experienced and interpreted. Figure 21.2 reveals that there are different scenarios to
 423

Ethical considerations 423

Individualist Approach of the Clinical Ideal

10
9
8
7
Quality of Life

6
5
4
3
2
1
0
0 2 4 6 8 10
Degrees of Enhancement
Figure 21.2 Graphic representation of various potential enhancement scenarios: ▲ represents
the clinical ideal where increased degree of quality of life must be equal or superior to the degree
of increased enhancement; ◆ represents the case of a disabled person where increased degree
of enhancement minimally influences quality of life; ◆ represents the case of a disabled person
where increased degree of enhancement decreases quality of life beyond a certain point; ✕
represents the case of a disabled person whereas increased degree of enhancement negatively
impacts quality of life.

consider: in certain cases cognitive enhancement might indeed not improve quality of
life (person ✕), in other cases the magnitude of enhancement only slightly changes the
quality of life (person ◆), whereas in other instances there might be a dramatic improve-
ment of quality of life up to a certain level of enhancement and then a drastic drop (per-
son ◆). This is not a comprehensive list of scenarios nor is it based on empirical data, but
it illustrates that each individual should be treated as a unique case, with specific needs
and a particular experience and expression of well-​being.
To summarize, the clinical ideal avoids the challenge of determining the normal range
of human capacities, even in the case of the mentally impaired, or human standards. It
simply states that, with regard to the mentally impaired, the moral evaluation of enhance-
ment #2 can take place within the context of the patient’s clinical condition and in relation
to the notion of quality of life. There is a subjective and evaluative dimension that escapes
any attempt to standardize enhancement #2. The alteration of the physical, mental, and
social capacities of the mentally impaired is justified if it improves the overall well-​being
of the patient.

Ethical considerations
It is important to keep in mind that no study on the long-​term effects of cognitive
enhancers on healthy subjects has been completed so far and that no accepted ethi-
cal and legal framework has been fully developed for the use of cognitive enhancers.
42

424 Cognitive enhancement of today may be the normal of tomorrow

Consequently, we ought to adopt a prudent approach in establishing standards for

the use of cognitive enhancers in the mentally impaired. The following key points
might provide a general framework for the development of more fine-​tuned ethical
approaches and guidelines (Jotterand et al. 2015). First, we need to keep in mind that
the mentally impaired are a vulnerable population with specific needs and, therefore,
there is always a danger of taking advantage of their condition. For this reason, extra
layers of protection should be determined and implemented considering the experi-
mental nature of the use of cognitive enhancers in the mentally impaired (enhance-
ment #2). Second, the best-​interest standard must guide any decision concerning the
use of cognitive enhancers. Clinicians should always act in a way that promotes the
well-​being of their patients in accordance to the patient’s being and wishes and avoid
harm, even more so since these procedures would be experimental at this stage and
no data is available as to their safety. Finally, there is a broader concern about the
perception of the use of cognitive enhancers in the mentally impaired. Disability advo-
cates stress the importance of allowing people with disabilities to have an adequate
level of protection with regard to choice, empowerment, self-​determination, and self-​
expression when possible (Fujiura & RRT Expert Panel on Health Measurement 2012).
There is a danger that mentally impaired people may be used and abused for experi-
mental purposes.

Conclusion
This chapter provides a philosophical justification of the potential clinical use of cognitive
enhancers in the mentally impaired. The concept of the clinical ideal constitutes a pos-
sible approach that takes into account the complexities of clinical work in determining
the overall experience of a patient with mental impairment in terms of expressed and
perceived quality of life, and the interpretation of the notion of enhancement in medi-
cine. While a philosophical justification is a first step toward a hypothetical acceptance
case-​by-​case of cognitive enhancers in the clinical context, a more robust analysis needs
to take place for the development of ethical guidelines and policies based on sound sci-
ence. Without such analysis, public opinion might be influenced by various stakehold-
ers concerned with the protection of the targeted patient population but might miss the
opportunity to support an endeavor with potential clinical benefits.

References
Agar, N. (2014). Truly Human Enhancement: A Philosophical Defense of Limits. Cambridge, MA: The
MIT Press.
Boorse, C. (1975). On the distinction between disease and illness. Philosophy & Public Affairs, 5, 49–​68.
Boorse, C. (1977). Health as a theoretical concept. Philosophy of Science, 44, 542–​573.
Boorse, C. (1997). A rebuttal on health. In: Humber, J.M. and Almeder, R.F. (Eds.) What is Disease?,
pp.1–​134. Totowa, NJ: Humana Press.
Bostrom, N. (2005). In defense of posthuman dignity. Bioethics, 19, 202–​214.
 425

References 425

Chadwick, R. (2008). Therapy, enhancement and improvement. In: Gordijn, B. and Chadwick, R.

(Eds.) Medical Enhancement and Posthumanity, pp.25–​37. Dordrecht: Springer Science + Business
Media B.V.
Engelhardt, H.T., Jr. (1984). Clinical problems and the concept of disease. In: Nordenfelt, L. and
Lindahl, B.I.B. (Eds.) Health, Disease and Causal Explanations in Medicine. Dordrecht: Kluwer.
Engelhardt, H.T., Jr (1996). The Foundations of Bioethics. Oxford: Oxford University Press.
Fujiura, G.T. and RRT Expert Panel on Health Measurement (2012). Self-​reported health of people
with intellectual disability. Intellectual and Developmental Disabilities, 50(4), 352–​369.
Gehring, K., Patwardhan, S.Y., Collins, R., et al. (2012). A randomized trial on the efficacy of
methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with
a primary brain tumor. Journal of Neurooncology, 107(1), 165–​174.
Gunther, D.F. and Diekema, D.S. (2006). Attenuating growth in children with profound developmental
disability. Archives of Pediatrics and Adolescent Medicine, 160(10), 1013–​1017.
Houdsen, C.R., Morein-​Zamir, S., and Sahakian, B.J. (2011). Cognitive enhancing drugs: neuroscience
and society. In: Savulescu, J., Meulen, T.R., and Kahane, G. (Eds.) Enhancing Human Capacities,
pp.113–​126. Oxford: Blackwell Publishing.
Jotterand, F. and Wangmo, T. (2014). The principle of equivalence reconsidered: assessing the relevance
of the principle of equivalence in prison medicine. American Journal of Bioethics, 14(7), 4–​12.
Jotterand, F., McCurdy, J., and Elger, B. (2015). Cognitive enhancers and mental impairment: emerging
ethical issues. In: Rosenberg, R.N. and Pascual, J.M. (Eds.), Rosenberg’s Molecular and Genetic Basis
of Neurological and Psychiatric Disease (5th edn.), pp.119–​126. Philadelphia, PA: Elsevier, Inc.
Juengst, E.T. (1998). What does enhancement mean? In: Parens, E. (Ed.) Enhancing Human
Traits: Ethical and Social Implications, pp.29–​47. Washington, DC: Georgetown University Press.
Kass, L.R. (1985). Toward a More Natural Science: Biology and Human Affairs. New York: The
Free Press.
Kittelsaa, A.M. (2014). Self-​presentations and intellectual disability. Scandinavian Journal of Disability
Research, 16(1), 29–​44.
Lo, B. (2000). Revolving Ethical Dilemmas. Philadelphia, PA: Lippincott Williams & Wilkins.
Morein-​Zamir, S., Turner, D.C., and Sahakian, B.J. (2007). A review of the effects of modafinil on
cognition in schizophrenia. Schizophrenia Bulletin, 33, 1298–​1306.
Morein-​Zamir, S., Robbins, T.W., Turner, D., and Sahakian, B.J. (2008). State-​of-​science review: SR-​
E9: pharmacological cognitive enhancement. In: UK Government Foresight Mental Capital and
Mental Wellbeing Project Mental Capital and Wellbeing: Making the Most of Ourselves in the 21st
Century, pp.–​16. London: The Government Office for Science.
Sandberg, A. (2011). Cognition enhancement: upgrading the brain. In: Savulescu, J, Meulen, T.R., and
Kahane, G. (Eds.) Enhancing Human Capacities, pp.71–​91. Oxford: Blackwell Publishing.
Schneiderman, L.J., Jecker, N.S., and Jonsen, A.R. (1990). Medical futility: its meaning and ethical
implications. Annals of Internal Medicine, 112, 949–​954.
Smith, M.E. and Farah, M.J. (2011). Are prescription stimulants “smart pills”? The epidemiology and
cognitive neuroscience of prescription stimulant use by normal health individuals. Psychological
Bulletin, 137(5), 717–​741.
426

Chapter 22

Environmental neuroethics: Setting

the foundations
Laura Y. Cabrera

At the intersection of brain and mental health, ethics, and

environment
Humans have altered their environments in pursuit of self-​improvement and for enhanced
opportunities since ancient times, but the scope and impact of current changes are
unprecedented. While human-​initiated environmental changes have generally improved
standards of living and provided new ways of protecting human health, paradoxically
such changes have also contributed to global climate change, suburban sprawl, ecosystem
loss, and increased health risks from toxic exposures and stress.
The various ways in which humans affect and are affected by their environments has
been the focus of study across disciplines. For example, environmental ethics deals with
questions concerning the value and moral standing of the natural environment, including
whether the environment has instrumental or intrinsic value (Sagoff 2008) and whether
present humans have particular moral obligations to protect and preserve the environ-
ment for future generations, and equally, if there should be limits imposed on the amount
and rate of change that humans inflict in their environments; epigenetics considers the
effect of present and past environments in gene expression (such as DNA methylation
and hydroxymethylation, in addition to a plethora of histone modifications) (Crews
2010; Petronis & Mill 2011); and finally, environmental health focuses on those aspects of
human health and disease affected by factors in the environment.
Questions emerging at the intersection of health, ethics, and environment, are
complex and diverse. To properly address the associated breadth and depth, collabo-
ration among environmental scientists, physicians, public health professionals, ethi-
cists, lawyers, and policymakers is required. The variety of ethical issues at the nexus
of environmental concerns and human health include issues of solid and hazardous
waste disposal, regulation of pesticide use, environmental justice, and climate change.
Those ethical issues explored by environmental health ethics commonly involve con-
flicts among fundamental values, including human-​centered concerns, such as public
health and human rights, as well as environmentally oriented concerns, such as protec-
tion of habitats and biodiversity (Shrader-​Frechette 2006; Cranor 2011; Elliott 2011;
Resnik 2009, 2012). Yet despite the wide range of disciplinary approaches examining
 427

Environmental influences on brain and mental health 427

the relationship between the environment and human health, and the attendant ethical
implications, insufficient attention has been paid to the ethical, social, and legal impli-
cations that arise from environmental impacts and deleterious exposure in terms of
brain and mental health effects.
In this chapter, I introduce environmental neuroethics as an emerging approach at the
intersection of environmental studies, biomedical and social understandings of brain and
mental health, and ethics. In order to make the case that environmental neuroethics is
an important and needed approach, I provide in the next section examples of the various
ways in which environmental exposures impact brain and mental health, both in positive
and negative ways, and explore why those related impacts are a matter of moral concern.
In the last sections I lay out the foundations for a first generation of environmental neu-
roethics and discuss key challenges ahead.

Environmental influences on brain and mental health

Humans have long recognized the interdependent relationship between environmental
factors and health and disease. Today, it is widely accepted that health is determined by
complex interactions between individual genetic predispositions, social and economic
factors, behaviors, and perception of, as well as interactions with, the environment (Blas
et al. 2011; Public Health Agency of Canada 2011). This chapter focuses on the interac-
tions between the environment and brain health. Beyond neurological and physiological
effects, environmental influences also impact psychological well-​being, including inter-
ference both with the capacity to cope with normal stresses of life and to work produc-
tively and make useful contributions to community life. It is the latter group that I refer to
as mental health impacts. I use brain health to refer to both brain and mental health. It is
also important to clarify that while the environment encompasses all the physical, chemi-
cal, biological, and social forces that are external to a person (Smith et al. 1999), the focus
here largely will be on the first three factors. However, I will touch on social aspects of
the environment as this important area merits ongoing attention. As Marmot (2005) cor-
rectly observes, only in the most remote wilderness can a distinction be drawn between
the social and other aspects of the environment.
Prior to the 1950s, some cases pointed to an association between neurological func-
tion and environmental changes; however, it was with the availability of more systematic
epidemiological data that scientific consensus on that association was achieved. At pres-
ent, there are some areas in which there is sufficient evidence linking brain and mental
health impacts to environmental exposures, as in the case of chronic lead exposure and
cognitive impairment, but in other areas the evidence is still limited as in the case of
pesticide exposure and attention deficit hyperactivity disorder (ADHD). Among the bar-
riers to identifying strong relational evidence is the fact that detrimental environmental
exposures vary greatly depending on pollutant type, exposed population vulnerability,
and dose and length of the exposure. In light of ongoing studies on environmental factors
and their impact on brain health, in this section I review the evidence for environmental
428

428 Environmental neuroethics

factors to be considered as developmental neurotoxicants and neurotoxic agents or as

protective and enablers of brain health.

Developmental neurotoxicants and neurotoxic agents

Neurotoxic agents interfere with the functioning of the brain. Developmental neurotoxi-
cants are agents that have the capacity to disrupt brain and nervous system development.

Metals, pesticides, and solvents

Based on robust animal data and large prospective epidemiological studies, there is well-​
documented evidence for the neurotoxic properties of certain metals (e.g., lead, methyl-
mercury, arsenic, and manganese) as well as for certain industrial chemicals and solvents
(e.g., organophosphate and organochlorine pesticides, polychlorinated biphenyls (PCBs),
and toluene). For other substances such as cadmium, bisphenol A (BPA), and perfluoro-
chemicals (PCFs) there is only limited animal data and a few, small epidemiological stud-
ies that would allow them to be categorized as suspected neurotoxicants.
Lead
United States medical journals began reporting on cases of paint-​related lead poisoning in
1914. Patterson’s influential paper “Contaminated and natural lead environments of man”
(Patterson 1965), prompted investigations of lead as a pollution problem with human
health impacts. A few years after the release of Patterson’s findings, epidemiological stud-
ies demonstrated the inverse relationship between neurobehavioral functioning and
blood-​lead concentrations (Needleman et al. 1979, 1990). Higher levels of lead in child-
hood were found to be significantly associated with lower class standing in high school,
increased absenteeism, lower vocabulary and grammatical-​ reasoning scores, poorer
hand–​eye coordination, and longer reaction times (Needleman et al. 1979). Recent stud-
ies are more worrisome, suggesting that chronic low-​level lead exposure, even at prenatal
stages, can adversely interfere with optimal brain development and functioning (Hu et al.
2006; Grandjean 2013), adversely affect cognitive skills later in life (Schwartz et al. 2000;
Shih et al. 2007; Weisskopf et al. 2007; Grashow et al. 2013), and may even be linked to
schizophrenia (Opler et al. 2008). Moreover, it is now widely recognized that there simply
is no safe threshold that would avert deleterious effects of blood lead on neurobehavioral
function (Lanphear et al. 2005).
Mercury
A well-​known case documenting the neurological impact of a heavy metal comes from
Minamata, Japan, where in the 1950s, hundreds of children were born with cerebral
palsy, blindness, and seizures as a consequence of mercury exposure through eating
contaminated local fish (Grandjean et al. 2010; Grandjean & Herz 2011). Other epide-
miological studies have pointed to subclinical neurotoxicity in children from prenatal
methylmercury exposure and its effects on attention, motor function, language, visual-​
spatial abilities, and verbal memory of those children (Grandjean et  al. 1997; Debes
et al. 2006).
 429

Environmental influences on brain and mental health 429

Other metals
Arsenic is yet another neurotoxic heavy metal (Miodovnik 2011). In Japan, in 1955,
arsenic-​induced developmental neurotoxicity was reported as a result of consumption of
contaminated dried milk powder. In follow-​up studies, infants who survived the poison-
ing had lower IQs and higher rates of severe mental retardation when compared with
control groups (Dakeishi et al. 2006). Other studies have found that arsenic exposure is
associated with declines in verbal learning and memory (Wright et al. 2006), in attention
(Tsai et al. 2003), and in intelligence in school-​age children (Rosado et al. 2007).
There is also evidence that manganese (Lucchini et al. 2014) and cadmium (de Burbure
et al. 2006; Rodríguez-​Barranco et al. 2014) affect neurological function, either by acting
directly on the brain or alternatively by adversely impacting hormones necessary to main-
tain healthy neurological function (Grandjean 2013; Grossman 2014). When accumu-
lated in excess, copper and manganese can lead to liver failure, which in turn can trigger
hepatocerebral disorders with morphologic changes similar to those seen in Alzheimer’s
disease, and neurological symptoms including parkinsonism1 and cognitive dysfunction
(Butterworth 2010).

Industrial chemicals and pesticides

A number of chemical compounds, such as pesticides (e.g., paraquat, maneb, DDT, and
hexachlorobenzene) and solvents (e.g., toluene and trichloroethylene) are used widely
worldwide and up to 201 compounds have been confirmed to be neurotoxic to humans
with 8 specifically damaging to the developing brain (Miodovnik 2011). Long-​term expo-
sure to solvents and pesticides can affect verbal memory, attention, and spatial skills (Dick
2006; Tang et al. 2011).
Pesticides constitute the largest group of substances shown to produce neurological
signs and symptoms (Grandjean & Landrigan 2006; Grandjean 2013). Research indicates
that children born to mothers exposed to pesticides during pregnancy lag an average of
2 years behind in motor and spatial development when compared to children of mothers
without exposure (Grandjean et al. 2006; Harari et al. 2010). Other studies have found
an association between residential proximity to agricultural fields where pesticides were
being applied during pregnancy and an increased risk of having children with neurode-
velopmental disorders (Roberts et al. 2007; Shelton et al. 2014). However, few laboratory
studies have addressed issues of concurrent exposure to multiple pesticides to consider
the impact of synergistic or cumulative effects (Grandjean 2013). There is evidence con-
necting long-​term exposure to certain metals, pesticides, and solvents with increased risk
of developing Parkinson’s disease and amyotrophic lateral sclerosis (Hertzman et al. 1990;
Alavanja et  al. 2004; Kamel & Hoppin 2004; Elbaz et  al. 2009). Perrin and colleagues
reported that paternal occupation as dry cleaners, working with the dry cleaning industry
solvent tetrachloroethylene, was associated with a threefold increased risk of schizophre-
nia in offspring (Perrin et al. 2007). This study suggests that the spread of environmental
contaminants not only directly affects individuals, but also increases adverse brain and
mental health effects for future generations.
430

430 Environmental neuroethics

Other industrial chemicals with sufficient evidence to suggest neurotoxicity are PCBs.
While PCBs were banned in the 1970s, they remain present in many products and mate-
rials produced before 1979. Various longitudinal studies have examined neurodevelop-
mental outcomes associated with exposure to PCBs, supporting modest associations with
poorer attention (Jacobson & Jacobson 2003), IQ (Stewart et al. 2008), impulse control
(Korrick & Sagiv 2008), and learning skills (Grandjean et al. 2001).

Industrialization and urban development

There are a myriad of ways in which industrialization and urban development impact
brain and mental health.
Air and water pollution
Air pollution has a mixed exposure impact; in limited doses it is associated with headaches
but in chronic exposure it is linked to neurodevelopmental deficits, including depres-
sion (Lim et al. 2012), fatigue, and reduced mental function (Calderon-​Garcidueñas et al.
2002, 2004, 2008; Peters et al. 2006; Field et al. 2014). A study linked severe air pollution
to lesions and growth abnormalities in the prefrontal cortex of children and dogs grow-
ing up in Mexico City (Calderon-​Garcidueñas et al. 2008). Other studies have found that
higher maternal exposure to particulate matter up to 2.5 micrometers in size during preg-
nancy is associated with greater odds of a child having autism spectrum disorders (Raz
et al. 2014) and there are also potential associations between autism and estimated metal
concentration (Windham et al. 2006). In the case of elderly adults, Lim and colleagues
found that increases in particulate matter with an aerodynamic diameter less than 10
micrometers (PM10), such as nitrogen dioxide and ozone, are strongly associated in this
population with emotional symptoms (Lim et al. 2012).
Water pollution represents yet another area of concern (Villanueva et al. 2013). More
than 100  million people worldwide are chronically exposed to arsenic concentrations
in drinking water at levels exceeding the World Health Organization guideline value
(Miodovnik 2011). Ocean contamination represents another example of water pollution,
in particular as bioaccumulation of heavy metals in the food chain or other chemical
compounds found in water affect both brain and mental health.

Urban exposures
Another way in which brain and mental health are affected by the environment is through
urbanization which introduces sources of urban pollution as well as toxic social circum-
stances (Bentall & Fernyhough 2008), including stress, fleeting social relationships,
technology-​driven remote interactions, higher crime rates, increased social competition,
and wider socioeconomic disparities (Tost et al. 2015). Schizophrenia has the notorious
recognition of being the mental health disorder with the best-​examined link regarding
urban birth, urban upbringing, and urban residence (Kelly et al. 2010; van Os et al. 2010).
When compared with rural areas, psychiatric disorders are on average 34% more frequent
in urbanized areas (Peen et al. 2010). A prospective study in Ireland found an incidence
rate ratio of 1.92 for males and 1.34 for females in cities when compared to their rural
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Environmental influences on brain and mental health 431

counterparts (Kelly et al. 2010). Magnetic resonance imaging studies support the idea that
on the functional level the degree of urbanization has implications for the neural social
stress response system, and that the degree of exposure to urban environments is associ-
ated with para-​anterior cingulate cortex activation and decreased gray matter volume in
the prefrontal cortex (Lederbogen et al. 2011; Haddad et al. 2015). That finding plausibly
relates to the high incidence of schizophrenia in the cities.
Proximity to noxious facilities
In addition to industry-​generated chemicals polluting air and water supplies, simply liv-
ing near to noxious facilities and waste repositories such as mining waste, nuclear plants,
or natural resources extraction sites, can be harmful to brain health (Heiervang et al. 2010;
Rabinowitz et al. 2015). A 2003 study noted that: “wastes from oil refineries can create
health risks to facility workers and surrounding communities... including exposure to heat,
polluted air, noise, and hazardous materials, including asphalt, asbestos, aromatic hydro-
carbons, arsenic, hexavalent chromium, nickel, carbon monoxide, coke dust, hydrogen
sulfide, lead alkyls, natural gases, petroleum, phenol, and silica” (O’Rourke & Connolly
2003). Brain health impacts from exposure to such material can include headaches, psy-
chosis, and peripheral neuropathies (O’Rourke & Connolly 2003; Colborn et al. 2011).
There are associated mental health problems as well. Two studies documented concerns
from residents living in boom town communities in rural Northeastern Pennsylvania and
Texas (Perry 2012; Stedman et al. 2012). They observed feelings of powerlessness, shock,
and disgust among community members as a result of the rapid landscape change from
agricultural and forested to industrial. They also noted stress associated with living within
the vicinity of industrial facilities. Similar findings have been reported for communities
who have experienced oil spills (Gay et al. 2010). There is a condition aptly labeled “eco-​
anxiety” which describes a chronic fear of living with the consequences of potentially
unsound environmental practices (Watson 2008).
Extreme weather and changes in landscape
There is considerable evidence that human activities, such as those involved in industrial-
ization and urbanization, are primarily responsible for climate change and the related side
effects of global warming, including extreme weather fluctuations leading to more fre-
quent droughts, deadly heat waves, and more damaging rainstorms, as well as landscape
changes precipitated by the melting of glaciers, coastal flooding due to rising sea levels,
and wildfires (APA Task Force 2011; Resnik 2012).
Climate change impacts on public health have primarily focused on physical health
outcomes, linking changes in availability of food and water quality and quantity to mal-
nutrition and vector-​borne diseases, examining increasingly evident and oftentimes more
visible health issues such as respiratory, cardiovascular, and kidney diseases. However,
literature on the impact of climate change on mental health is now emerging (APA Task
Force 2011). For example, research by Cunsolo and colleagues documents the impact of
climate change on the mental health and well-​being of Inuit people over time (Cunsolo
Willox et al. 2013). Cunsolo and colleagues demonstrate how temperature increases and
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432 Environmental neuroethics

the concomitant thinning of the ice layer has prevented the Nunuvut Inuit from engaging
in cultural food procurement practices, such as hunting, as frequently as they had done so
in the past (Cunsolo et al. 2013). This cultural shift was found to be associated with men-
tal health consequences including increased family stress and amplification of previous
traumas and mental health stressors.2 The term solastalgia (Albrecht et al. 2007) describes
a particular distress experienced as a consequence of being deprived of the solace one
derives from contact with one’s native environment. Other research has focused on men-
tal health impacts such as acute and post-​traumatic stress disorder, depression, anxiety
disorders, drug and alcohol abuse; higher suicide attempts and completions; and the gen-
eral increased vulnerability of those with preexisting severe mental health issues suffer-
ing from climate change associated loss, disruption, and displacement (Fritze et al. 2008;
Berry et al. 2010, 2011). Clearly, changes in the environment can have important direct
impacts on the mental health and well-​being of residents as well as disrupting underlying
determinants of health.

Other factors: Diet and social support

There are other environmental exposures, such as diet and social support that can also
negatively affect brain and mental health.
Diet
Over the past decade there has been good evidence for the influence of dietary factors on
specific molecular systems and mechanisms involved in mental function. Dietary factors
can negatively affect brain and mental health (for how diet can improve mental health
see ‘Diet’ in the ‘Protective/​health-​enabling environmental factors’ section). The dramatic
increase over the past 100 years in the intake of saturated fatty acids, linoleic acid, and
trans fatty acids, together with a decreased consumption in omega-​3 fatty acids might well
be related to the elevated incidence of major depression in Western countries (Gómez-​
Pinilla 2008). Diets high in saturated fat are associated with reducing molecular sub-
strates that support cognitive processing and increase the risk of neurological dysfunction
(Greenwood & Winocur 2005). Studies have also found that higher blood glucose levels
exert a negative influence on cognition (Kerti et al. 2013). A systematic review by O’Neil
and colleagues found a significant relationship between unhealthy dietary patterns and
compromised mental health in children and adolescents (O’Neil et al. 2014).
Social support
Among all possible stressors, negative parenting behaviors have the most profound effect
on development, including increased risks for learning disabilities, emotional and behav-
ioral abnormalities, and a broad range of disorders including depression, post-​traumatic
stress disorder, borderline personality disorder, anxiety, and schizophrenia (Tost et  al.
2015). Individuals with a history of childhood maltreatment (including physical and emo-
tional abuse and neglect) are likely to suffer from depression, anxiety disorders, and post-​
traumatic stress disorder (Teicher & Samson 2013), and to exhibit learning disabilities.
The quality and extent of social support, or lack thereof, is also important in adulthood.
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Environmental influences on brain and mental health 433

Ethnic minority status is a well-​recognized social–​environmental risk factor for schizo-

phrenia (van Os et al. 2010). Perceived discrimination and social isolation from the larger
community are likely psychological mechanisms linking increased mental health risks
with minority status (Tost et al. 2015). Finally, the current explosion of digital technol-
ogy and the ubiquitous exposure to it (e.g., computers, smart phones, search engines, and
apps) is not only changing the way we communicate and live but is also altering our brains
in profound ways (Small & Vorgan 2008), gradually strengthening new neural pathways
while simultaneously weakening old ones. Emerging research links these changes to
increases in social isolation, Internet addiction, ADHD, and related mental health risks.

Protective/​health-​enabling environmental factors

Research related to environmental influence and brain health has typically focused on
the identification of adversity-​related factors and their neural underpinnings. Less atten-
tion has been paid to those environmental exposures that in fact might be protective and
enablers of brain and mental health; the following are examples of emerging evidence.

Experience with nature
A deep-​seated connection between mental health and the natural world would, from an
evolutionary perspective, be quite plausible. Several cross-​cultural studies reinforce this
view. Certain indigenous worldviews see identity, conceptions of the self, and mental
wellness as linked directly and intimately to the environment, and one’s ability to hunt,
trap, fish, forage, and travel on the land, as well as to practice cultural traditions related
to being “on the land” (Kirmayer & Valaskakis 2008; Vukic et al. 2011). This understand-
ing, of the importance of land and land-​based activities, highlights connections between
individuals and their environments on well-​being and mental health.
A growing body of literature demonstrates that exposure to natural landscapes, or to
their composite features such as flora and fauna, has beneficial effects for child develop-
ment, well-​being, mental health, mood, mortality, and recovery from illness (Frumkin
2001; Maas 2006; Haluza et al. 2014). This connection is what David Cumes describes as
“wilderness rapture” (Cumes 1998). That rapture includes feelings of awe, wonder, and
humility, a sense of comfort and connection to nature, and feelings of renewal and vigor.
Although the topic is under-​researched, there is evidence associating exposure to natural
environments with restoration from attention fatigue, recovery from stress, feelings of
relaxation, as well as enhanced mental alertness, attention, and cognitive performance
(Bowler et al. 2010; Tost et al. 2015). A large-​scale epidemiological study revealed a rela-
tionship between the abundance of green space and human health (Maas 2006). This
finding can be inversely related to the ill-​health effects observed in urban settings, as a
key difference between urban and rural settings is the available green space. Although
the neurobiological effects of experiencing nature require further study, the current data
suggests that human contact with nature is more than an aesthetic luxury. This knowledge
has recently been integrated in horticultural therapy and wilderness therapy (Frumkin
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434 Environmental neuroethics

2001), as well as in animal-​facilitated therapy for treatment of psychiatric conditions

(Matuszek 2010).
Further research is needed into the specific neural mechanisms linking nature exposure
to mental health benefits, as well as to variation based on past experiences, social context,
age, and gender.

Enriched environments
Seminal observations in the 1960s on the effect of environments rich in sensory stimuli to
gross brain structures stimulated further research on the influence of enriched environ-
ments to brain function and behavior (van Praag et al. 2000). Nowadays it is recognized
that environmental enrichment profoundly and positively affects the central nervous sys-
tem at the functional, anatomical, and molecular level (Mora et al. 2007; Baroncelli et al.
2010), during critical developmental periods and in adulthood. In turn, this promotes
various plastic responses in the brain, ranging from biochemical parameters to the arbo-
rization of dendrites and neurogenesis (van Praag et al. 2000).
Environmental enrichment improves quality of life by providing a “combination of mul-
tisensory/​cognitive stimulation, increased physical activity, enhanced social interactions
and by eliciting natural explorative behaviors” (Baroncelli et al. 2010, p.1093). While envi-
ronmental enrichment studies are largely based on rodent research, they provide insights
for application to humans. The admittedly minimal data from human studies and envi-
ronmental enrichment suggests that a higher level of mental and physical activity reduces
disease risk, including those associated with compromised brain function and cognition
(Kramer et al. 2006; Baroncelli et al. 2010). A study with human subjects revealed that
exercise promotes neurogenesis in the brain, suggesting that new proliferating neurons
might possibly contribute to the effects of exercise on memory and learning (Pereira et al.
2007). Another study with children found environmental enrichment to be somewhat
effective in ameliorating autism symptoms (Woo & Leon 2013). Considering evidence
linking sustained stress with impaired immunity, disease, and neurological changes char-
acteristic of major depressive illness and chronic anxiety disorders, it stands to reason
that stress-​reduced environments can positively impact brain health (Crews 2010). These
findings corroborate the need for expanded attention to environmental enrichment para-
digms both for therapy as well as to avert neurological disorders.

Other factors: Diet and social support

Dietary factors and social support factors were mentioned in the section on “Developmental
neurotoxicants and neurotoxic agents” in relation to adverse health effects. Here I high-
light the potential of dietary factors and social support for promoting brain and mental
health.
Diet
Several studies point to the relationship between nutritional factors and mental
health (O’Neil et al. 2014). By regulating neurotransmitter pathways, membrane flu-
idity, synaptic transmission, and signal transduction pathways, dietary factors can
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Environmental influences on brain and mental health 435

affect multiple brain processes (Gómez-​Pinilla 2008). Lai and colleagues systemati-
cally reviewed the literature to conduct a meta-​analysis of the association between
dietary patterns and depression. They found that a healthy diet—​one high in fruit,
vegetables, fish, and whole grains—​was significantly associated with reduced likeli-
hood of depression (Lai et al. 2014). Another meta-​analysis examined the association
between adherence to a Mediterranean diet and the risks of stroke, cognitive impair-
ment, depression, and Parkinson disease. High adherence to this diet was found to
be associated with reduced risks for ischemic stroke, depression, and mild cognitive
impairment (Psaltopoulou et al. 2013). Diets rich in antioxidants have become increas-
ingly popular as they are linked with positive effects on neural function and might
lower risks of developing age-​related neurodegenerative diseases (Joseph et al. 2007).
Finally, studies have shown that probiotics can improve anxiety levels, perceptions
of stress, and mental outlook (Bested et  al. 2013). Not surprisingly the production
of neurotransmitters such as serotonin, as well as the function of various neurons, is
highly influenced by the billions of “good” bacteria comprising the intestinal micro-
biota. Although these studies underscore the important effect of dietary factors on the
brain, further work is necessary to determine mechanisms of action and how to best
enhance brain function and mental health.

Social support
The extent and the quality of human social bonds influence positive affect, self-​esteem,
recovery, and risk for mental illness (Tost et  al. 2015). Seeman and McEwen’s study
provides support for the hypothesis that the positive influence of social environment
features reduces neuroendocrine reactivity (Seeman & McEwen 1996) which in turn
decreases the odds for exaggerated physiological stress responses and negative emo-
tional states (Tost et al. 2015). Laboratory experiments have corroborated the benefits
of social support in managing psychological stress (Chen et al. 2011). As mentioned
in the section on enriched environments, dynamic social interactions are critical, in
particular during childhood between caregivers (particularly parents) and infants.
Parenting behavior has demonstrable long-​lasting effects on development. Stable,
supportive, and loving caregiver behavior promotes one’s ability to form trusting and
empathetic social relationships as well as mitigating the detrimental effects of adverse
life effects (Shonkoff 2012). Similarly, when older adults are satisfied with their avail-
able social support, they report a better health status than those who are dissatisfied
(White et al. 2009).
Despite the available evidence, knowledge and understanding as to the effects of envi-
ronmental changes and toxic exposures for brain and mental health is still in its infancy.
Further research is required to gain a more complete understanding of the current and
possible brain health impacts stemming from environmental influences. Given the cur-
rent rapid rate of environmental changes, ongoing study both of risks and resilience
mechanisms offers hope for developing preemptive and therapeutic approaches for brain
and mental health disorders.
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436 Environmental neuroethics

Setting the foundations for environmental neuroethics

The idea of combining neuroethics with the study of the effects of environmental expo-
sures stems from cross-​cultural research with a First Nations family, undertaken by
researchers at the University of British Columbia. That collaboration examined expe-
riences and understandings of early-​onset familial Alzheimer’s disease (EOFAD). The
EOFAD study was a reminder about the need to consider how cultural differences
mediate one’s perceiving and valuing of the environment. Equally, it emphasized the
increased vulnerability of certain populations to environmental changes and expo-
sures. A  closer look at the literature prompted recognition that ethical and social
implications from environmental exposures and changes for brain and mental health
were underexplored areas (Cabrera et al. 2016). This set the foundation for environ-
mental neuroethics. This novel neuroethics approach aims to better understand and
respond to those ethical and societal issues raised by the impact of environmental
exposures on brain and mental health. The initial environmental neuroethics work
largely focused on brain and mental health impacts from anthropogenic environmen-
tal changes—​such as those brought forward by technological change, new industries,
economic expansion, and population growth (Illes et al. 2014). As research moves for-
ward, other areas such as the impact of natural environments, enriched environments,
and social and technological environments are included within the scope of environ-
mental neuroethics.

Why environmental neuroethics matters: A neuroethics perspective

Several neuroethics reasons support the claim that environmental neuroethics matters.

Brains matters
Environmental neuroethics matters because brain and mental health matter. The brain is
arguably the most complex organ crucial to human well-​being. It orchestrates all bodily
functions, is in charge of affective and cognitive capacities of reasoning and decision-​
making, and is considered the seat of self-​identity, autonomy, and self-​narrative. The com-
plicated development of the brain, as well as its plasticity, make it uniquely sensitive to
environmental exposures, especially during development (Grandjean 2013). Such expo-
sures can trigger either adverse or positive effects that can be manifested over a lifetime.
A  growing body of evidence suggests that neurological function in the elderly can be
manifestations of exposures from earlier years (Landrigan et al. 2005). Likewise, evidence
suggests that the brains of fetuses, infants, and children are uniquely sensitive to neuro-
toxicants at levels far below those known to harm adults.

Public health
Global impact studies have identified brain and mental health disorders as key contribu-
tors to disabilities and morbidity worldwide. Those disorders have a critical public health,
societal, and economic impact (Prüss-​Üstün & Corvalán 2006). Developmental disabili-
ties or developmental delays (including mental retardation, autism, ADHD, and learning
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Setting the foundations for environmental neuroethics 437

disabilities) occur in about one in six children in the United States (Centers for Disease
Control and Prevention 2015). While the impact of the environment on brain and men-
tal health cannot easily be measured and assessed with certainty, cumulative interactive
effects are likely to be profound. Considering the role of the brain in defining a person,
even small deficits can negatively impact mental health.

Policy implications
It is estimated that over 25% of the burden of human illness worldwide can be attributed
to modifiable environmental conditions (Prüss-​Üstün & Corvalán 2006). While urban-
ization and industry-​precipitated environmental changes are unwittingly creating toxic
environments for brain and mental health, we potentially could modify our lived envi-
ronments to foster brain and mental health. Certain scholars have suggested that shaping
our environments to optimize brain and mental health is likely to be more effective and
less ethically problematic than genetic or pharmaceutical modifications of our capacities
(Levy 2012; Cabrera 2015). In terms of exposures, approximately 200 chemicals have been
found to be neurotoxic in humans (Grandjean & Landrigan 2006). However, thousands
of chemicals commonly found in the environment and in consumer products have not
undergone extensive neurotoxicity testing. Since even low levels of exposure can have
far-​reaching brain and mental health effects, prior to entering the market there should
be more rigorous regulation in assessing the neurotoxic profile of chemicals and other
substances (Cranor 2011).

Social justice and human rights

People live and work in diverse environments that vary in type and amount of chemi-
cal exposure. Equally, living experiences vary according to factors such as occupation,
education, income, and ethnicity, leading to environmental risk and disease inequalities.
Living in a healthy environment, one that optimizes well-​being and mental health, should
be considered a human right. Yet exactly what factors constitute a healthy environment
requires further elaboration, as environments can vary dramatically from those that are
truly awful to those that promote positive brain development.
What features are requisite for a given environment to be regarded as “healthy?” Indeed,
while conceptually this might be difficult to define, the conversation opens the door for
discussion of procedural rights to have a say over changes to one’s environment that
might affect brain and mental health. From that perspective, governments have a duty to
promote healthy environments for all their citizens, environments that promote positive
brain development and function, and to protect their citizens from the consequences of
toxic environments.

Generational justice and social responsibility

After decades of research, evidence suggests that many chemicals in the environment
and in consumer products not only affect those currently exposed, but also can dam-
age the next generation’s brain functioning. If nothing is done to mitigate environmen-
tal risks, future generations will bear extraordinarily disproportionate risks. Not only is
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438 Environmental neuroethics

the developing brain more vulnerable to environmental exposures, there are epigenetic
mechanisms through which the dire consequences of environmental exposures are real-
ized in the next generation. In his video “Little Things Matter,” Bruce Lanphear argues that
the widespread and chronic exposure to brain-​damaging toxins can lead to an increase
in the number of US children who are mentally challenged, from 6 million to more than
11 million (Canadian Environmental Health Atlas 2014). Thus in terms of environmen-
tal impacts for brain and mental health, the related concerns are intergenerational, and
problematic both from a temporal distributive justice perspective as well as participa-
tive justice’s grounds of equal rights to self-​determination in societal decision-​making
(Shrader-​Frechette 2006). Future generations are, in principle, unlikely to consent to
environmental pollution depletion of natural resources, and other environmental changes
that might pose a risk to their brain and mental health. To this concern, certain schol-
ars make the argument that our choices will cause a different person to exist—​the iden-
tity problem—​so that future individuals have no moral grounds for lodging complaints
against choices made by the present generation (Parfit 1971). Yet in the ethical assessment
of acts that will impact future generations it does not in fact matter who the members of
the future generation turn out to be. What matters is that future generations will suffer the
consequences of our actions, and as such have serious grounds for complaint. John Rawls’
veil of ignorance concept suggests that any reasonable person, not knowing to which gen-
eration, social class, or intelligence bracket they would belong, would accept as fair the
principle of equal apportionment of risks, resources, and goods (Rawls 1971).
Principles of equality in the distribution of opportunity such as this as well as those
suggested by the advocates of the capability approach seem intuitively fair (Nussbaum &
Sen 1993). Other arguments touch on the notion of a social contract among all genera-
tions. According to this view, as beneficiaries of ancestral legacies, members of present
generations have similar duties to future persons—​regardless of whether or not those
future persons can reciprocate their giving; regardless of whether or not the future per-
sons are asked if they wish to receive benefits; and finally regardless of the degree to
which the present persons might know the needs of future generations (Shrader-​Frechette
2006, p.102). Minimally, we know that they will require clean water and air to flourish as
human beings. Thus, at the simplest level, regardless of which generation they happen to
belong to, each and every person will have the same opportunity as any other to use and
benefit from resources. There is then a moral duty to provide future generations with
the same level of opportunity as they would have had if the present generation had not
depleted some resources or polluted their environment (Shrader-​Frechette 2006, p.103).
This moral duty is recognized in national and international documents, such as the 1972
preamble to the Stockholm Declaration on the Human Environment, which affirms that
humans have “a solemn responsibility to protect and improve the environment for present
and future generations” (United Nations Environment Programme 1972). In the United
States, the first stated goal of the National Environmental Policy Act (NEPA) is to “fulfill
the responsibilities of each generation as trustee of the environment for succeeding gener-
ations” (NEPA 1969). NEPA also states that present generations should not impose undue
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Setting the foundations for environmental neuroethics 439

risks on “a future generation … greater than those acceptable to the current generation”
(NEPA 1969). There are approximately 50 federal statutes in the United States that contain
explicit reference to future generations, many of which aim at preserving some current
benefit for future generations (Shrader-​Frechette 2006).
Considering the sensitivity and vulnerability of the brain to environmental exposures,
environmental neuroethics reflects a timely, necessary research trajectory. The focus
and investigation methods put forth by neuroethics provide a meaningful foundation
to address the brain and mental health impacts of environmental change. Neuroethics-​
informed perspectives on environmental change and exposure impacts provide a theo-
retically and empirically based understanding of the brain and its relationship with the
environment at the individual, community, and societal level. A neuroethics perspec-
tive also can help to prioritize and rank important environmental change causes, conse-
quences, or responses as well as to make connections to research and concepts from other
social, engineering, and natural science fields. In sum, a neuroethics lens is crucial to
understand the ethical and social consequences of environmental change, to help reduce
the adverse brain and mental health impacts from environmental change, and to enable
effective individual and social adaptation strategies.

Useful principles and frameworks

The interaction between brain health and the environment puts a new twist on how we
might understand and address those ethical and societal issues at stake. However, there
are issues similar to those already explored in bioethics and environmental ethics, includ-
ing conflicts between individual well-​being and the common good, as well as different
perspectives on justice (e.g., social or generational). Environmental health ethics scholars
have provided guiding principles (Resnik 2012), some of which are relevant to environ-
mental neuroethics, in particular those that appeal to the ethical principle of avoiding
harm (nonmaleficence) and ensuring human welfare (beneficence), fairness and justice,
utility, responsibility, and respect for rights. Determining the proper role of such prin-
ciples in environmental neuroethics will require further attention, yet they currently have
value in drawing attention to the environment’s moral significance for its contribution to
brain and mental health.
Currently, we face difficult environmental neuroethics questions involving conflicts
among values, such as the value of human health, the intrinsic and instrumental value
of the environment, and the value of economic development for societies. Human health
and particularly brain and mental health, can be seen as a distinct human value. Brain
health helps people to achieve their goals, promotes equality of opportunity (Daniels
2008), and prevents suffering and disability. From a social perspective, brain health deters
money and productivity costs, associated with brain disease and mental disorders. There
are, however, other values that modern society cherishes including economic growth.
Environmental changes undertaken in the pursuit of economic growth might unwittingly
create toxic environments for brain and mental health. In addition to the aforementioned
value conflicts, issues at the intersection of brain health and the environment involve a
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440 Environmental neuroethics

Box 22.1  Useful frameworks for environmental neuroethics

Normative: relational, global bioethics.
Justice: social and environmental justice, human rights.
Vulnerability and resilience: vulnerability as layers, individual vs. social
vulnerability.
Social constructionism: sociology of knowledge, traditional ecological knowledge.

clash of different understandings about the environment and its role in promoting or
hindering brain health. Given those complexities, it is a crucial part of environmental
neuroethics to bring together conceptual and methodological frameworks from diverse
disciplines that do not often directly engage, including neuroscience, sociology, environ-
mental science, and ethics (Illes et al. 2014). This drawing together of multidisciplinary
insights launches the field of neuroethics and environmental ethics into broader interac-
tive biomedical and social understandings of environmental change.
There are a variety of frameworks that are relevant to environmental neuroethics, as
illustrated in Box 22.1.

Ethics frameworks
Normative frameworks focused on examining general concepts and principles of ethics,
as well as empirical ethics frameworks focused on moral reasoning, judgment, behavior,
development, and learning, are broad frameworks to explore environmental neuroethics
issues. Van Rensselaer Potter’s global bioethics is another useful normative framework.
Potter’s Global Bioethics (Potter 1988) focuses on integrating biological knowledge with
diverse humanistic knowledge to systematically establish medical and environmental pri-
orities for acceptable survival at a global scale. Rather than viewing neuroethics and envi-
ronmental ethics as separate and distinct entities, within this strategy those two branches
are harmonized to a consensual point, stressing the importance of brain and mental
health consequences of environmental change, as well as the intimate human health and a
healthy environment relationship. Care ethics is another useful framework, capturing the
importance of the environment and human health and well-​being relationship. The dis-
tinct relational perspective incorporated by care ethics and feminist approaches acknowl-
edges that an individual’s health and well-​being are inextricably linked to the flourishing
of others, of communities, and the natural environment (Held 2006; Slote 2007). The
conceptual contribution frames human beings as “constituted [simultaneously] both as
organisms within systems of ecological relations, and as persons within systems of social
relations” (Ingold 2000, p.3). Such a view is intrinsic to certain indigenous considerations
of an individual’s relationship to their community and ecosystem. A  quotation from a
First Nation’s member captures this well: “I am part of an environment and if my environ-
ment suffers I  suffer as well.” A  relational framework rejects privileging individualistic
values and instead promotes communal values, viewing the individual and community
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Setting the foundations for environmental neuroethics 441

as vitally interconnected. From an ethical perspective, a relational framework is helpful

to address individual and community interdependence with the environment, broadly
construed to include natural, built, social, or cultural.

Social justice
A social justice framework considers unequal distribution, in the particular case of envi-
ronmental neuroethics, distribution of exposure to neurotoxicants and environmental
changes differentially impacting various populations in relationship to sociodemographic
determinants, such as income, occupation, education, and ethnicity (Commission on
Social Determinants of Health 2008). Those with lower socioeconomic status generally
have experienced greater exposure to detrimental environmental conditions both within
their homes and as part of their occupations. Minority groups, such as indigenous com-
munities, might suffer greater burdens of exposure if the natural resources they hunt and
fish are contaminated by industries operating near their communities. A  social justice
framework additionally takes into consideration vulnerable subpopulations, such as chil-
dren, pregnant women, and the elderly, who due to age, genetics, or health status are
especially susceptible to the effects of environmental exposures. From a social justice
perspective, when making environmental planning decisions, such as choosing where to
build an industrial site, locate a waste dump, or where to establish parks and green areas,
communities and nations have a societal obligation to minimize and mitigate environ-
mental injustices. There is an obligation to better regulate and ensure safety in consumer
products and in the workplace. These decisions should be transparent, democratic, and
fair, and should solicit and take into account in deliberation from those especially vulner-
able to environmental risks (Resnik & Portier 2008).
Environmental justice
A related and important framework is that of environmental justice, which is based
upon the idea that the health and well-​being of the members of a community, both
individually and collectively, are a product of the relationship between four interrelated
environments:  natural, built, social, and cultural/​spiritual (Lee 2002). It represents a
transformative public discourse on what constitutes truly healthy, livable, sustainable, and
vital communities. It expands the discourse concerning public health and environmental
risks to include issues of multiple, cumulative, and synergistic risk. Environmental injus-
tice occurs whenever some individual or group bears disproportionate environmental
risk, has unequal access to environmental goods, such as clean air, or has less opportu-
nity to participate in the environmental decision-​making (Shrader-​Frechette 2006). In
Western societies, poor and minority people who are disadvantaged in terms of educa-
tion, income, and occupation have been especially affected by environmental injustices,
as they are more likely than affluent Caucasians to live near polluting facilities, eat con-
taminated fish, and be employed at risky occupations. Environmental injustice is wrong
because it presents multiple threats to well-​being and health (both for present and future
people), it violates the principle of prima facie political equity, including its components
of distributed and participative justice (Shrader-​Frechette 2006), including aspects of
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442 Environmental neuroethics

human rights to equal protection, due process, consent, and compensation. An environ-
mental justice framework sets the foundations for conducting community-​driven science
and holistic, placed-​based, systems-​wide environmental protection (Lee 2002). It strives
for a more equitable distribution of environmental goods and burdens, while at the same
time it fosters greater public participation in evaluating and apportioning these goods and
burdens (Shrader-​Frechette 2006).

Vulnerabilities and resilience

Vulnerability has to do with a lack of capacity within individuals and communities to
cope with, recover from, and adapt to external stresses placed on their livelihoods and
well-​being. While vulnerability is inherent in all human beings, it comes in different
degrees. For example, children and elderly adults are considered more vulnerable to envi-
ronmental exposures than young adults because their brains are either in development
or because aging has mitigated the capacity for their brains to adapt to environmental
stressors. However, vulnerability and resilience are not just a biological matter, broader
issues of social, economic, and political inequality also affect them. Thus, economically
disadvantaged, and racial and ethnic minorities are also vulnerable populations.
Florencia Luna nicely captures that the concept of vulnerability as a label is not suf-
ficient to describe the underlying complexities. A better approach is to see vulnerabilities
as layers. Different layers in operation can render a given individual more vulnerable than
another from the same age group but with less layers of vulnerability operating (Luna
2009). A research framework focused on vulnerabilities and resilience from this point of
view can help identify, address, and mitigate associated environmental factors. In addi-
tion, while considerable research attention has examined vulnerability from an individual
perspective, not much attention has been paid to social vulnerability, which is “the prod-
uct of social factors that influence or shape the susceptibility of various groups to harm
and that also govern their ability to respond”, as well as “those characteristics of com-
munities and the built environment, such as the level of urbanization, growth rates, and
economic vitality, that contribute to the social vulnerability of places” (Cutter et al. 2003).
This is an important aspect of vulnerability that needs to be taken into account.

Human rights
After World War II, there was international consensus on the need to identify those
activities, conditions, and freedoms that all human beings are entitled to enjoy by virtue
of being human. These are regarded as human rights, and they include political, civil,
social, economic, and cultural rights. Human rights cannot be granted or taken away, the
enjoyment of one right affects the enjoyment of others and they must all be respected.
A human rights framework focuses on ways to establish mechanisms for addressing seri-
ous breaches and promoting national governments’ adherence regarding human rights
obligations. In relation to environmental neuroethics, key human rights to be discussed
would include the right to brain and mental health, to healthy environments, to access to
healthy food and clean water, and equal protection from environmental risks.
 43

Environmental neuroethics and future research 443

Social constructionism
According to this theoretical framework, reality cannot be accessed directly; the world
can only be perceived through our understandings. Thus what we know about the world
is socially constructed, and this knowledge is developed, transmitted, and maintained in
social situations. Social construction as a process refers then to how people collectively
and through social interaction perceive and interpret, impose meaning and order on their
world, and shape their shared reality (Berger & Luckmann 1966; Gergen 2001). Our per-
ception of the world, including the environment, is influenced by the underlying culture,
values, and local knowledge, by political and governance processes, by economic oppor-
tunities and costs, as well as by understandings of past experience, the present situation,
and future goals together with appraisals of risk, environmental threat, and environmen-
tal change (see Box 22.1).
Finally, adapting previous work in neuroethics (Marcus 2002), there are five founda-
tional areas (see Box 22.2) in which ethical issues that arise from environmental changes
impacts on brain and mental health can be conceptualized and problematized (Cabrera
et al. 2016).
Considering that environmental neuroethics is a relatively new approach within neu-
roethics, the principles and frameworks suggested here require further elaboration and
analysis; however, they lay a strong foundation to continue interdisciplinary work and
research in this important area.

Environmental neuroethics and future research

Investigation and discussion of the ethical, social, and policy implications of environ-
mental change and exposures on brain and mental health is, both from a consequential-
ist and prudential perspective, needed in order to clarify ethical concepts and values at
stake, address prioritization strategies, and make informed compromises at the interface
of environment, brain, individuals, and society. Nonetheless, we should bear in mind
that future research on environmental neuroethics is not without challenges. This sec-
tion introduces key challenges to be addressed in moving forward with environmental
neuroethics.

Conceptual
There are at least two conceptual issues that need to be addressed. The first one deals with
the environment being too broad a concept or too complex as to be the object of discus-
sion for mitigating brain disorders or fostering brain health. While it is true that the envi-
ronment can include many variables, there are ways in which the discussion of how the
environment affects brain and mental health is valuable. One way is to be specific about
the particular aspect of the environment (e.g., physical or social, or air quality). Another
way is to step back from a highly individualized perspective to a relational and interre-
lated one, embracing the underlying complexity and acknowledging how interconnected
brain and mental health is to the environments we grow and live in.
4

444 Environmental neuroethics

Box 22.2  Environmental neuroethics: Top areas of contribution

Brain science and the environment: assessment of neuroscience methods and
practices involved in studying the impact of environmental change and exposures;
measurement and evaluation of factors that affect the way individuals, communities,
and society adapt and cope with real or perceived environmental threats and
unfolding impacts of environmental change on brain and mental health.
The relational self, the brain, and the environment: examination of the
interdependence between the environment and brain and mental health, including
relations underlying vulnerability and resilience in brain and mental health within
the context of changing environments and environmental stressors; assessment of
mechanisms by which exposures at key points in life may contribute to different
brain and mental effects.
Cross-​cultural factors, the brain, and the environment: exploration of the role of
culture in the relationship and impact that environmental change has on brain and
mental health; assessment of interactions between Traditional Ecological Knowledge
and neuroscience knowledge and evidence.
Social policy, the brain, and the environment: consideration of priorities and
allocation of resources to deal with environmental impacts on brain and mental
health; deliberation and development of social policy related to environmental
injustices affecting brain and mental health.
Public discourse, the brain, and the environment: facilitation of international,
cross-​disciplinary, transdisciplinary collaborations; engagement of diverse
professional disciplines and communities in multidirectional communication and
discourse about neurological, psychological, sociological and ethical dimensions
of environmental change and exposures; creation of effective outreach programs
that promote public understanding about the impact of environmental change and
exposures on brain and mental health.

A second conceptual challenge has to do with how to distinguish between harm ver-
sus benefit with respect to environmental exposures. These concepts are relative to what
an individual would have been like in the absence of a particular environmental factor.
There is not a straightforward baseline level that would enable classification of a given
environmental factor as being beneficial if it increases brain health above that level and
harmful if it decreases brain health below that level. For many of the environmental fac-
tors already mentioned there seems to be a continuum, and there is not an obvious point
on the continuum that counts as the presumed normal amount of that environmental
factor. What counts as beneficial or harmful environmental exposure, or even what is a
healthy environment, is open to debate and is in need of both more empirical evidence
and normative discussion.
 45

Environmental neuroethics and future research 445

Knowledge
There are epistemic challenges. The rigid boundaries among disciplines of knowledge
along with semiautonomous development of knowledge in each field have been long-
standing obstacles to interdisciplinary thinking and practice necessary for integrated envi-
ronmental impact assessment on brain and mental health. This raises questions such as
“What knowledge should be counted in the assessment and how to assess diverse sources
of knowledge?” There is also a relative lack of expertise bridging the different areas that
are needed to obtain a better understanding of the issues involved, and to adequately
project their expertise into the state and national debates (Goldstein et al. 2012). Political
obstacles and time constraints are also a challenge for knowledge creation and dissemina-
tion. Policymakers typically use quantitative risk assessment and benefit–​cost analysis in
ways that are not sensitive to social and environmental justice issues.

Methodologies
The comparative dearth in understanding environmental impacts on brain and mental
health has been partly due to methodological challenges in satisfying the scientific rigors of
cause and effect in epidemiology. Useful methodologies, such as population-​based studies
that measure subtle effects on neurobehavioral outcomes, are often times challenging to
interpret and costly to conduct (Miodovnik 2011). Evidence linking a particular exposure
to brain health conditions relies on observational epidemiological studies or toxicity test-
ing using animal models, or both. For obvious ethical reasons, experimental studies with
purposeful dosing of substances with potential neurotoxic effects are not conducted in
humans. Therefore, while cause and effect is not proven with any one epidemiology study,
several well-​designed studies in different populations, alone or combined with inferential
evidence from animal exposures, can strongly support the likelihood that a given associa-
tion is in fact causal in nature. There are also challenges in terms of accounting for the
long timeframes of onset for many neurological illnesses, distinguishing environmental
impacts from other influences on brain and mental health, and the fact that research on
the brain is a relative latecomer to environmental and health impact studies.
The employment of locally accepted terminology and assessment strategies, study of
the synergistic or additive effects from exposure to mixture compounds, the inefficiency
of traditional research methods to obtain documentation and continuous monitoring of
impacts, for example, in relation to the cumulative effects of contaminants, and the dif-
ficulties in analyzing biomarkers of exposure in human tissue (Cranor 2011) are other
examples of the difficulties ahead.

Evidence
A related challenge is connected to evidence. Different environmental factors may not
appear by themselves to cause any obvious or serious risk for brain and mental health,
and damage might only be detectable from the combination of various chemicals often
after continued exposure, which makes it difficult to assess causality (Grandjean 2013;
46

446 Environmental neuroethics

Grossman 2014). Likewise, while there is widespread agreement that exposing organisms
to environmental toxins at high dose levels constitutes a significant threat to environmen-
tal and public health, low-​dose effects continue to be a matter of intense disagreement
among scientists, policymakers, and activist groups (Elliott 2011). There is also the issue
of how to weigh scientific evidence and the role it has in decision-​making. Some argue,
for example, that we already have plenty of evidence to support actions aimed at protect-
ing our brain and mental health, while others disagree, adding that the benefits of certain
practices (e.g., use of pesticides) clearly outweigh the possible harms on brain and mental
health. Others have argued that society cannot afford to wait for complete evidence, as the
consequences could be catastrophic and irreversible. An alternative approach endorsed
by a number of commentators and organizations is based on a precautionary principle,
where the idea is that society should take reasonable steps to prevent or mitigate sig-
nificant harm even when scientific evidence is incomplete or contested (Steel 2014). This
leads to a related challenge, that of conflicts of interest.

Conflict of interest and bias

The debates around scientific evidence and the ethical issues at stake are exacer-
bated not only by uncertainty regarding risks and potential consequences, but also
by vested interests, including profits from industry, as well as organized efforts by
interest groups to strategically design studies, and spread confusing and mislead-
ing information in an effort to support their preferred positions (Oreskes & Conway
2010; Elliott 2013).
There are also issues connected to bias. An example of government bias is that of
the lead-​contaminated water scandal in Flint, MI. Water contamination continued for
18 months after citizens first voiced complaints about water quality. Presumably, action
would have been taken more quickly, were Flint a more affluent community. Even more
evident than government biases are the vested interests of industry. In cases where public
safety and environmental protection get in the way of profit, these factors are often not
considered (Shrader-​Frechette 2006). An example of this relates to the fact that in the
United States, industrial chemicals, with the exception of pesticides, have no restrictions
prior to marketing (Cranor 2011). Furthermore, military and industry funding can be
regarded as introducing bias in academic work related to the environment and its impact
on brain and mental health.

Risks
Different social actors, based on their different worldviews and values, perceive and han-
dle risks differently (Slimak & Dietz 2006). Risks can be overestimated or underestimated
based on how they are perceived and communicated. Brain and mental health, for exam-
ple, often lack the clearly detectable experience characteristic of other more observable
bodily reactions such as coughing or red eyes resulting from high levels of air pollution,
which could lead to an underestimation of the associated risks.
 47

Conclusion 447

There are different dimensions of risk: “dread risk” captures emotional reactions to

hazards such as nuclear reactor accidents where people become anxious because of
a perceived lack of control over exposure to the risks and due to their catastrophic
consequences. An example of this comes from the Ojibway who referred to mercury
pollution as pijibowin, or poison, arguing that: “You can’t see it or smell it, you can’t
taste it or feel it, but you know it’s there. You know it can hurt you, make your spirit
sick” (quoted in Grandjean 2013). Another dimension is that of “unknown risk”, which
refers to the degree to which a risk is new, with unforeseeable consequences. There are
also challenges regarding the impacts on future generations and compensating them
for environmental changes and pollution that affected their brain and mental health.
Finally, by addressing a particular risk for a given group of individuals, we can end up
creating new problems for a different group of individuals (the solution turns into a
new problem).
While there are clearly various challenges ahead, environmental neuroethics provides a
needed approach to start a discussion on priorities and strategies that we as a society can
reasonably agree on regarding the type of environments that should be promoted without
becoming a burden to innovation and progress.

Conclusion
Environmental neuroethics aims to identify pragmatic starting points and alternatives
to resolve difficult ethical challenges presented at the intersection of environment and
brain, from strategies to reduce the adverse brain and mental health impacts from envi-
ronmental change and toxic exposures, to policies and strategies to foster healthy envi-
ronments. It provides a platform to discuss different ethical principles and perspectives
at the intersection of environmental change and its impact for brain and mental health,
including issues of beneficence and nonmaleficence (avoiding harm and ensuring welfare
for individuals and communities), social justice, and responsibility. It offers a novel con-
ceptual, normative, and empirical approach, bringing various disciplines together into an
interaction with broader ethical, biomedical, and social understandings of environmental
change and exposures and their role for brain and mental health. The various frameworks
and principles discussed here set the foundation to move forward the first generation of
environmental neuroethics scholarship.
While many challenges lay ahead in the future of environmental neuroethics, it is clear
that the unprecedented consequences for both present and future generations in terms
of environmental impacts on brain and mental health make this new trajectory a needed
and timely one.

Acknowledgments
The author would like to thank Kevin Elliot, Len Fleck, and Libby Bogdan-​Lovis for their
insightful comments and for helping with proofreading this chapter.
48

448 Environmental neuroethics

Notes
1. This is the clinical definition of a variety of different underlying pathologies that can cause Parkinson’s-​
like symptoms.
2. There is also emerging evidence that chronic stress contributes to depression, post-​traumatic stress
disorder, and the development of certain pathologies by accelerating and/​or exacerbating preexisting
vulnerabilities.

References
Alavanja, M.C.R., Hoppin, J.A., and Kamel, F. (2004). Health effects of chronic pesticide
exposure: cancer and neurotoxicity. Annual Review of Public Health, 25, 155–​197.
Albrecht, G., Sartore, G.M., Connor, L., et al. (2007). Solastalgia: the distress caused by environmental
change. Australasian Psychiatry, 15(Suppl. 1), S95–​S98.
APA Task Force (2011). Psychology and Global Climate Change. American Psychological Association.
Available from: http://​www.apa.org/​science/​about/​publications/​climate-​change.aspx [accessed
January 18, 2016].
Baroncelli, L., Braschi, C., Spolidoro, M., Begenisic, T., Sale, A., and Maffei, L. (2010). Nurturing brain
plasticity: impact of environmental enrichment. Cell Death and Differentiation, 17(7), 1092–​1103.
Bentall, R.P. and Fernyhough, C. (2008). Social predictors of psychotic experiences: specificity and
psychological mechanisms. Schizophrenia Bulletin, 34(6), 1012–​1020.
Berger, P.L. and Luckmann, T. (1966). The Social Construction of Reality: A Treatise in the Sociology of
Knowledge. London: Penguin Books.
Berry, H.L., Hogan, A., Owen, J., Rickwood, D., and Fragar, L. (2011). Climate change and farmers’
mental health: risks and responses. Asia-​Pacific Journal of Public Health, 23(Suppl. 2), 119S–​132S.
Berry, H.L., Bowen, K., and Kjellstrom, T. (2010). Climate change and mental health: a causal pathways
framework. International Journal of Public Health, 55(2), 123–​132.
Bested, A.C., Logan, A.C., and Selhub, E.M. (2013). Intestinal microbiota, probiotics and mental
health: from Metchnikoff to modern advances: part III—​convergence toward clinical trials. Gut
Pathogens, 5(1), 4.
Blas, E., Sommerfeld, J., and Kurup, A.S. (2011). Social Determinants Approaches to Public Health.
Geneva: World Health Organization.
Bowler, D.E., Buyung-​Ali, L.M., Knight, T.M., and Pullin, A.S. (2010). A systematic review of
evidence for the added benefits to health of exposure to natural environments. BMC Public Health,
10(456), 1–​10.
Butterworth, R.F. (2010). Metal toxicity, liver disease and neurodegeneration. Neurotoxicity Research,
18(1), 100–​105.
Cabrera, L.Y. (2015). Rethinking Human Enhancement. London: Palgrave Macmillan.
Cabrera, L.Y., Tesluk, J., Chakraborti, M., Matthews, R., and Illes, J. (2016). Brain matters: from
environmental ethics to environmental neuroethics. Environmental Health, 15(20), 1–​5.
Calderon-​Garcidueñas, L., Azzarelli, B., Acuna, H., et al. (2002). Air pollution and brain damage.
Toxicologic Pathology, 30(3), 372–​389.
Calderon-​Garcidueñas, L., Reed, W., Maronpot, R.R., et al. (2004). Brain inflammation and
Alzheimer’s-​like pathology in individuals exposed to severe air pollution. Toxicologic Pathology,
32(6), 650–​658.
Calderon-​Garcidueñas, L., Mora-​Tiscareño, A., Ontiveros, E., et al. (2008). Air pollution, cognitive
deficits and brain abnormalities: a pilot study with children and dogs. Brain and Cognition, 68(2),
117–​127.
 49

References 449

Canadian Environmental Health Atlas (2014, November 11). Little Things Matter: The Impact of
Toxins on the Developing Brain. [Online video.] https://​youtu.be/​E6KoMAbz1Bw [accessed January
29, 2016].
Centers for Disease Control and Prevention (2015). Developmental Disabilities. Available from: http://​
www.cdc.gov/​ncbddd/​developmentaldisabilities/​index.html [accessed January 29, 2016].
Chen, F.S., Kumsta, R., von Dawans, B., Monakhov, M., Ebstein, R.P., and Heinrichs, M. (2011).
Common oxytocin receptor gene (OXTR) polymorphism and social support interact to reduce
stress in humans. Proceedings of the National Academy of Sciences of the United States of America,
108(50), 19937–​19942.
Colborn, T., Kwiatkowski, C., Schultz, K., and Bachran, M. (2011). Natural gas operations from a
public health perspective. Human and Ecological Risk Assessment: An International Journal, 17(5),
1039–​1056.
Commission on Social Determinants of Health (2008). Closing the Gap in a Generation: Health
Equity Through Action on the Social Determinants of Health. Geneva: World Health Organization.
Cranor, C. (2011). Legally Poisoned: How the Law Puts Us at Risk from Toxicants. Cambridge,
MA: Harvard University Press.
Crews, D. (2010). Epigenetics, brain, behavior, and the environment. Hormones, 9(1), 41–​50.
Cumes, D. (1998). Nature as medicine: the healing power of the wilderness. Alternative Therapies in
Health and Medicine Journal, 4(2), 1–​8.
Cunsolo Willox, A., Harper, S.L., Ford, J.D., et al. (2013). Climate change and mental health: an
exploratory case study from Rigolet, Nunatsiavut, Canada. Climatic Change, 121(2), 255–​270.
Cutter, S.L., Boruff, B.J., and Shirley, W.L. (2003). Social vulnerability to environmental hazards. Social
Science Quarterly, 84, 1–​20.
Dakeishi, M., Murata, K., and Grandjean, P. (2006). Long-​term consequences of arsenic poisoning
during infancy due to contaminated milk powder. Environmental Health, 5(31), 1–​7.
Daniels, N. (2008). Just Health. New York: Cambridge University Press.
de Burbure, C., Buchet, J.P., Leroyer, A., et al. (2006). Renal and neurologic effects of cadmium, lead,
mercury, and arsenic in children: evidence of early effects and multiple interactions at environmental
exposure levels. Environmental Health Perspectives, 114(4), 584–​590.
Debes, F., Budtz-​Jørgensen, E., Weihe, P., White, R.F., and Grandjean, P. (2006). Impact of prenatal
methylmercury exposure on neurobehavioral function at age 14 years. Neurotoxicology and
Teratology, 28(3), 363–​375.
Dick, F.D. (2006). Solvent neurotoxicity. Occupational and Environmental Medicine, 63(3), 221–​226.
Elbaz, A., Clavel, J., Rathouz, P.J., et al. (2009). Professional exposure to pesticides and Parkinson
disease. Annals of Neurology, 66(4), 494–​504.
Elliott, K.C. (2011). Is a Little Pollution Good for You?: Incorporating Societal Values in Environmental
Research. Oxford: Oxford University Press.
Elliott, K.C. (2013). Financial conflicts of interest and criteria for research credibility. Erkenntnis,
79(S5), 917–​937.
Field, R.A., Soltis, J., and Murphy, S. (2014). Air quality concerns of unconventional oil and natural gas
production. Environmental Science: Processes & Impacts, 16(5), 954–​969.
Fritze, J.G., Blashki, G.A., Burke, S., and Wiseman, J. (2008). Hope, despair and
transformation: climate change and the promotion of mental health and wellbeing. International
Journal of Mental Health Systems, 2(1), 13.
Frumkin, H. (2001). Beyond toxicity: human health and the natural environment. American Journal of
Preventive Medicine, 20(3), 234–​240.
Gay, J., Shepherd, O., Thyden, M., and Whitman, M. (2010). The Health Effects of Oil
Contamination: A Compilation of Research. Worcester, MA: Worcester Polytechnic Institute.
450

450 Environmental neuroethics

Gergen, K.J. (2001). Social Construction in Context. London: SAGE.

Goldstein, B.D., Kriesky, J., and Pavliakova, B. (2012). Missing from the table: role of the
environmental public health community in governmental advisory commissions related to
Marcellus shale drilling. Environmental Health Perspectives, 120(4), 483–​486.
Gómez-​Pinilla, F. (2008). Brain foods: the effects of nutrients on brain function. Nature Reviews
Neuroscience, 9(7), 568–​578.
Grandjean, P. (2013). Only One Chance: How Environmental Pollution Impairs Brain Development—​and
How to Protect the Brains of the Next Generation. New York: Oxford University Press.
Grandjean, P. and Herz, K.T. (2011). Methylmercury and brain development: Imprecision and
underestimation of developmental neurotoxicity in humans. Mount Sinai Journal of Medicine, 78(1),
107–​118.
Grandjean, P. and Landrigan, P.J. (2006). Developmental neurotoxicity of industrial chemicals. The
Lancet, 368, 2167–​2178.
Grandjean, P., Weihe, P., White, R.F., et al. (1997). Cognitive deficit in 7-​year-​old children with prenatal
exposure to methylmercury. Neurotoxicology and Teratology, 19(6), 417–​428.
Grandjean, P., Weihe, P., Burse, V.W., et al. (2001). Neurobehavioral deficits associated with PCB in 7-​
year-​old children prenatally exposed to seafood neurotoxicants. Neurotoxicology and Teratology, 23,
305–​317.
Grandjean, P., Harari, R., Barr, D.B., and Debes, F. (2006). Pesticide exposure and stunting as
independent predictors of neurobehavioral deficits in Ecuadorian school children. Pediatrics,
117(3), e546–​e556.
Grandjean, P., Satoh, H., Murata, K., and Eto, K. (2010). Adverse effects of
methylmercury: environmental health research implications. Environmental Health Perspectives,
118(8), 1137–​1145.
Grashow, R., Spiro, A., Taylor, K.M., et al. (2013). Cumulative lead exposure in community-​dwelling
adults and fine motor function: Comparing standard and novel tasks in the VA Normative Aging
Study. NeuroToxicology, 35, 154–​161.
Greenwood, C.E. and Winocur, G. (2005). High-​fat diets, insulin resistance and declining cognitive
function. Neurobiology of Aging, 26(1), 42–​45.
Grossman, E. (2014). Time after time: environmental influences on the aging brain. Environmental
Health Perspectives, 122(9), A238–​A243.
Haddad, L., Schäfer, A., Streit, F., et al. (2015). Brain structure correlates of urban upbringing, an
environmental risk factor for schizophrenia. Schizophrenia Bulletin, 41(1), 115–​122.
Haluza, D., Schönbauer, R., and Cervinka, R. (2014). Green perspectives for public health: a narrative
review on the physiological effects of experiencing outdoor nature. International Journal of
Environmental Research and Public Health, 11(5), 5445–​5461.
Harari, R., Julvez, J., Murata, K., et al. (2010). Neurobehavioral deficits and increased blood pressure
in school-​age children prenatally exposed to pesticides. Environmental Health Perspectives, 118(6),
890–​896.
Heiervang, K.S., Mednick, S., Sundet, K., and Rund, B.R. (2010). Effect of low dose ionizing radiation
exposure in utero on cognitive function in adolescence. Scandinavian Journal of Psychology, 51(3),
210–​215.
Held, V. (2006). The Ethics of Care. New York: Oxford University Press.
Hertzman, C., Wiens, M., Bowering, D., Snow, B., and Calne, D. (1990). Parkinson’s disease: a case-​
control study of occupational and environmental risk factors. American Journal of Industrial
Medicine, 17(3), 349–​355.
Hu, H.W., Téllez-​Rojo, M.M., Bellinger, D., et al. (2006). Fetal lead exposure at each stage of pregnancy
as a predictor of infant mental development. Environmental Health Perspectives, 114, 1730–​1735.
 451

References 451

Illes, J., Davidson, J., and Matthews, R. (2014). Environmental neuroethics: changing the
environment –​changing the brain. Recommendations submitted to the Presidential Commission
for the Study of Bioethical Issues. Journal of Law and the Biosciences, 1(2), 221–​223.
Ingold, T. (2000). The Perception of the Environment. London: Psychology Press.
Jacobson, J.L. and Jacobson, S.W. (2003). Prenatal exposure to polychlorinated biphenyls and attention
at school age. Journal of Pediatrics, 143(6), 780–​788.
Joseph, J.A., Shukitt-​Hale, B., and Lau, F.C. (2007). Fruit polyphenols and their effects on neuronal
signaling and behavior in senescence. Annals of the New York Academy of Sciences of the United
States of America, 1100(1), 470–​485.
Kamel, F. and Hoppin, J.A. (2004). Association of pesticide exposure with neurologic dysfunction and
disease. Environmental Health Perspectives, 112(9), 950–​958.
Kelly, B.D., O'Callaghan, E., Waddington, J.L., et al. (2010). Schizophrenia and the city: a review of
literature and prospective study of psychosis and urbanicity in Ireland. Schizophrenia Research,
116(1), 75–​89.
Kerti, L. Witte, A.V., Winkler, A., Grittner, U., Rujescu, D., and Flöel, A. (2013). Higher glucose levels
associated with lower memory and reduced hippocampal microstructure. Neurology, 81, 1746–​1752.
Kirmayer, L.J. and Valaskakis, G.G. (2008). Healing Traditions. Vancouver, BC: UBC Press.
Korrick, S.A. and Sagiv, S.K. (2008). Polychlorinated biphenyls, organochlorine pesticides and
neurodevelopment. Current Opinion in Pediatrics, 20(2), 198–​204.
Kramer, A.F., Erickson, K.I., and Colcome, S.J. (2006). Exercise, cognition, and the aging brain. Journal
of Applied Physiology, 101, 1237–​1242.
Lai, J.S., Hiles, S., Bisquera, A., et al. (2014). A systematic review and meta-​analysis of dietary patterns
and depression in community-​dwelling adults. American Journal of Clinical Nutrition, 99(1),
181–​197.
Landrigan, P.J., Sonawane, B., Butler, R.N., Trasande, L., Callan, R., Droller, D. (2005). Early
environmental origins of neurodegenerative disease in later life. Environmental Health Perspectives,
113(9), 1230–​1233.
Lanphear, B.P., Hornung, R., Khoury, J., et al. (2005). Low-​level environmental lead exposure and
children’s intellectual function: an international pooled analysis. Environmental Health Perspectives,
113(7), 894–​899.
Lederbogen, F., Kirsch, P., Haddad, L., et al. (2011). City living and urban upbringing affect neural
social stress processing in humans. Nature, 474(7352), 498–​501.
Lee, C. (2002). Environmental justice: building a unified vision of health and the environment.
Environmental Health Perspectives, 110, 141–​144.
Levy, N. (2012). Ecological engineering: reshaping our environments to achieve our goals. Philosophy &
Technology, 25(4), 589–​604.
Lim, Y.-​H., Kim, H., Kim, J.H., et al. (2012). Air pollution and symptoms of depression in elderly
adults. Environmental Health Perspectives, 120(7), 1023–​1028.
Lucchini, R.G., Guazzetti, S., Zoni S., et al. (2014). Neurofunctional dopaminergic impairment in
elderly after lifetime exposure to manganese. NeuroToxicology, 45, 309–​317.
Luna, F. (2009). Elucidating the concept of vulnerability: layers not labels. International Journal of
Feminist Approaches to Bioethics, 2(1), 121–​139.
Maas, J. (2006). Green space, urbanity, and health: how strong is the relation? Journal of Epidemiology &
Community Health, 60(7), 587–​592.
Marcus, S. (2002). Neuroethics: Mapping the Field. San Francisco, CA: Dana Press.
Marmot, M. (2005). Social determinants of health inequalities. The Lancet, 365(9464), 1099–​1104.
Matuszek, S. (2010). Animal-​facilitated therapy in various patient populations. Holistic Nursing Practice,
24(4), 187–​203.
452

452 Environmental neuroethics

Miodovnik, A. (2011). Environment neurotoxicants and developing brain. Mount Sinai Journal of
Medicine, 78, 58–​77.
Mora, F., Segovia, G. and del Arco, A. (2007). Aging, plasticity and environmental
enrichment: structural changes and neurotransmitter dynamics in several areas of the brain. Brain
Research Reviews, 55(1), 78–​88.
Needleman, H.L., Gunnoe, C., Leviton, A., et al. (1979). Deficits in psychologic and classroom
performance of children with elevated dentine lead levels. New England Journal of Medicine,
300(13), 689–​695.
Needleman, H.L., Schell, A., Bellinger, D., Leviton, A., and Allred, E.N. (1990). The long-​term effects
of exposure to low doses of lead in childhood. An 11-​year follow-​up report. New England Journal of
Medicine, 322(2), 83–​88.
NEPA (1969). The National Environmental Policy Act. Available from: https://​ceq.doe.gov/​laws_​and_​
executive_​orders/​the_​nepa_​statute.html [accessed March 5, 2016].
Nussbaum, M. and Sen, A. (1993). The Quality of Life. Gloucestershire: Peterson’s.
O’Neil, A., Quirk, S.E., Housden, S., et al. (2014). Relationship between diet and mental health in
children and adolescents: a systematic review. American Journal of Public Health, 104, e31–​e42.
O’Rourke, D. and Connolly, S. (2003). Just oil? The distribution of environmental and social impacts of
oil production and consumption. Annual Review of Environment and Resources, 28(1), 587–​617.
Opler, M.G.A., Buka, S.L., Groeger, J., et al. (2008). Prenatal exposure to lead, δ-​aminolevulinic acid,
and schizophrenia: further evidence. Environmental Health Perspectives, 116(11), 1586–​1590.
Oreskes, N. and Conway, E.M. (2010). Merchants of Doubt. New York: Bloomsbury Publishing USA.
Parfit, D. (1971). Personal identity. The Philosophical Review, 80, 3–​27.
Patterson, C.C. (1965). Contaminated and natural lead environments of man. Archives of Environmental
Health, 11, 344–​360.
Peen, J., Schoevers, R.A., Beekman, A.T., and Dekker, J. (2010). The current status of urban-​rural
differences in psychiatric disorders. Acta Psychiatrica Scandinavica, 121(2), 84–​93.
Pereira, A.C., Huddleston, D.E., Brickman, A.M., et al. (2007). An in vivo correlate of exercise-​induced
neurogenesis in the adult dentate gyrus. Proceedings of the National Academy of Sciences of the
United States of America, 104(13), 5638–​5643.
Perrin, M., Opler, M.G., Harlap, S., et al. (2007). Tetrachloroethylene exposure and risk of
schizophrenia: offspring of dry cleaners in a population birth cohort, preliminary findings.
Schizophrenia Research, 90(1–​3), 251–​254.
Perry, S.L. (2012). Development, land use, and collective trauma: the Marcellus shale gas boom in rural
Pennsylvania. Culture, Agriculture, Food and Environment, 34(1), 81–​92.
Peters, A., Veronesi, B., Calderón-​Garcidueñas, L., et al. (2006). Translocation and potential
neurological effects of fine and ultrafine particles a critical update. Particle and Fibre Toxicology,
3(1), 1–​13.
Petronis, A. and Mill, J. (2011). Brain, Behavior and Epigenetics. New York: Springer.
Potter, V.R. (1988). Global Bioethics. East Lansing, MI: MSU Press.
Prüss-​Üstün, A. and Corvalán, C. (2006). Preventing Disease Through Healthy Environments.
Geneva: World Health Organization.
Psaltopoulou, T., Sergentanis, T.N., Panagiotakos, D.B., Sergentanis, I.N., Kosti, R., and Scarmeas, N.
(2013). Mediterranean diet, stroke, cognitive impairment, and depression: a meta-​analysis. Annals of
Neurology, 74(4), 580–​591.
Public Health Agency of Canada (2011). What determines health? Public Health Agency of Canada,
1–​4. Available from: http://​www.phac-​aspc.gc.ca/​ph-​sp/​determinants/​index-​eng.php [accessed
January 18, 2016].
 453

References 453

Rabinowitz, P.M., Slizovskiy, I.B., Lamers, V., et al. (2015). Proximity to natural gas wells and reported
health status: results of a household survey in Washington County, Pennsylvania. Environmental
Health Perspectives, 123(1), 21–​26.
Rawls, J. (1971). A Theory of Justice. Cambridge, MA: Harvard University Press.
Raz, R., Roberts, A.L., Lyall, K., et al. (2014). Autism spectrum disorder and particulate matter air
pollution before, during, and after pregnancy: a nested case–​control analysis within the nurses’
health study II cohort. Environmental Health Perspectives, 123(3), 264–​270.
Resnik, D.B. (2009). Human health and the environment: in harmony or in conflict? Health Care
Analysis, 17(3), 261–​276.
Resnik, D.B. (2012). Environmental Health Ethics. Cambridge: Cambridge University Press.
Resnik, D.B. and Portier, C.J. (2008). Environment and Health. Garrison, NY: The Hastings Center.
Roberts, E.M., English, P.B., Grether, J.K., Windham, G.C., Somberg, L., and Wolff, C. (2007).
Maternal residence near agricultural pesticide applications and autism spectrum disorders among
children in the California central valley. Environmental Health Perspectives, 115, 1482–​1489.
Rodríguez-​Barranco, M., Lacasaña, M., Gil, F., et al. (2014). Environmental research. Environmental
Research, 134(C), 66–​73.
Rosado, J.L., Ronquillo, D., Kordas, K., et al. (2007). Arsenic exposure and cognitive performance in
Mexican schoolchildren. Environmental Health Perspectives, 115(9), 1371–​1375.
Sagoff, M. (2008). Zuckerman’s dilemma a plea for environmental ethics. Hastings Center Report,
21, 32–​40.
Schwartz, B.S., Stewart, W.F., Bolla, K.I., et al. (2000). Past adult lead exposure is associated with
longitudinal decline in cognitive function. Neurology, 55, 1144–​1150.
Seeman, T.E. and McEwen, B.S. (1996). Impact of social environment characteristics on
neuroendocrine regulation. Psychosomatic Medicine, 58, 459–​471.
Shelton, J.F., Geraghty, E.M., Tancredi, D.J., et al. (2014). Neurodevelopmental disorders and prenatal
residential proximity to agricultural pesticides: the CHARGE study. Environmental Health
Perspectives, 122, 1103–​1109.
Shih, R.A., Hu, H., Weisskopf, M.G., and Schwartz, B.S. (2007). Cumulative lead dose and cognitive
function in adults: a review of studies that measured both blood lead and bone lead. Environmental
Health Perspectives, 115(3), 483–​492.
Shonkoff, J.P. (2012). Leveraging the biology of adversity to address the roots of disparities in health
and development. Proceedings of the National Academy of Sciences of the United States of America,
109(Suppl. 2), 17302–​17307.
Shrader-​Frechette, K.S. (2006). Environmental Justice. Oxford: Oxford University Press.
Slimak, M.W. and Dietz, T. (2006). Personal values, beliefs, and ecological risk perception. Risk
Analysis, 26(6), 1689–​1705.
Slote, M. (2007). The Ethics of Care and Empathy. New York: Routledge.
Small, G. and Vorgan, G. (2008). iBrain. New York: Harper Collins.
Smith, K.R., Corvalan, C.F., and Kjellstrom, T. (1999). How much global ill health is attributable to
environmental factors? Epidemiology, 10(5), 573–​584.
Stedman, R.C., Jacquet, J.B., and Filteau, M.R. (2012). Marcellus shale gas development and new
boomtown research: wiews of New York and Pennsylvania residents. Environmental Practice, 14,
382–​393.
Steel, D. (2014). Philosophy and the Precautionary Principle. Cambridge: Cambridge University Press.
Stewart, P.W., Lonky, E., Reihman, J., et al. (2008). The relationship between prenatal PCB exposure
and intelligence (IQ) in 9-​year-​old children. Environmental Health Perspectives, 116(10), 1416–​1422.
45

454 Environmental neuroethics

Tang, C.Y., Carpenter, D.M., Eaves, E.L., et al. (2011). Occupational solvent exposure and brain
function: an fMRI study. Environmental Health Perspectives, 119(7), 908–​913.
Teicher, M.H. and Samson, J.A. (2013). Childhood maltreatment and psychopathology: a case for
ecophenotypic variants as clinically and neurobiologically distinct subtypes. American Journal of
Psychiatry, 170, 1114–​1133.
Tost, H., Champagne, F.A. and Meyer-​Lindenberg, A. (2015). Environmental influence in the brain,
human welfare and mental health. Nature Neuroscience, 18(10), 1421–​1431.
Tsai, S.-​Y., Chou, H.Y., The, H.W., Chen, C.M., and Chen, C.J. (2003). The effects of chronic
arsenic exposure from drinking water on the neurobehavioral development in adolescence.
NeuroToxicology, 24(4–​5), 747–​753.
United Nations Environment Programme (1972). Report of the United Nations Conference on the
Human Environment. Available from: http://​www.unep.org/​Documents.multilingual/​Default.asp?D
ocumentID=97&ArticleID=150 [accessed March 5, 2016].
van Os, J., Kenis, G., and Rutten, B.P.F. (2010). The environment and schizophrenia. Nature, 468(7321),
203–​212.
van Praag, H., Kempermann, G., and Gage, F.H., 2000. Neural consequences of environmental
enrichment. Nature Reviews Neuroscience, 1(3), 191–​198.
Villanueva, C.M., Kogevinas, M., Cordier, S., et al. (2013). Assessing exposure and health consequences
of chemicals in drinking water: current state of knowledge and research needs. Environmental
Health Perspectives, 122, 213–​221.
Vukic, A., Gregory, D., Martin-​Misener, R., and Etowa, J. (2011). Aboriginal and Western conceptions
of mental health and illness. Pimatisiwin: A Journal of Aboriginal & Indigenous Community Health,
9(1), 65–​86.
Watson, S. (2008, October 8). How Eco-​anxiety Works. Available from: http://​science.howstuffworks.
com/​environmental/​green-​science/​eco-​anxiety.htm [accessed January 23, 2015].
Weisskopf, M.G., Hu, H., Sparrow, D., Lenkinski, R.E., and Wright, R.O. (2007). Proton magnetic
resonance spectroscopic evidence of glial effects of cumulative lead exposure in the adult human
hippocampus. Environmental Health Perspectives, 115(4), 519–​523.
White, A.M., Philogene, G.S., Fine, L., and Sinha, S. (2009). Social support and self-​reported health
status of older adults in the United States. American Journal of Public Health, 99(10), 1872–​1878.
Windham, G.C., Zhang, L., Gunier, R., Croen, L.A., and Grether, J.K. (2006). Autism spectrum
disorders in relation to distribution of hazardous air pollutants in the San Francisco Bay area.
Environmental Health Perspectives, 114(9), 1438–​1444.
Woo, C.C. and Leon, M. (2013). Environmental enrichment as an effective treatment for autism: a
randomized controlled trial. Behavioral Neuroscience, 127(4), 487–​497.
Wright, R.O., Amarasiriwardena, C., Woolf, A.D., Jim, R., and Bellinger, D.C. (2006).
Neuropsychological correlates of hair arsenic, manganese, and cadmium levels in school-​age
children residing near a hazardous waste site. NeuroToxicology, 27(2), 210–​216.
 45

Chapter 23

First Nations and environmental

neuroethics: Perspectives on brain
health from a world of change
Jordan Tesluk, Judy Illes, and Ralph Matthews

First Nations and environmental neuroethics: A call for

understanding
This chapter calls for the bridging of knowledge between First Nations1 and Western insti-
tutions of environmental and medical science to inform ethical debates related to envi-
ronmental impacts on the brain. Amid changing environmental conditions and persisting
health deficits, First Nations people in Canada face mounting risks to their neurologi-
cal and mental health. Effective engagement between Western science and First Nations
people requires an understanding of differences in the ontological and epistemological
foundations of respective knowledge systems, so that the ethical issues related to environ-
mental impacts on the brain can be brought into a space of common language and prac-
tice. This not only requires reconciling differences in understandings of the environment
and the brain, but also requires reflection on the foundations of thought and reason that
underpin First Nations’ and settler society’s respective systems of ethical decision-​making.
Like other indigenous populations, First Nations people occupy a sensitive location
where the consequences of industrial activity collide with traditional lifestyles, and where
environmental change is experienced as a direct impact on communities and individu-
als. While the influence of environmental change on the human brain is a concern for all
people, the ethical implications of such impacts are different for indigenous peoples who
hold closer cultural and subsistence-​based relationships with the environment. Animals,
plants, and the elements of nature play a central role in the traditional mythology, art-
work, social structure, economy, and belief systems of First Nations people. A majority of
First Nations communities in Canada are located in isolated rural areas, where reliance
upon the local environment for food and resources is high, and access to the amenities
and services of urban life is often limited. The proximity of First Nations to the frontiers of
development for mining, oil and gas development, and hydroelectric industries, together
with their direct reliance upon the environment thus compounds the neurological risks
of environmental change with complex social impacts that threaten the future of their
culture and their communities.
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456 First Nations and environmental neuroethics

It is for these reasons that the experience of First Nations has become an important
research focus. Environmental change and the development of natural resources have
important implications for the neurological and mental health of both First Nations and
for indigenous people throughout Canada and the rest of the world. While we draw on
findings from other Canadian aboriginal populations, we place First Nations at the center
of this chapter with the understanding that the concerns they share with other popula-
tions are bound together by the global scope of environmental change that is occurring,
and by common experiences under the institutions of Western science and medicine that
have spread their influence across so much of the planet.
In this chapter, we examine past research that intersects studies of the environment,
neurological and mental health, and First Nations experience. We begin with an examina-
tion of vulnerability to diseases of the brain and to environmental change in First Nations
people, and situate these issues within the broader scope of change occurring in their
societies. We examine some of the challenges that exist in conducting research on neu-
rological and mental health with First Nations people, and identify examples of recent
research that has helped create positive relationships between neurological researchers
and First Nations people. We then explore how the corresponding progressions in classi-
cal Western thought and the study of brain and environment contrast with First Nations’
paths of development. We use this analysis to confront the challenges inherent to the con-
vergence of contrasting systems of knowledge, and we address the role that neuroethics
can play in bringing First Nations and Western institutions of science together in protect-
ing the health of the brain.2
This chapter focuses upon First Nations people, and their distinct experiences related to
the environment and brain health. We remain cognizant of the related but distinct experi-
ences of Metis and Inuit peoples in Canada, as well as aboriginal people in other regions.
We acknowledge the need for exploration of the specific issues related to the intersections
between their respective experiences and environmental neuroethics. We also recognize
the diversity of experiences and perspectives that exists both between different groups of
aboriginal people and among the 630 recognized First Nations governments and bands
that are located across Canada.

Environment, brain, and knowledge

Environmental neuroethics takes as a central premise that the human brain is malleable,
and that it changes in response to its environment (Rose & Abi-​Rached 2013; Cabrera
et al. 2016). Environmental factors can shape central nervous system health and psycho-
pathology, and contribute to epigenetic processes that affect DNA and predispositions to
neurological disease. Perceptions of the environment, and beliefs and knowledge about
the environment, can directly influence mental health and shape behaviors that affect
neurological health (Wilson 2003; Masuda & Garvin 2006; Jackson 2011) Perceptions of
the environment are based in both information shared among individuals and in sensory
experience. The environment is perceived through sensory systems (particularly sight,
 457

First Nations and the context of change 457

smell, and taste), which send signals to which the brain responds, and adapts, and which
it ultimately translates into information and knowledge related to a person’s surroundings
and circumstances.
Both perceptions of the environment, and understandings of the brain in relation to
human health and agency, are mediated through cultural frames of reference that define
the boundary between the self and the natural environment, and that shape individuals’
interactions with the environment. These frames of reference include systems of thought
that situate humans as separate from nature (e.g., in traditional Western worldviews) and
perspectives that see the environment and the self as intimately interconnected (such as
traditional First Nations worldviews). Our most fundamental understandings of the rela-
tionship between environment and the brain are thus rooted in culturally situated systems
of knowledge, and are shaped and reshaped through cumulative experience.
Thus, efforts to understand the impact of environmental factors on neurological and
mental health among First Nations people must go beyond a mere acknowledgment of
differences in vulnerability, perspectives, and experiences. Indeed, the fulsome investiga-
tion of this topic involves a broader endeavor. Thoughtful research must reach beyond
the development of “culturally sensitive” programs and regulatory-​based research eth-
ics. Between the social dimensions of culture that link humans to the environment, and
the neurological dimensions of environmental impacts on the central nervous system,
is a broad space that spans biological, social, cultural, psychological, and genetic link-
ages between the brain and the environment. As a multidisciplinary field that examines
environmental impacts on brain and mental health, environmental neuroethics seeks to
develop a framework for understanding how new forms of knowledge are produced from
the interaction between Western scientific worldviews and those of First Nations and
other indigenous people.

First Nations and the context of change

The past four centuries of colonization have introduced many radical changes to First
Nations people that have reshaped their environment and affected their neurological and
mental health. The arrival of European settlers brought great troubles to First Nations
people in the form of degradation of their environment, marked deficits in health and
material privilege, and marginalization within the modern Western institutions that
dominate the land around them (Stanbury 1973; Pinkerton 1987; Tennant 1990; High
1996; Anderson R.B. 1999). Among the challenges faced by First Nations people are
high rates of suicide, depression, and substance abuse, and greater risks for brain injuries
and neural tube defects among infants (Ray et al. 2004; Lehti et al. 2009; Northern Brain
Injury Association 2015). The Public Health Agency of Canada (2014) acknowledges that
First Nations and Metis people experience unique impacts as a result of neurological con-
ditions, and illnesses of the brain compound disadvantage with existing hardship and
inequality. Despite these concerns, data on neurological conditions among First Nations
have not been gathered in Canadian census and national surveys, and neurological
458

458 First Nations and environmental neuroethics

disorders such as cerebral palsy and autism that are disproportionately prevalent among
other North American aboriginal people remain understudied among Canadian popula-
tions (Di Pietro and Illes 2014).
The need for a better understanding of the environmental impact on First Nations peo-
ple’s neurological and mental health is made more pressing by human-​induced global
climate change and ongoing natural resource development activities affecting territories
of First Nations. Across Canada, First Nations are engaged in battles to assert control
over the environment, and to deal with the impact of environmental change on their
brains, bodies, and communities. In the north, for example, the Mikisew Cree and the
Athabasca Chipewyan are confronting ongoing and unknown future health impacts
resulting from oil and gas development in the Albertan tar sands projects (Kelly et  al.
2009, 2010; Timoney & Lee 2009; Scarlett et al. 2012). In the east, the Grassy Narrows
and Whitedog First Nations continue to fight the Canadian Government for the release
of information and settlements related to mercury contamination that has negatively
affected their neurological health over the past 70 years (Harada et al. 2011; McQuigge
2012; Crowe 2014). In the west, numerous First Nations are working to understand the
potential future impacts of unconventional natural gas production (known as fracking).
This includes the extraction of gas using hydraulic fracturing processes in the territories
of the Treaty Six First Nations, and the compression and shipment of liquid natural gas
through the territories of the Tsimshian, Haisla, and Squamish First Nations, among oth-
ers (Goodine 2011; Benusic 2013; Jang 2015; Nikiforuk 2015).
These events are occurring within a broader context of change that includes historic
transformation of First Nations traditional territories into industrialized landscapes, and
the more dynamic and unpredictable impacts of global climate change. First Nations
have experienced a more rapid and disruptive trajectory of change than other parts of
the Canadian population with respect to the ways that environmental change has affected
their health and their communities. The gradual industrialization of Western society that
proceeded in step with the evolution of medical science and social adaptation has been
compressed into a short and violent reorganization of life for First Nations people (Barron
1984; Tennant 1990; Young 1994; Furniss 1999; Yazzie 2000). Over the past four centuries
of colonization, First Nations have witnessed the near extinction and recovery of their
population, and the rise of resource industries that have reshaped the land and waters
around them. Throughout this period, First Nations social needs and their traditional
methods of health and healing have been marginalized by Western systems of science,
education, and political control.
For some First Nations, these disruptions have been concentrated into a mere century
of experience, with current generations bearing the direct impact of their lands being
logged, mined, or flooded, and their communities forcibly relocated and reorganized by
the state.3 As these events have unfolded, many First Nations have been cut off from a life
based on harvesting and hunting across vast territories, and forced into life within state-​
built modular housing accompanied by reliance upon limited healthcare services and
unfamiliar Western food systems (Gladstone 1953; Tennant 1990; Parsons & Prest 2003;
 459

Environmental impacts on First Nations neurological and mental health 459

Woolford & Thomas 2011). However, the central focus for this discussion is the implica-
tion that these radical transformations of environment and social organization hold for
the neurological and mental health of First Nations people. Given the persisting deficits in
the health of First Nations people, the need for research on the impact of environmental
change on their brain and mental health has never been higher; yet significant obstacles
remain to be overcome in creating new knowledge in this field.

Environmental impacts on First Nations neurological

and mental health
Research on environmental impacts on First Nations neurological health occurs within a
broader need for understanding of such issues for all populations. Assessments of human
health risks posed by global climate change have focused more heavily on issues such as
respiratory illness, skin cancer, malaria, and water-​borne illnesses (McMichael et al. 2003,
2006; Patz et al. 2005; Haines et al. 2006) with little attention to the implications posed to
neurological and mental health. Similarly, research on human health impacts from new
forms of natural resource development, such as fracking, has moved more quickly with
respect to diseases of the body, such as cancer and asthma, than with diseases specific to
the brain (Illes et al. 2014). The comparative dearth in understanding of environmental
impacts on brain and mental health compared to studies of impacts on general health has
been partly due to methodological challenges in satisfying the scientific rigors of cause
and effect in epidemiology. This includes accounting for the long timeframes of onset for
many neurological illnesses, distinguishing environmental impacts from other influences
on brain and mental health, and the fact that research on the brain is a relative latecomer
to environmental and health impact studies.
As awareness of the impact of pollution on human health increased through the twenti-
eth century, the earliest targets of scientific study were the impacts most readily corrobo-
rated by public experience. Examples include the effects of smog on respiratory illnesses,
made self-​evident by breathing difficulties experienced by people living in heavily indus-
trialized areas (Schaefer 1907; Klotz 1914; Russell 1924; Mills 1943). However, neurologi-
cal diseases often lack the clearly detectable experiential characteristics associated with
afflictions affecting breathing, circulation, and other observable bodily processes.4 The
discovery of Minamata disease in 1959 due to methylmercury poisoning in Japanese vil-
lagers stands among the few known examples of a definitively established link between
the environment and diseases of the brain (McAlpine & Araki 1958; Takeuchi et al. 1959).
The convergence of an easily identifiable and previously suspected source of contamina-
tion with an unprecedented appearance of neurological illness in the people of Minamata
provided an unusual recipe for direct causal attribution. However, extensive and clear
linkages between environmental factors and other neurological illnesses have proven elu-
sive until recent years.
Over the past two decades, increasing evidence has been found to support environ-
mental change as a factor in neurological and mental illnesses. This includes research
460

460 First Nations and environmental neuroethics

linking air pollution to neuroinflammation and autism spectrum disorder (Calderon-​

Garciduenas et  al. 2004; Block & Calderon-​Garciduenas 2009; Raz et  al. 2015; Talbott
et al. 2015), water pollution to sensory and neurodevelopmental deficits (Murata et al.
2004; Grandjean & Herz 2011; Grandjean & Landrigan 2014), and noise and light pollu-
tion to psychological illnesses (Passchier-​Vermeer & Passchier 2000; De Kluizenaar et al.
2001; Chepesiuk 2009). In Canada, the vulnerability of First Nations and their extensive
reliance upon natural resources has placed them at the center of several research initia-
tives. These include studies of methylmercury poisoning of First Nations people through
water supplies and fisheries (Wheatley and Wheatley 2000; Gilbertson & Carpenter 2004),
and contamination of marine food supplies with polychlorinated biphenyls, dioxins, and
other chemicals (Kuhnlein et al. 1995; Van Oostdam et al. 1999; Wiseman & Gobas 2002).
Social impact studies have shown that changes in land and natural resources have dis-
rupted First Nations communities and interfered with the fundamental cultural practices
that support community structures and practices that support positive mental health for
First Nations people (Jackson 2011; Wilson 2003).
Stout and colleagues argue that the wide array of environmental impacts on the neuro-
logical and mental health of First Nations and other aboriginal people in Canada demands
an expansion of research in this area (Stout et al. 2009). With climate change forming an
increasing point of concern for society, it is unsurprising that research on environmental
impacts on the brain have proliferated in Arctic Canada, where the most noticeable shifts
in climate are occurring. The changing climate has affected ice cover and weather pat-
terns, and is suspected as a key factor in the fluctuation of mercury levels that are impli-
cated in the contamination of food sources for Inuit and northern First Nations (El-​Hayek
2007). While signs of neurological deficits have been observed among these groups, there
has been limited success in tracing these deficits to the environmental changes in question
(El-​Hayek 2007). However, with growing awareness of the potential impacts of climate
change on mental health (Haines et al. 2006; Berry et al. 2008), attention has increasingly
turned toward the broader web of environmental–​health relationships that affect the lives
of northern aboriginal people.
Like other aboriginal people in Canada, First Nations and Inuit people in the Arctic
region experience high levels of mental illness (Lehti et  al. 2009). Ample research has
linked these problems to the impacts of colonization and the trauma of community and
family disruptions (Sullivan & Brems 1997; Csonka & Schweitzer 2004; Hicks 2007). More
recent work has focused on the role of climate change in undermining the mental health
and coping capacity of Canadian aboriginal people in the arctic and subarctic regions.
This includes climate change as a stressor affecting emotional wellness, anxiety, depres-
sion, chronic stress, mood disorders, and the ability to cope with other forms of mental
illness (Macdonald et al. 2013; Willox et al. 2013a; Willox et al. 2015).
Researchers have found that negative impacts of climate change accrue as a result of
disruptions to First Nations/​Inuit seasonal practices, interruption of activities that sup-
port community and kin relations, and growth of physiological problems due to changes
in traditional diet and difficulties hunting and gathering (Fritze et al. 2008; Willox et al.
 461

Engaging First Nations in research of the brain 461

2013b; Bourque & Willox 2014). The psychological distress experienced as a result of
being deprived of the comfort derived from contact with one’s native environment has
been described as solastalgia (Albrecht et al. 2007).5 While sharing a basis with nostalgia
in the role of sensations of one’s surroundings, solastalgia draws a focus on the role the
environment plays in calming the mind, thus framing responses to drastic changes in the
environment as a form of psychoterratic illnesses that can only be understood with refer-
ence to both environmental and psychological factors (Albrecht et al. 2007).6
Researchers working closely with Inuit people found the mental distress brought about
by environmental change runs deeper than affective states, and is tied to changes in cog-
nition and thinking. Willox and colleagues describe the ecological affect as a set of “prag-
matic and site-​specific tracing of infinitely complex ecological arrangements” (Willox
et al. 2013a, p.17). These comprise patterns of thinking and feeling that shape everyday
behaviors, recognition, and information processing that support human interactions with
the environment. Emotions, rather than merely an affective state, embody a response to
environmental stimuli that acts as a necessary and integral form of cognition for guiding
instrumental and social behaviors among Inuit people such as navigation and dietary
decision-​making (Willox et al. 2013a). These intimate ties between environment and cog-
nition reveal the blurring of lines between human and nature and between environment
and the mind.
First Nations have been asserting the negative impacts of environmental change on
their lives long before the most recent acknowledgments or discoveries of environmental
impacts on neurological and mental health.7 Meanwhile, researchers continue to work
to understand the linkages between what is classified as affective experience and neuro-
logical health. There are many pieces to the puzzle that defines environmental impacts
on neurological and mental health, but there is an ongoing lack of definitive cause-​and-​
effect findings to bind these pieces together in a cohesive body of knowledge. However, if
one accepts the premise that the neurological and mental health of First Nations people
has historically been supported by a specific set of physiological, cultural, and cognitive
relationships with the environment, then it stands to reason that upon the reshaping of
the environment, these relationships will be disrupted and negative impacts to brain and
mental health could follow.

Engaging First Nations in research of the brain

Engaging First Nations people on the subject of neurological and mental health is made
complicated by the history of troubled relationships between First Nations people and
medical researchers. The eugenics movement occupies the extreme end of this scale,
including racist medical research and public policy that resulted in the involuntary steril-
ization of First Nations women in Canada as recently as the 1970s (Boyer Y. 2004). In some
cases, research has been conducted with inadequate respect for First Nations and without
securing consent. In a prominent case in western Canada, a genetic researcher used blood
samples originally gathered for the purpose of studying rheumatism to conduct unrelated
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462 First Nations and environmental neuroethics

research on HIV without permission from the Nuu-​chah-​nulth people who participated
in the original study (Wiwchar 2004). The same researcher later used the genetic materials
in published research about human migration that contradicted the Nuu-​Chah-​Nulth’s
historical accounts, causing insult to the band and introducing theories that undermined
their historical claims to their territories. This case has been cited in the fields of phar-
macogenetics, sexual wellness, and genetic ancestry as part of the historical mistrust that
must be overcome by researchers seeking to develop relationships with First Nations pop-
ulations (Lee et al. 2009; Devries & Free 2010; Boyer B.B. et al. 2011).
In other cases, research has been criticized for stigmatizing and attaching essential-
ist judgments to First Nations populations. For example, the thrifty gene hypothesis
attempted to link the high incidence of diabetes among First Nations in Manitoba to
genetic predispositions among hunter-​gatherer populations that equipped them to sur-
vive periods of hardship through retention of nutrients, but which resulted in maladap-
tive weight problems under modern Western diets. Like the warrior gene hypothesis
that sought to link risk-​taking behavior among Maori people to genetic variants that
affect aggressive behavior, the thrifty gene hypothesis has been criticized for failing to
adequately consider the disruptive impacts of colonization and the social and material
disadvantages suffered by aboriginal people under Western institutions (Abraham 2011;
Gillett & Tamatea 2012).
Even in cases where researchers are quite deliberate about approaching environmental
health issues without imposing value judgments upon the study population, First Nations
can be negatively impacted by the results. For example, research identifying the neuro-
logical health risks of consuming seafood contaminated with methylmercury and other
chemicals can have negative consequences for First Nations. Proof of contamination can
weaken First Nations people’s relationships with the fisheries that form a critical basis
of their culture and identity, and encourage increased reliance upon less healthy dietary
choices in areas where food alternatives are scarce (Wiseman & Gobas 2002; Gilbertson
& Carpenter 2004). The potential consequences of such research place scientific indica-
tors of health at odds with cultural values, and raises ethical questions about the nature of
research that must be explored before analysis even begins.

Bringing the brain into First Nations experience

First Nations have endured generalized stigma from their health being defined accord-
ing to deficits and negative comparisons with the broader population (Hodge et al. 2002;
Smylie et  al. 2008; Allan & Smylie 2015). Too often, deficit-​based explanations fail to
account for the historical circumstances of First Nations, and fail to demonstrate respect
for the pride of First Nations people as they seek to recover from a history of marginaliza-
tion and mistreatment. As research on the neurological and mental health of First Nations
proceeds, it is paramount that the brains of First Nations people are not treated as objects
of study defined primarily by their flaws and vulnerabilities. In a study of health and well-
ness among American Indians, Hodge and colleagues advanced an alternative model of
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Bringing the brain into First Nations experience 463

defining aboriginal health that centers on the practices that comprise positive health and
wellness, and the storytelling techniques that are used to promote and define the wellness
of community members (Hodge et al. 2002).8 Indeed, to bring the study of the brain into
the experience of First Nations people, efforts are needed to understand the dimensions
of their culture and relationships with the environment that define positive neurological
and mental health.
Researchers based in Edmonton, Alberta, focused upon First Nations practices that
support healthy brains in their study of the Cree First Nations’ traditional child-​rearing
practices and their impacts on neurological development (Pazderka et  al. 2014). The
researchers found correspondence between findings in neuroscience and Cree practices
related to pre-​birth nutrition, feeding, and handling of newborns. For example, they
found that Cree practices of carrying infants in traditional leather pouches close to the
body reflects recent findings in Western sciences that indicate such practices support
maternal attachment and social integration, and improve the capacity for handling stress
(Anderson G.C. et al. 2003; Feldman 2011; Pazderka et al. 2014). Such findings suggest
that although First Nations may not commonly speak the technical language of neurology
and medical science in their everyday lives, they have millennia of lived experience that
informs the practices they follow and the relationships they hold with the environment in
order to support the health of their brains.
Engaging First Nations on their own terms in matters of neurological and mental health
requires moving beyond the limits of Western medical science and characterizations of
the brain as merely an infinitely complex system of tissues, chemical reactions, electri-
cal signals, and psychological processes. Native American geneticist Dr. Frank Dukapoo
explains that biological materials that scientists view as merely tissue and personal prop-
erty may be viewed by First Nations as the sacred essence of a person (Dukapoo in Arbour
& Cook 2006, p.155).9 This not only prompts important ethical considerations in rela-
tion to the handling and stewardship of bodily materials (Arbour & Cook 2006; Gillett
& McKergow 2007), but also suggests that those who conduct research on the brain with
First Nations and other indigenous people must question the very nature of that which
they seek to study.
Health researchers working in Australia followed an innovative path to bring studies of
neurological health into alignment with Aboriginal concepts of the brain.10 Rather than
focusing on the physiology of the brain or functioning of the central nervous system,
researchers were able to advance their studies and serve Aborigine needs by focusing on
representations of the brain according to its role in social and cultural processes (D’Abbs
& MacLean 2000). A team of psychologists and psychiatrists collaborated with Aboriginal
artists to create pictures of the brain that depicted different levels of cultural engagement
focusing on stories, family, country, and body. These dimensions corresponded with dis-
tinct dimensions of functional cognition, including memory, socialization, identity, and
motor function (Petrol Link-​up 1994; Cohen & Stemmer 2011). The approach assisted in
the development of resources to educate Aborigines about the impacts of specific drugs
on neurological health.
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464 First Nations and environmental neuroethics

Recent research on early-​onset familial Alzheimer’s disease with a northern First Nation
in British Columbia provided a similar example of how beneficial partnerships can be
formed by attending to the distinct needs of the study population and recognizing the
complex relationship between traditional beliefs and medical science. Researchers facili-
tated the creation of a community advisory group, and engaged in dialogue with com-
munity members to explore their concerns about the stigmatization of dementia and to
discuss the potential harms and benefits that may come from further examination of the
issue (Stevenson et al. 2013). This engagement assisted in drawing attention to the wider
range of ethical considerations, including concerns about their future ability to obtain
medical insurance, potential stigmatization of families and individuals, and delicate mat-
ters of consent related to determining who speaks for a community when disclosing the
existence of a health problem.
The work also yielded insight into the way that First Nations people integrate tradi-
tional beliefs and information gained through medical science into their understand-
ings of brain disease. Participants in the research drew simultaneously from medical
knowledge and traditional definitions of wellness to explain the illness, demonstrat-
ing the potential for different knowledge systems to converge with positive outcomes
(Cabrera et al. 2015). In turn, the researchers drew on these hybrid understandings to
create educational resources that combined the First Nations narrative and epidemio-
logical data to assist community members in identifying and managing the disease.11
These findings show how aboriginal and Western scientific worldviews can be united,
and that First Nations people need not choose between exclusively traditional and
scientific frames of reference. First Nations people do not reject medical science or
empirical inquiry; they simply do not privilege it above all other ways of knowing, and
seek to reconcile it with the traditional knowledge they have held since time immemo-
rial. Researchers who study issues related to the environment and neurological health
among First Nations must thus come to terms with their entry into a dynamic world
of information exchange within which knowledge is continually being created and
recreated.

First Nations ethics and environmental neuroethics

Bridging environmental neuroethics with First Nations experiences involves not only
the percolation of medical science into the context of indigenous experiences, but also
the introduction of indigenous knowledge systems into the realm of the researcher. This
requires researchers to embrace alternative views on the environment, the mind, and the
nature of the relationship between them, thus expanding the ontological bases of inquiry.
First Nations people may view the environment as an autonomous sentient force, and
their own bodily and neurological health as a reflection of the state or the will of the envi-
ronment. Harm to the spirit, or to the relationship that joins the body, mind, and nature
together may be viewed as more important than links between environmental factors and
neurological disease that are apparent through reductive science.
 465

First Nations ethics and environmental neuroethics 465

Researchers must thus be prepared to discuss phenomena that may not otherwise enter
their field of examination, and be willing to alter their research designs to accommodate
dimensions that First Nations see as important. Definitions of both nature and medicine
must be expanded to embrace First Nations perspectives that include views of the body as
an integrated whole linked with its environment: “It [traditional medicine] looks at all of
you. … Non-​traditional looks at that cut on your hand or that ankle you keep spraining,
whereas traditional medicine looks at the whole person” (First Nation Elder in interview
dealing with well-​being).
Cajete explains that while Western scientific methods revolve around establishing objec-
tive views to determine “a factual blueprint of the world,” indigenous views emphasize
experience and locate the center of thought and cognition within the interconnectedness
of the body with the environment (Cajete 2000, pp.24–​25). And, although the interaction
of body, mind, and environment may not be directly observable through common scien-
tific methods, Huntington reminds us that such experiences must nonetheless be taken
into account when examining the impact of environmental change on indigenous people
(Huntington in Krupnik & Jolly 2002, pp.xxii–​xxiii).
The specifics of beliefs of First Nations people about the nature of the environment and
their own bodies and brains may vary from nation to nation and even family to family; the
epistemological foundations of indigenous knowledge systems are not based in central-
ized rational scientific authority, but instead within oral histories, traditional practices,
and ceremonies (Battiste 2002). In light of these considerations, research on environmen-
tal brain impacts with First Nations necessarily becomes a multidisciplinary endeavor
that draws from medical sciences, sociology, anthropology, and other potential contribut-
ing fields.
Beyond the considerations identified earlier in forming trusting relationships between
researchers and First Nations, there are numerous conceptual and methodological chal-
lenges inherent in this field of study. Clearly there are many concepts that defy opera-
tionalization within pure medical research models. For example, the unmeasurable
phenomena that comprise the spirit demands that qualitative inquiry form a central part
of any research effort. In turn, the ability to establish cause–​effect relationships becomes
problematic when examining the way that environmental change affects the brain when
the focus shifts to a wider definition of what the brain and body encompass, and when
these parts of a person are viewed as being inseparable from the environment.
One of the most important considerations is that First Nations knowledge cannot be
treated in the same manner as other forms of knowledge, particularly scientific knowl-
edge. In this respect, traditional knowledge is not a currency that is exchanged within
the public domain, and is not subject to the same processes of scrutiny and revision that
characterize peer-​reviewed scientific inquiry. Traditional knowledge is often bound in
stories passed down between generations as sacred or private learnings. Knowledge of
the environment and of medicine is often linked to the social and political structure of a
nation, and is interwoven in the bonds of clan and family that give shape to a First Nation
community. Researchers must recognize the importance of incorporating traditional
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466 First Nations and environmental neuroethics

knowledge into their work, but at the same time must understand the local conventions
and customs that accompany engagement with this knowledge. Traditional medicine
does not exist independently as a solution that is introduced to an afflicted body. Instead
it is, like the body and the mind, part of a broader web of experience.
If you look at cultural, even the medicinal parts of Cedar you know? You may get traditional medi-
cine. It’s not just what you swallow or rub on you, because I think the traditional medicine also may
include that whole process of making yourself ready to even go get the bark. Because that’s part
of the healing. So, if you look at traditional healing it’s not just a medicinal sense, you know, it’s a
whole mindset or way of thinking, the healing part of it. (First Nation Elder in interview dealing
with issues of well-​being)

First Nations beliefs about the environment and its relationship with health form the basis
of many studies, and several volumes of books would be required to provide a compre-
hensive summary of the respective intricacies found among the many existing nations.
The proliferation of research in this area indicates that Western science has at least begun
to recognize the importance of respecting and integrating First Nations knowledge
into studies of the environment and the brain. However, there remains the delicate and
complex matter of moving beyond acknowledgments of differences in perspectives, to
incorporating First Nations perspective into research models, and addressing the ethical
implications of the knowledge that is produced in these endeavors. That is, how do we
reconcile the belief systems of First Nations people with the normative foundations of
decision-​making that lie at the core of neuroethics?

Bridging ethical foundations

Scholars and researchers in the field of neuroethics occupy a space of debate within which
they evaluate and apply various philosophical perspectives and normative theories for
the purpose of developing acceptable and beneficial guidelines for action as related to
matters of the brain. Our objectives do not necessarily focus on reaching definitive judg-
ments of right or wrong, but instead support the articulation of decision-​making prac-
tice and ethical tools. Within this space of debate, it is not yet clear where First Nations
perspectives fit, or how the established normative theories that define the field of neuro-
ethics and bioethics fit into First Nations people’s own conceptualizations of right and
wrong, harmony and balance, and other ethical notions. As one explores issues related to
First Nations and environmental neuroethics, it may be tempting to locate First Nations
perspectives among established normative theories or find consistencies between their
beliefs and established normative theories. However, this consideration of normative eth-
ics must be approached with an appreciation that the fundamental way in which ethical
decision-​making is conducted within Western institutions of science and medicine and
within First Nations contexts flows from distinct and different, yet inextricably linked
trajectories of historical, cultural, and legal development.
As Pinker (2003) observes, the contributions of classical ethical theorists continue
to provide a basis for the systems of thought that shape the way society grapples with
 467

Bridging ethical foundations 467

bioethical and moral issues, including those related to the human mind and the environ-
ment. Kant’s assertion of human autonomy continues to form an influential reference
point as scholars debate over the point at which the treatment of biological materials must
include consideration of the personhood of the materials, or how to weigh the auton-
omy of the person against that of the public when forming policies dealing with neuro-
logical enhancements (Racine 2010, pp.131–​133; Barker & Beaufort 2013). The friction
between utilitarianism and the alternative methods of evaluating nature forms an endur-
ing point of conflict as society deliberates over issues such as the genetic modification of
food sources and the associated implications for human health (Faunce 2012). Questions
regarding the extent to which the state should enforce the duty of care have arisen when
the right to utilize traditional healing has been pitted against medical positions regarding
the best interests of the patient (McLaren 2015).12 These contemporary debates serve as
a reminder that normative ethics not only express particular frameworks of reason, but
also articulate responses to changes in the world around us and the evolution of society’s
relationship with the state and notions of the self. If we view Kantian deontology and utili-
tarian ethics along with their contemporary manifestations as part of a broader response
to change in society and the world around us, how then might we view the expression of
First Nations ethics? More specifically, how do we understand First Nations ethics in rela-
tion to complicated matters of neurological health as we confront the converging impli-
cations of advancing medical science and a changing environment? We must look more
closely not only at the different traditions from which Western and First Nations respec-
tive notions of ethics arise, but also the conditions within which they have come to be
expressed and defended.
When one seeks to identify the substance of what is referred to as First Nations ethics,
some of the most commonly encountered ideas are respect, balance, interconnectedness,
sustainability, reciprocity, community, and self-​determination. Expressions of these ideas
are pervasive within literature that examines environmental and health issues related to
First Nations people (Browne 1995; Wilson 2003; McGregor 2004; Isaak & Marchessault
2008; King et al. 2009; Beckford et al. 2010; Jones et al. 2010). Of course, such values do
not comprise a clear body of normative thought as commonly recognized within Western
society, nor do they provide a clear means of determining how decisions should be made
in relation to issues of environmental impacts on brain and mental health. Indeed, when
one searches for a body of normative ethics within literature on First Nations people, there
is no common body of knowledge to be found among the diversity that comprises this
population. Certainly these concepts are not alien to Western society, and First Nations
are not alone in their valuation of these ideals or their application of these concepts to
ethical matters. However, the way in which these concepts are defined differently between
cultures, and the way in which these concepts have emerged as the primary expressions of
First Nations ethics provides important cues for engaging First Nations in discussions of
environmental impacts on neurological health.
For example, the impact of neurological conditions must be communicated in more
than physiological and cognitive terms. Discussing the impact of environmental change
468

468 First Nations and environmental neuroethics

on the brain needs to attend to the way symptoms may be understood as impacts on the
community. At the same time, the emphasis on community needs to be understood as an
effort to reassert the importance of the bonds within and between First Nations families
in response to the Western emphasis on personal autonomy and the individualization of
medical practices as a process that occurs between doctor and patient. Discussing neuro-
logical conditions, environmental change, and the relationships between these issues with
First Nations populations must also attend to the issue of balance. This not only includes
remaining open to different ideas of how balance exists among mind, body, spirit, and
nature, but also understanding the emphasis on balance as a response to Western systems
of human and environmental care that have disrupted First Nations lives.
It is self-​determination which provides the most powerful compass point in this
endeavor. The ethics of First Nations are articulated within the context of the assertion
of their aboriginal rights. While the autonomy of the individual forms a central refer-
ence point in ethical debates regarding Western studies of neurological health, it is the
autonomy of each individual nation that is central to First Nations decision-​making. First
Nations people deserve to be able to choose their own path as they address impacts on
their brains and bodies, and it is the internal and intimate pathways of decision-​making
that occur within their communities, families, and histories that shape the normative
basis of their thought in regard to these matters. These positions are not always for outsid-
ers to know, and the ethical values that are articulated (e.g., balance, interconnectedness)
may only serve as course-​corrections or a response to the dominant institutions of science
and health that surround them.
Like that of most other indigenous people, the First Nations experience is forever altered
by the impact of colonialism. When words such as interconnectedness and community
are cited as First Nations ethics, they arise not only as an expression of their ethical foun-
dations, but also as a response to the decisions that have shaped their current circum-
stances. These ethical compass points redirect scientific inquiry to alternative ontologies,
and different targets for study and analysis. Western researchers must remain aware of
how First Nations ethics are expressed in part as a response to the incursion of Western
thought into explaining their lives. Even assumptions of time must be suspended:  the
ethic of interconnectedness implies that time may not be linear in their worldview, and
the future and the past remain interconnected. The choices made today may have impacts
on both the future and histories of a First Nation.
These ethical compass points direct researchers toward a broader appreciation of how
First Nations people experience and perceive environmental impacts on the brain. When
seeking guidance on decision-​making related to the environment and the health of the
brain, one must be prepared to submit to each First Nation’s distinct flows of ethical pro-
cessing. This may or may not be made visible or shared, and it may vary from group to
group. Close collaboration is required with each individual nation along with a commit-
ment to developing relationships of trust before such knowledge may be shared. Moreover,
there is a need for intellectual flexibility, and a readiness to understand the process of
change First Nations are continuing to experience. Only in this manner can we build
 469

The way forward 469

bridges between the contrasting ontologies and normative ethics that define approaches
of First Nations and Western institutions to understanding environmental impacts on the
brain as a process of change.
Neuroethics represents a relatively recent shift in the way we consider the brain, and
environmental neuroethics constitutes a new direction in this field. These studies not only
embody advances in science, but also reflect changes in society’s concerns over our rela-
tionships with nature and the way it shapes our lives and our minds. We must not lose
sight of the ongoing changes within our societies that are shaping our ethical reason-
ing. In this sense, the West may have more to gain than First Nations in the bridging of
our respective foundations of knowledge. Over the past 50  years, Western society has
faced a reckoning over the impact of technology and industry on our planet, and we have
collectively struggled to develop normative positions with sufficient power to provoke
the changes necessary to protect our health and that of the environment we rely upon.
While we cannot and should not view First Nations through a romantic lens that casts
them nobly as one-​with-​the-​land, we can benefit from observing the way that they inte-
grate sciences of neurology and the environment with their own understandings of the
brain as they articulate normative positions regarding these matters. The way forward
for environmental neuroethics is to view our engagement with First Nations as a process
of mutual learning, and the co-​production of knowledge regarding environment–​brain
relationships.

The way forward

The pursuit of the goal of creating new understandings and new knowledge of
environmental–​brain relationships demands engagement with the specifics of local mean-
ings. Researchers must continue and extend existing metaphysical lines of inquiry and
engage First Nations in discussion of questions such as “What is the brain?” and “What is
the environment?” In turn, this can lead to engaging First Nations on meta-​ethical ques-
tions that are central to their ethical ontology, such as “What is community?” and “What
is sustainability?” and “What is balance?”
The study of environmental neuroethics as related to First Nations people is confronted
by a dilemma. The serious risks posed to the mental and neurological health of First
Nations as a result of mounting environmental changes demand that immediate actions
be taken to address these problems. Indeed, the downstream costs to healthcare systems,
communities, and society require that steps be taken to mitigate these impacts. At the
same time, production of new understandings related to these issues cannot proceed
without addressing the fundamental gaps between First Nations and Western scientific
worldviews, and their respective domains of ethical thought. However, this dilemma does
not amount to an antimony based on one form of knowledge being used to define another.
Indeed, we should not be paralyzed by the concern that the gap between First Nations
and Western institutions of science are either too great to be overcome or that the his-
tory of their interaction has produced a state of irreconcilable differences. Environmental
470

470 First Nations and environmental neuroethics

neuroethics acknowledges that studies with First Nations about environmental impacts
on the brain involve co-​creation of knowledge that is equally applicable to both First
Nations and Western society; that our cultures and ways of viewing the world are indeed
distinct, but that they are also frequently parallel and driving toward problems of mutual
concern.
For Western scholars, the explicit emphasis on human–​nature relationships within First
Nations population creates an object of study, defined by its seemingly stark contrast with
Western notions of separation between society and nature. In turn, this contrast provides
reason to pause and to reconsider the impact of environmental change on the brain and
ethics of environmental care for all. Through the past half century, during which Western
society has come to confront the impacts of environmental change on human health, the
focus has been primarily upon the body. The study of the environment has been shaped
around these concerns. As we confront impacts on the brain, we enter new territory in
our consideration of ethics related to the environment and our use of natural resources.

Notes
1. First Nations people, along with Inuit and Metis, comprise the groups referred to as aboriginal people
in Canada. Inuit include the aboriginal people in the northern and arctic regions of Canada, and Metis
include people with mixed origins that share First Nations and other (generally Western European)
ancestry. First Nations were formerly referred to as Indians, and while this term is still utilized in the
United States, the word Indian is no longer used in Canada to refer to aboriginal people.
2. The pronoun “we” is used extensively throughout this chapter, and its reference to Western society is
by design. Indeed, it identifies a specific audience for this chapter with which not all readers may iden-
tify. However, the use of “we” is done self-​consciously by the authors in acknowledgment of the social
and cultural separation of First Nations from the society around them.
3. For many First Nations in British Columbia, for example, the wholesale industrialization of their
forests and the flooding of their traditional lands occurred largely throughout the 1940s to 1960s.
Examples include the Cheslatta and the Tsay Keh Dene, who were both displaced by large hydro-​elec-
tric projects accompanied by the expansion of logging and mineral development in their territories.
4. Exceptions to this include severe central nervous system failure as a result of exposure to pollution
at an extreme level, such as the events witnessed in Bhopal, India following the release of toxic gasses
from a pesticide plant in 1984.
5. Solastalgia is taken from the words nostalgia and solace (Albrecht et al., 2007, p.96). Nostalgia, which
was classified as a diagnosable illness until the late nineteenth century, is linked to the attachment of
smells, tastes, and sounds to previous locational and geographic contexts (Hirsch 1992).
6. Albrecht (2011, 2012) defines psychoterratic illnesses as earth-​based (terra) mental (psyche) health
states or conditions that are caused by disruption of the conditions that shape people’s feelings and
emotions about nature and space.
7. First Nations have long expressed resistance to colonial impacts on their lands, but it is only in the past
half-​century that their voices have received proper legal recognition. Between 1927 and 1950, First
Nations faced legal bans on their ability to mount protests latter half of the twentieth century. Between
1951 and 2000, there were an estimated 616 acts of Aboriginal protest in Canada (Clairmont & Potts
2006, p.20).
8. The term American Indian is the accepted terminology for indigenous people in the United States.
 471

References 471

9. Indeed, it should be acknowledged that the infusion of the body with some intangible dimension of
spirit is not exclusive to First Nations. As Pinker (2003) points out, the idea of a physical body indel-
ibly imbued with sacred qualities or a predisposition toward a particular social nature also affects
Western systems of thought and religious belief.
10. The word “Aboriginal” is capitalized when referring to the indigenous people of Australia. The term
“Aborigine” is utilized when referring to a person of Aboriginal ancestry.
11. Resources included information folders that explained risk factors and described experiences
of community members affected by Alzheimer’s disease, and story books aimed at helping chil-
dren understand brain functions and the way that the disease affects community and family
relationships.
12. McLaren provides an account of a young First Nations girl from the Canadian province of Manitoba
who was supported by her parents in refusing potentially life-​saving chemotherapy in favour of tra-
ditional healing methods.

References
Abraham, C. (2011, February 25). How the diabetes-​linked ‘thrifty gene’ triumphed with prejudice over
proof. The Globe and Mail. Available from: http://​www.theglobeandmail.com/​news/​national/​how-​
the-​diabetes-​linked-​thrifty-​gene-​triumphed-​with-​prejudice-​over-​proof/​article569423/​?page=all
[accessed July 15, 2015].
Albrecht, G. (2011). Chronic environmental change: emerging “psychoterratic” syndromes.
In: Weissbecker, I. (Ed.) Climate Change and Human Well-​Being, pp.43–​56. New York: Springer.
Albrecht, G. (2012). Psychoterratic conditions in a scientific and technological world. In: Kahn, P.H.
and Hasbach, P. (Eds.) Ecopsychology: Science, Totems, and the Technological Species, pp.241–​264.
Cambridge, MA: MIT Press.
Albrecht, G., Sartore, G.M., Connor, L., et al. (2007). Solastalgia: the distress caused by environmental
change. Australasian Psychiatry, 15(Suppl. 1), S95–​S98.
Allan, B. and Smylie, J. (2015). First Peoples, Second Class Treatment: The Role of Racism in the Health
and Well-​Being of Indigenous Peoples in Canada. Toronto, ON: The Wellesley Institute.
Anderson, G.C., Moore, E., Hepworth, J., and Bergman, N. (2003). Early skin-​to-​skin contact for
mothers and their healthy newborn infants. Cochrane Database of Systematic Reviews, 2, CD003519.
Anderson, R.B. (1999). Economic Development Among the Aboriginal peoples of Canada: The Hope for
the Future. Toronto, ON: Captus Press.
Arbour, L. and Cook, D. (2006). DNA on loan: issues to consider when carrying out genetic research
with aboriginal families and communities. Public Health Genomics, 9(3), 153–​160.
Barker, R.A. and de Beaufort, I. (2013). Scientific and ethical issues related to stem cell research and
interventions in neurodegenerative disorders of the brain. Progress in Neurobiology, 110, 63–​73.
Barron, F.L. (1984). A summary of federal Indian policy in the Canadian west, 1867–​1984. Native
Studies Review, 1(1), 28–​39.
Battiste, M. (2002). Indigenous Knowledge and Pedagogy in First Nations Education: A Literature Review
with Recommendations. Ottawa, ON: Apamuwek Institute.
Beckford, C.L., Jacobs, C., Williams, N., and Nahdee, R. (2010). Aboriginal environmental wisdom,
stewardship, and sustainability: lessons from the Walpole Island First Nations, Ontario, Canada. The
Journal of Environmental Education, 41(4), 239–​248.
Benusic, M. (2013). Fracking in BC: a public health concern. British Columbia Medical Journal, 55(5),
238–​239. Available from: http://​www.bcmj.org/​council-​health-​promotion/​fracking-​bc-​public-​
health-​concern [accessed August 17, 2015].
472

472 First Nations and environmental neuroethics

Berry, H.L., Kelly, B.J., Hanigan, I.C., et al. (2008). Rural Mental Health Impacts of Climate Change.
Commissioned Report for the Garnaut Climate Change Review. Canberra, ACT: The Australian
National University.
Block, M.L. and Calderón-​Garcidueñas, L. (2009). Air pollution: mechanisms of neuroinflammation
and CNS disease. Trends in Neurosciences, 32(9), 506–​516.
Bourque, F. and Willox, AC. (2014). Climate change: the next challenge for public mental health?
International Review of Psychiatry, 26(4), 415–​422.
Boyer, B.B., Dillard, D., Woodahl, E.L., Whitener, R., Thummel, K.E., and Burke, W. (2011).
Ethical issues in developing pharmacogenetic research partnerships with American Indigenous
communities. Clinical Pharmacology & Therapeutics, 89(3), 343–​345.
Boyer, Y. (2004). First Nations, Métis and Inuit Health Care: The Crown’s Fiduciary Obligation.
[Discussion Paper Series in Aboriginal Health: Legal Issues, No. 2.] Ottawa, ON: National
Aboriginal Health Organization, Native Law Centre, University of Saskatchewan.
Browne, A.J. (1995). The meaning of respect: a First Nations perspective. Canadian Journal of Nursing
Research, 27, 95–​109.
Cabrera, L.Y., Beattie, B.L., Dwosh, E., and Illes, J. (2015). Converging approaches to understanding
early onset familial Alzheimer disease: a First Nation study. SAGE Open Medicine, 3,
2050312115621766.
Cabrera, L.Y., Tesluk, J., Chakraborti, M., Matthews, R., and Illes, J. (2016). Brain matters: from
environmental ethics to environmental neuroethics. Environmental Health, 15(1), 20.
Cajete, G. (2000). Native Science: Natural Laws of Interdependence. Santa Fe, NM: Clear Light
Publishers.
Calderon-​Garciduenas, L. Reed, W., Maronpot, R.R., et al. (2004). Brain inflammation and
Alzheimer’s-​like pathology in individuals exposed to severe air pollution. Toxicologic Pathology,
32(6), 650–​658.
Chepesiuk, R. (2009). Missing the dark: health effects of light pollution. Environmental Health
Perspectives, 117(1), A20–​A27.
Clairmont, D.H. and Potts, J. (2006). For the Nonce: Policing and Aboriginal Occupations and
Protests. [A Background Paper Prepared for the Ipperwash Inquiry.] Ottawa, ON: Ipperwash
Inquiry.
Cohen, H. and Stemmer, B. (Eds.) (2011). Consciousness and Cognition: Fragments of Mind and Brain.
London: Academic Press.
Crowe, K. (2014, September 2). Grassy Narrows: why is Japan still studying the mercury poisoning
when Canada isn’t? CBC News. Available from: http://​www.cbc.ca/​news/​health/​grassy-​narrows-​
why-​is-​japan-​still-​studying-​the-​mercury-​poisoning-​when-​canada-​isn-​t-​1.2752360 [accessed August
17, 2016].
Csonka, Y. and Schweitzer, P. (2004). Societies and cultures: change and persistence. In: Einarsson,
N., Larsen, J.N., Nilsson, A., and Young, O.R. (Eds.) Arctic Human Development Report, pp.45–​68.
Akureyri, Iceland: Stefansson Arctic Institute.
D'Abbs, P. and MacLean, S. (2000). Petrol Sniffing in Aboriginal Communities: A Review of Interventions.
Casuarina, NT: Cooperative Research Centre for Aboriginal and Tropical Health.
De Kluizenaar, Y., Passchier-​Vermeer, W., and Miedema, H. (2001). Adverse Effects of Noise Exposure to
Health. Report prepared for the EC Project UNITE by TNO PG. Leiden, the Netherlands: Division
of Public Health.
Devries, K.M. and Free, C. (2010). “I told him not to use condoms”: masculinities, femininities and
sexual health of Aboriginal Canadian young people. Sociology of Health & Illness, 32(6), 827–​842.
Di Pietro, N.C. and Illes, J. (2014). Disparities in Canadian indigenous health research on
neurodevelopmental disorders. Journal of Developmental & Behavioral Pediatrics, 35(1), 74–​81.
 473

References 473

El-​Hayek, Y.H. (2007). Mercury contamination in Arctic Canada: possible implications for aboriginal
health. Journal of Developmental Disabilities, 13, 67–​89.
Faunce, T. (2012). Governing planetary nanomedicine: environmental sustainability and a UNESCO
universal declaration on the bioethics and human rights of natural and artificial photosynthesis
(global solar fuels and foods). Nanoethics, 6(1), 15–​27.
Feldman, R. (2011). Maternal touch and the developing infant. In: Hertenstein, M.J. and Weiss, S.J.
(Eds.) The Handbook of Touch: Neuroscience, Behavioral and Health Perspectives, pp.373–​407.
New York: Springer Publishing Company.
Fritze, J.G., Blashki, G.A., Burke, S., and Wiseman, J. (2008). Hope, despair and
transformation: climate change and the promotion of mental health and wellbeing. International
Journal of Mental Health Systems, 2, 13.
Furniss, E. (1999). The Burden of History: Colonialism and the Frontier Myth in a Rural Canadian
Community. Vancouver, BC: UBC Press.
Gilbertson, M. and Carpenter, D.O. (2004). An ecosystem approach to the health effects of mercury in
the Great Lakes basin ecosystem. Environmental Research, 95(3), 240–​246.
Gillett, G. and Tamatea, A.J. (2012). The warrior gene: epigenetic considerations. New Genetics and
Society, 31(1), 41–​53.
Gillett, G. and McKergow, F. (2007). Genes, ownership, and indigenous reality. Social Science &
Medicine, 65(10), 2093–​2104.
Gladstone, P. (1953). Native Indians and the fishing industry of British Columbia. The Canadian Journal
of Economics and Political Science/​Revue canadienne d’Economique et de Science politique, 19(1),
20–​34. Available from: http://​www.jstor.org.ezproxy.library.ubc.ca/​stable/​10.2307/​138471?origin=api
[accessed July 9, 2016].
Goodine, C. (2011, October). Fracking controversy: rethinking the low-​carbon label for natural
gas. Canadian Geographic. Available from: https://​www.canadiangeographic.ca/​article/​fracking-​
controversy [accessed July 9, 2016].
Grandjean, P. and Herz, K.T. (2011). Methylmercury and brain development: imprecision and
underestimation of developmental neurotoxicity in humans. Mount Sinai Journal of Medicine, 78(1),
107–​118.
Grandjean, P. and Landrigan, P. J. (2014). Neurobehavioural effects of developmental toxicity. Lancet
Neurology, 13(3), 330–​338.
Haines, A., Kovats, R.S., Campbell-​Lendrum, D., and Corvalán, C. (2006). Climate change and human
health: impacts, vulnerability and public health. Public Health, 120(7), 585–​596.
Harada, M., Hanada, M., Jajiri, M., et al. (2011). Mercury pollution in first nations groups in Ontario,
Canada: 35 years of Canadian Minamata disease. Journal of Minamata Studies, 3, 3–​30.
Hicks, J. (2007). The social determinants of elevated rates of suicide among Inuit youth. Indigenous
Affairs, 4, 30–​37.
High, S. (1996). Native wage labour and independent production during the “Era of Irrelevance.”
Labour/​le travail, 243–​264. Available from http://​www.jstor.org.ezproxy.library.ubc.ca/​stable/​
10.2307/​25144044?origin=api [accessed August 17, 2016].
Hirsch, A.R. (1992). Nostalgia –​a neuropsychiatric understanding. Advances in Consumer Research, 19,
390–​395.
Hodge, F.S., Pasqua, A., Marquez, C.A., and Geishirt-​Cantrell, B. (2002). Utilizing traditional
storytelling to promote wellness in American Indian communities. Journal of Transcultural Nursing,
13(1), 6–​11.
Illes, J., Davidson, J., and Matthews, R. (2014). Environmental neuroethics: changing the
environment—​changing the brain. Recommendations submitted to the Presidential Commission for
the Study of Bioethical Issues. Journal of Law and the Biosciences, 1(2), 221–​223.
47

474 First Nations and environmental neuroethics

Isaak, C.A. and Marchessault, G. (2008). Meaning of health: the perspectives of Aboriginal adults
and youth in a northern Manitoba First Nations community. Canadian Journal of Diabetes, 32(2),
114–​122.
Jackson, D.D. (2011). Scents of place: the dysplacement of a First Nations community in Canada.
American Anthropologist, 113(4), 606–​618.
Jang, B. (2015, July 9). Five First Nations join forces to assess environmental impact of LNG exports.
The Globe and Mail. Available from: http://​www.theglobeandmail.com/​report-​on-​business/​industry-​
news/​energy-​and-​resources/​five-​first-​nations-​join-​forces-​to-​assess-​impact-​of-​bc-​lng-​exports/​
article25388272 [accessed July 9, 2016].
Jones, R., Rigg, C., and Lee, L. (2010). Haida marine planning: First Nations as a partner in marine
conservation. Ecology and Society, 15(1), 12.
Kant, I. (1785). Groundwork of the Metaphysics of Morals.
Kelly, E.N., Short, J.W., Schindler, D.W., et al. (2009). Oil sands development contributes polycyclic
aromatic compounds to the Athabasca River and its tributaries. Proceedings of the National Academy
of Sciences of the United States of America, 106(52), 22346–​22351.
Kelly, E.N., Schindler, D.W., Hodson, P.V., Short, J.W., Radmanovich, R., and Nielsen, C.C. (2010). Oil
sands development contributes elements toxic at low concentrations to the Athabasca River and its
tributaries. Proceedings of the National Academy of Sciences of the United States of America, 107(37),
16178–​16183.
King, M., Smith, A., and Gracey, M. (2009). Indigenous health part 2: the underlying causes of the
health gap. The Lancet, 374(9683), 76–​85.
Klotz, O. (1914). Pulmonary anthracosis—​a community disease. American Journal of Public Health,
4(10), 887–​916.
Krupnik, I. and Jolly, D. (2002). The Earth is Faster Now: Indigenous Observations of Arctic
Environmental Change. [Frontiers in Polar Social Science.] Fairbanks, AK: Arctic Research
Consortium of the United States.
Kuhnlein, H.V., Receveur, O., Muir, D.C.G., Chan, H.M., and Soueida, R. (1995). Arctic indigenous
women consume greater than acceptable levels of organochlorines. The Journal of Nutrition,
125(10), 2501.
Lee, S.S.J., Bolnick, D.A., Duster, T., Ossorio, P., and TallBear, K. (2009). The illusive gold standard in
genetic ancestry testing. Science, 325(5936), 38.
Lehti, V., Niemelä, S., Hoven, C., Mandell, D., and Sourander, A. (2009). Mental health, substance use
and suicidal behaviour among young indigenous people in the Arctic: a systematic review. Social
Science & Medicine, 69(8), 1194–​1203.
MacDonald, J.P., Ford, J.D., Willox, A.C., and Ross, N.A. (2013). A review of protective factors and
causal mechanisms that enhance the mental health of indigenous circumpolar youth. International
Journal of Circumpolar Health, 72, 21775.
McAlpine, D. and Araki, S. (1958). Minamata disease an unusual neurological disorder caused by
contaminated fish. The Lancet, 272(7047), 629–​631.
McGregor, D. (2004). Coming full circle: indigenous knowledge, environment, and our future. The
American Indian Quarterly, 28(3), 385–​410.
McLaren, L. (2015, January 21). Makayla Sault: whose rights are served when a little girl dies? Special to
The Globe and Mail. Available from: http://​www.theglobeandmail.com/​life/​parenting/​whose-​rights-​
are-​served-​when-​a-​little-​girl-​dies/​article22562573/​ [accessed August 18, 2015].
McMichael, A.J. (2003). Climate Change and Human Health: Risks and Responses. Geneva: World
Health Organization.
McMichael, A.J., Woodruff, R.E., and Hales, S. (2006). Climate change and human health: present and
future risks. The Lancet, 367(9513), 859–​869.
 475

References 475

McQuigge, M. (2012, June 4). Two Ontario first nations still plagued by mercury poisoning: report. The
Globe and Mail. Available from: http://​www.theglobeandmail.com/​news/​politics/​two-​ontario-​first-​
nations-​still-​plagued-​by-​mercury-​poisoning-​report/​article4230507/​ [accessed August 17, 2015].
Masuda, J.R. and Garvin, T. (2006). Place, culture, and the social amplification of risk. Risk Analysis,
26(2), 437–​454.
Mills, C.A. (1943). Urban air pollution and respiratory diseases. American Journal of Epidemiology,
37(2), 131–​141.
Murata, K., Weihe, P., Budtz-​Jørgensen, E., Jørgensen, P.J., and Grandjean, P. (2004). Delayed
brainstem auditory evoked potential latencies in 14-​year-​old children exposed to methylmercury.
Journal of Pediatrics, 144(2), 177–​183.
Nikiforuk, A. (2015, January 10). Fracking industry shakes up northern BC with 231 tremors. TheTyee.
ca. Available from: http://​thetyee.ca/​News/​2015/​01/​10/​Fracking_​Industry_​Shakes_​Up_​Northern_​
BC/​[accessed August 17, 2015].
Northern Brain Injury Association (2015). First Nations. http://​nbia.ca/​first-​nations-​brain-​injury/​
[accessed August 17, 2015].
Parsons, R. and Prest, G. (2003). Aboriginal forestry in Canada. The Forestry Chronicle, 79(4), 779–​784.
Available from: http://​pubs.cif-​ifc.org.ezproxy.library.ubc.ca/​loi/​tfc?open=2003#id_​2003 [accessed
August 17, 2015].
Passchier-​Vermeer, W. and Passchier, W. F. (2000). Noise exposure and public health. Environmental
Health Perspectives, 108(Suppl. 1), 123.
Patz, J.A., Campbell-​Lendrum, D., Holloway, T., and Foley, J.A. (2005). Impact of regional climate
change on human health. Nature, 438(7066), 310–​317.
Pazderka, H., Desjarlais, B., Makokis, L., et al. (2014). Nitsiyihkâson: the brain science behind Cree
teachings of early childhood attachment. First Peoples Child & Family Review, 9(1), 53–​65.
Petrol Link-​up. (1994). Australian Government Department of Health and Aging, and Menzies School
of Health Research. Available from: http://​resources.menzies.edu.au/​download/​Sniffing_​and_​the_​
Brain.pdf [accessed July 15, 2015].
Pinker, S. (2003). The Blank Slate: The Modern Denial of Human Nature. Chicago, IL: Penguin.
Pinkerton, E. (1987). The fishing-​dependent community. In: Marchak, M.P., Guppy, N., and McMullan,
J.L. (Eds.) Uncommon Property: The Fishing and Fish-​Processing Industries in British Columbia,
pp.293–​325. Toronto, ON: Methuen Publications.
Racine, E. (2010). Pragmatic Neuroethics: Improving Treatment and Understanding of the Mind–​Brain.
Cambridge, MA: MIT Press.
Ray, J.G., Vermeulen, M.J., Meier, C., Cole, D.E., and Wyatt, P.R. (2004). Maternal ethnicity and risk
of neural tube defects: a population-​based study. Canadian Medical Association Journal, 171(4),
343–​345.
Raz, R., Roberts, A.L., Lyall, K., et al. (2015). Autism spectrum disorder and particulate matter air
pollution before, during, and after pregnancy: a nested case–​control analysis within the Nurses’
Health Study II Cohort. Environmental Health Perspectives, 123(3), 264–​270.
Rose, N. and Abi-​Rached, J.M. (2013). Neuro: The New Brain Sciences and the Management of the Mind.
Princeton, NJ: Princeton University Press.
Russell, W.T. (1924). The influence of fog on mortality from respiratory diseases. The Lancet, 204(5268),
335–​339.
Scarlett, A.G., West, C.E., Jones, D., Galloway, T.S., and Rowland, S.J. (2012). Predicted toxicity of
naphthenic acids present in oil sands process-​affected waters to a range of environmental and
human endpoints. Science of the Total Environment, 425, 119–​127.
Schaefer, T.W. (1907). The contamination of the air of our cities with sulphur dioxide, the cause of
respiratory disease. Boston Medical and Surgical Journal, 157(4), 106–​110.
476

476 First Nations and environmental neuroethics

Smylie, J., Kaplan-​Myrth, N., McShane, K., and Nation, P.F. (2008). Indigenous knowledge
translation: baseline findings in a qualitative study of the pathways of health knowledge in three
indigenous communities in Canada. Health Promotion Practice.
Stanbury, W.T. (1973). Indians in British Columbia: level of income, welfare dependency and poverty
rate. The British Columbian Quarterly, 20, 66–​78. Available from: http://​ojs.library.ubc.ca/​index.php/​
bcstudies/​issue/​view/​140 [accessed July 15, 2015].
Stevenson, S., Beattie, B.L., Vedan, R., Dwosh, E., Bruce, L., and Illes, J. (2013). Neuroethics,
confidentiality, and a cultural imperative in early onset Alzheimer disease: a case study with a First
Nation population. Philosophy, Ethics, and Humanities in Medicine, 8(1), 15.
Stout, R., Stout, T.D., and Harp, R. (2009). Maternal and Infant Health and the Physical Environment of
First Nations and Inuit Communities: A Summary Review. Winnipeg, MB: Prairie Women’s Health
Centre of Excellence.
Sullivan, A. and Brems, C. (1997). The psychological repercussions of the sociocultural oppression of
Alaska native peoples. Genetic, Social, and General Psychology Monographs, 123(4), 411–​440.
Takeuchi, T., Kambara, T., Morikawa, N., Matsumoto, H., Shiraishi, Y., and Ito, H. (1959). Pathologic
observations of the Minamata disease. Pathology International, 9(S1), 769–​783.
Talbott, E.O., Arena, V.C., Rager, J.R., et al. (2015). Fine particulate matter and the risk of autism
spectrum disorder. Environmental Research, 140, 414–​420.
Tennant, P. (1990). Aboriginal Peoples and Politics: The Indian Land Question in British Columbia, 1849–​
1989. Vancouver, BC: UBC Press.
Timoney, K.P. and Lee, P. (2009). Does the Alberta tar sands industry pollute? The scientific evidence.
The Open Conservation Biology Journal, 3, 65–​81.
Van Oostdam, J., Gilman, A., Dewailly, E., et al. (1999). Human health implications of
environmental contaminants in Arctic Canada: a review. Science of the Total Environment,
230(1), 1–​82.
Wheatley, B. and Wheatley, M.A. (2000). Methylmercury and the health of indigenous peoples: a risk
management challenge for physical and social sciences and for public health policy. Science of the
Total Environment, 259(1), 23–​29.
Willox, A.C., Harper, S.L., Edge, V.L., Landman, K., Houle, K., and Ford, J.D. (2013a). The land
enriches the soul: on climatic and environmental change, affect, and emotional health and well-​
being in Rigolet, Nunatsiavut, Canada. Emotion, Space and Society, 6, 14–​24.
Willox, A.C., Harper, S.L., Ford, J.D., et al. (2013b). Climate change and mental health: an exploratory
case study from Rigolet, Nunatsiavut, Canada. Climatic Change, 121(2), 255–​270.
Willox, A.C., Stephenson, E., Allen, J., et al. (2015). Examining relationships between climate change
and mental health in the Circumpolar North. Regional Environmental Change, 15(1), 169–​182.
Wilson, K. (2003). Therapeutic landscapes and First Nations peoples: an exploration of culture, health
and place. Health & Place, 9(2), 83–​93.
Wiseman, C.L. and Gobas, F.A. (2002). Balancing risks in the management of contaminated First
Nations fisheries. International Journal of Environmental Health Research, 12(4), 331–​342.
Wiwchar, D. (2004, December 16). Nuu-​chah-​nulth blood returns to west coast. Ha-​Shilth-​Sa. Canada’s
Oldest First Nations Newspaper, 31(25). Available from: http://​www.igb.illinois.edu/​sites/​default/​
files/​Wiwchar%202004%20Nuu-​chah-​nulth.pdf [accessed July 15, 2015].
Woolford, A. and Thomas, J. (2011). Genocide of Canadian First Nations. Genocide of Indigenous
Peoples, 8, 61–​86.
Yazzie, R. (2000). Postcolonial colonialism. Reclaiming Indigenous voice and vision. In: Battiste, M.
(Ed). Reclaiming Indigenous Voice and Vision, pp.39–​49. Vancouver, BC: UBC Press.
Young, T.K. (1994). The Health of Native Americans: Toward a Biocultural Epidemiology.
New York: Oxford University Press.
 47

Chapter 24

The neurobiology of addiction

as a window on voluntary control
of behavior and moral responsibility
Steven E. Hyman

Introduction
Drug addiction is a severe problem for public health, systems of justice, and for the func-
tioning of societies worldwide. Views of addicted people vary widely between and even
within countries. Perspectives range from seeing them as medically ill to having the sta-
tus of moral pariahs. Since possession of addictive drugs other than tobacco or alcohol
is a criminal offense within many jurisdictions, addiction to many drugs is de facto a
crime. In this chapter, I use insights that have emerged from neuroscience and psychol-
ogy in the last two decades to examine the predominant medical model of drug addiction
as a form of behavior that has escaped volitional control, that is, compulsive drug use
despite significant negative consequences. This model is codified in the fifth edition of the
Diagnostic and Statistical Manual of Mental Disorders (DSM-​5) (American Psychiatric
Association 2013) and similarly in the tenth edition of the International Classification of
Diseases (ICD-​10) (World Health Organization 1992). I contrast this view of addiction
with what might be called a moral model, which sees the behavior of the addicted person
as reflecting a series of bad choices that could be brought under volitional control with
appropriate effort. These contrasting views have significant ethical and pragmatic impli-
cations for how societies hold addicted people responsible for their behavior and how
they treat them.
Addiction is an apt subject for neuroethical analysis because (1) it problematizes the
concepts of volition and responsibility, which are central concerns for neuroscience, phi-
losophy, law, and ethics; and (2) because enough is known scientifically about addiction
to ground the discussion in a reasonable, if still incomplete body of knowledge. Addiction
is a topic about which too many ungrounded inferences and assertions are made. My brief
scientific discussion is a byproduct of mechanistic neurobiological analyses performed
for other reasons. The pursuit of neurobiological mechanisms is partly driven by a desire
for greater understandings of nature as well as human self-​understanding. However, as
with essentially all other medically significant conditions, mechanistic investigations of
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478 The neurobiology of addiction

addiction are also meant to yield knowledge that will ultimately prove actionable for pre-
vention and treatment.

Compulsion
Short of being externally coerced or psychotic, what can it mean to say that a person can-
not control his or her consciously planned behaviors? What does society make of a person
who has suffered dire health consequences from smoking tobacco, understands the health
risks perfectly well, states a credible intention to stop smoking, repeatedly tries to cut
down, but repeatedly resumes smoking? How do we interpret the behavior of an opioid
user who had entered a treatment facility under the threat of losing his job and spouse,
who soon after release from the facility (where he initially suffered painful withdrawal
symptoms, and later participated seriously in psychotherapy and rehabilitative services),
steals money from his spouse, buys heroin, prepares it for self-​injection, and consumes it?
Are these individuals likely to be lying glibly about their intentions to abstain? Are they
weak-​willed, heedlessly seeking pleasure or oblivion rather than effectively confronting
urges to smoke tobacco or use drugs? Or is there a convincing alternative explanation for
their behavior that can be grounded in the concepts of compulsion and loss of control that
dominate medical description of addiction?
Much is now known about neural mechanisms of decision-​making and control of behav-
ior and how these mechanisms can be altered long term by addictive drugs. Nonetheless,
addicted individuals, such as those briefly described in the vignettes, often attract moral
condemnation, and if caught breaking the law for possessing illegal drugs or commit-
ting illegal acts to obtain them, may face severe sanctions. Attribution of the continuing
drug use of addicted people to weak will or some kind of moral failure remains a potent
factor in social, policy, and legal spheres. For example, in 1988 the Supreme Court of
the United States decided two related cases, Traynor v. Turnage and McKelvey v. Turnage
(1988), upholding the denial of a petition of two veterans by the Veterans Administration
(VA) in the United States. The veterans had asked the VA to extend the usual 10-​year limit
on educational benefits because they suffered from complications of alcoholism, which,
they argued, was a medical illness. Extensions had previously been granted to veterans
who, because of other illnesses, had been unable to use their benefits during the allotted
10 years’ time. The Court, however, upheld the denial of an extension, with the majority
finding that the VA was reasonable in defining alcoholism as willful misconduct.
In contrast to the Court’s decision, the DSM-​5 (American Psychiatric Association
2013) defines drug addiction as compulsive drug use despite significant negative conse-
quences. Loss of control over drug use may be evidenced, inter alia, by multiple unsuc-
cessful attempts to cut down. Those who doubt that addicted individuals have truly lost
control of their behavior and, like the Court, see it instead as willful misconduct, at least
implicitly construe human decision-​making to be a conscious process of deliberation that
weighs costs and benefits (Heyman 2010). Based on such a model, a decision to use drugs
would represent a conscious choice of gratification or relief from distress over the risk of
 479

Compulsion 479

exacerbating drug-​related harms and perhaps committing illegal acts. In this model, a
decision to abstain from drug use, and thus to forego the pleasure or relief gained by drug
taking, might result from the incorporation of salient new information or recent aversive
experiences that tilt the decisional scales against continued drug taking (Heyman 2010).
Those skeptical of the idea that addicted people cannot control their substance use
have pointed out that seeking and using drugs often requires meticulous planning, first
to gain necessary resources and then drugs; may be played out over time, giving ample
opportunity for users to inhibit prepotent drug-​seeking impulses; and requires signifi-
cant cognitive and behavioral flexibility given real-​world obstacles to obtaining drugs,
especially when they are illegal or must be used furtively. Moreover, addicted people,
except when intoxicated or experiencing significant withdrawal symptoms, may act in
a rational manner, might at times display insight into their condition, and can typically
control most other aspects of their behavior—​unlike individuals with florid psychosis,
dementia, or delirium who would seem to be better candidates for the descriptor, lack of
control. A salient example of individuals who for the most part exhibit rationality outside
the sphere of their drug habit are tobacco smokers—​at least in part because tobacco is
legal and not intoxicating—​but to varying degrees, users of other drugs have periods of
rational control of behavior.
Opposition to medical models of addiction is also grounded in pragmatic concerns.
Medical models can be construed as decreasing incentives for recovery by appearing to
explain away drug use as uncontrollable and providing a rationalization for being unable
to abstain, (Satel 1999; Satel & Lillienfeld 2013). Concerns have been raised, in addition,
about a trend toward medicalizing all forms of deviance in society (Conrad & Schneider
1992). After all, criminality is a form of deviance that, like addiction, has identifiable
familial (presumably partly genetic), developmental, social, and contextual risk factors,
yet it is not included in the DSM-​5. Those concerned about what they see as creeping
medicalization of all deviance also express concern about the placement of compulsive
gambling in the same chapter with drug addiction in the DSM-​5, and about arguments
being made to further broaden the concept of behavioral addiction (Robbins & Clark
2015) based on shared risk factors and shared neural mechanisms. In fact, some scientists
and clinicians have been arguing for the inclusion as addictions in future DSM editions of
compulsive sex, compulsive shopping, compulsive use of the internet, and perhaps excess
eating associated with obesity (Volkow et al. 2013).
The idea that human decision-​making, including the choices made by addicted people,
represent conscious deliberations that yield freely chosen goals and actions, is consis-
tent with ubiquitous human intuitions that are sometimes described as folk psychology
(Morse 2008). Upon introspection, human beings intuit a self that has experiences, makes
decisions, and causes bodily actions. Thus folk psychology and systems of justice hold
that human beings act for reasons. This view is entirely contradicted by neurobiology,
which finds no evidence for anything like a self that possesses decisional capacity and
causes behavior. What have been found instead are diverse neural mechanisms—​opaque
to introspection—​that contribute to different aspects of decision-​making and that control
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480 The neurobiology of addiction

behavior. It appears that one of the outputs of the circuitry that controls action is the
experience—​but not the fact—​of a self that authors our behavior (Wegner 2002, 2003;
Haggard 2008). Without resorting to evolutionary “just so” stories, it can safely be posited
that cognitive and behavioral mechanisms were selected in evolution by their adaptive-
ness and survival value, not by their ability to capture objective truth.
Actions can be conceptualized as ranging from reflexes, which are the most stimulus
bound, to volitional acts in which external stimuli act only indirectly and do not directly
determine the timing or nature of the act (Gold & Shadlen 2007; Haggard 2008). A par-
tially overlapping way of parsing actions (which excludes simple reflexes) is to rank at one
extreme, actions that arise wholly from unconscious processing and at the other, actions
that reflect conscious, goal-​oriented, deliberative decisions. However, decision-​making is
more complex than might be implied by these extremes. For example, voluntary action
that might, on the evidence of introspection, appear to spring entirely from conscious,
deliberative decision-​making, is also invariably dependent on rapid, unconscious, parallel
processing by neural circuits with access to such information as previously stored values
(Gallagher et  al. 1999; Xie & Padoa-​Schioppa 2016), social stereotypes (Dunham et  al
2013; Stolier & Freeman 2016), and ingrained behavioral tendencies. The decision-​maker
cannot be directly aware of this processing, or of the neural mechanisms that control
motor outputs (Dayan 2007; Glockner 2007; Gold & Shadlen 2007; Koechlin & Hyafil
2007; Kable & Glimcher 2009; Cisek & Kalaska 2010; Custers & Aarts 2010). While such
work is focused on general aspects of mechanisms underlying decision-​making, it has
profound implications for addiction. The process of becoming addicted is one in which
drug taking begins as a volitional pursuit of such goals as pleasure, facilitation of social
behavior, or relief from distress, but mediated by processes that will be described, devolves
into behavior in which drug seeking becomes automatic, stimulus bound, extremely dif-
ficult to inhibit, and divorced from goals.

Individual differences in risk of drug use, addiction,

and recovery
Much neurobiological study focuses on discovering general principles governing the
development and functioning of cells, synapses, and circuits of the brain, and how cogni-
tion and behavior emerge from computations within those neural circuits. In this spirit,
much investigation into the neural basis of addiction has focused on identifying the archi-
tecture and both normal and pathological functioning of reward circuits that are activated
by drugs such as nicotine, ethyl alcohol, stimulants such as cocaine and amphetamines,
cannabinoids, opioids, and N-​methyl-​D-​aspartate receptor glutamate receptor blockers
such as phencyclidine and ketamine. Other addiction research focuses on neural path-
ways that exert cognitive control over reward seeking. Alongside such investigations of
general mechanisms, however, there are important questions, concerning individual dif-
ferences in responses to addictive drugs. Individual differences occur among virtually all
characteristics of humans and other living things. Humans exhibit diverse responses to
 481

Individual differences in risk of drug use, addiction, and recovery 481

environmental factors and perturbations ranging from microbes to nutrients to drugs.

Heterogeneity among humans afflicted with diverse diseases is currently a central preoc-
cupation of medical research, with the aim of being able to target precise interventions to
the right individuals based on specific markers—​precision medicine.
Based on individual differences, humans have differing likelihoods of experimenting
with drugs when made available, of getting “captured” by a particular drug or reward-
ing behavior, such as gambling, upon repeated exposure, and different risks of ill-​health
outcomes (e.g., cirrhosis or lung cancer) consequent to chronic use of particular drugs.
Individual differences in patterns of drug taking or reward seeking, including strength of
compulsion, are not unique to humans but also are observed in laboratory rodents and
other animals (Belin et al. 2011; Moreno et al. 2013; Pascoli et al. 2015).
Human individual differences in addiction liability result from the genetic makeup
of the individual (Tsuang et al. 1996; Merikangas et al. 1998), developmental processes
(many of which are stochastic) and environmental influences; these latter influences might
include stressors, availability of drugs at vulnerable times in the lifespan such as teen
years, and local social norms. In short, not every human or laboratory animal exposed to
drugs, whether tobacco, alcohol, cocaine, or heroin, ultimately becomes a regular user, or
for laboratory animals, regularly self-​administering. Not all people who are regular users
become addicted, and of those who do become addicted, some can cease drug use without
ever seeking medical help. Some who find their way to treatment respond well; yet others
continue to relapse despite many attempts at treatment and remain compulsive users until
death (Hser et al. 2001).
Risk factors both for initiating drug use and for becoming addicted include genetic risk,
male sex (across countries and cultures), chronic pain, certain mental disorders includ-
ing attention deficit hyperactivity disorder and the manic phase of bipolar disorder, and
availability of drugs in the person’s environment and culture. Twin and adoption studies
consistently demonstrate a significant influence of a person’s genes in risk. For example,
twin studies show higher rates of concordance for heavy drug use and addiction within
monozygotic twin pairs (who share 100% of their DNA sequences) than within dizygotic
twin pairs (who, on average, share 50%; Tsuang et al. 1996; Merikangas et al. 1998). Like
all common neuropsychiatric disorders (Sullivan et al. 2012), the genetic contributions
to risk of addictive disorders is significant, but highly complex, with variation in many
genetic loci influencing different aspects of these complex syndromes. Moreover, while
the role of genetic influences is significant, genes are not fate. The importance of envi-
ronmental influences in drug initiation and of environmental cues and context in main-
taining addiction is powerfully illustrated by the experience of US soldiers during the
Vietnam War. Given the stress on these individuals, the ready availability of cheap heroin,
and at least implicit permission to use heroin under certain circumstances, many soldiers
became regular users who met criteria for addiction. However, on return to the United
States most regular users were able to stop with the exception of those who had been
regular users before going to Vietnam and those who returned to neighborhoods where
heroin use was endemic (Robins et al. 1975).
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482 The neurobiology of addiction

Some specific genetic loci associated with smoking and nicotine dependence have
been identified in part because the behavior is legal, making research participation more
straightforward, and in part because it is relatively easy to know how many cigarettes
a person has smoked per day. Pointing to the complexity of addiction risk, different
genes have been associated with smoking initiation, smoking dependence, cessation, and
smoking-​associated diseases such as lung cancer (Thorgeirsson et al. 2010). Significant
efforts to discover specific genes associated with different stages of drug use among other
drug classes are currently under way. This research is being pursued because identifi-
cation, with certainty, of specific disorder-​associated genomic variants provides solid
biological clues to pathogenesis, and hopefully molecular targets for preventive or thera-
peutic interventions.

Reward circuitry
The drive to obtain natural rewards such as food, water, social interactions, and mat-
ing opportunities is required for the survival of free-​living animals and their species
(Kelley & Berridge 2002). Rewards can be operationally defined as stimuli that elicit
approach and appetitive behaviors; they also increase the probability that behaviors
aimed at obtaining them will be repeated, that is, rewards are positively reinforc-
ing. A specialized brain reward circuity that is conserved across mammalian evolu-
tion plays the central role in the ability of an organism to successfully obtain and
consume or consummate innately programmed rewards and learn about and pursue
new ones. This circuitry is comprised of neurons that synthesize and release the neu-
rotransmitter dopamine and that project from the ventral tegmental area (VTA) of
the midbrain to forebrain regions involved in motivation, emotion, and important
aspects of cognition, notably the nucleus accumbens (NAc), amygdala, hippocampus,
and prefrontal cortex. A separate cluster of midbrain dopamine neurons that proj-
ect from the substantia nigra to the caudate and putamen facilitate motor learning
that results in efficient reward seeking and consummatory behaviors. Reward circuitry
has been extensively characterized in the brains of multiple mammals including mice,
rats, several nonhuman primate species, and based on noninvasive methods such as
functional brain imaging, in humans as well (Breiter et al. 1997; Diederen et al. 2016).
Reward circuitry, which leads to appetitive and approach behaviors and amygdala-​
based and other circuits that produce aversion and avoidance, confer valuation and
valence on experiences encountered in the world, and undergird decision-​making and
control of behavior. Maladaptive functioning of reward circuitry plays a central role in
many human ills. Excessive stimulation of reward circuity is central to drug addiction
(Hyman et al. 2006; Nestler et al. 2015; Pascoli et al. 2015), to compulsive gambling
and other impulsive behaviors (Dagher & Robbins 2009; Robbins & Clark 2015), and
perhaps to obesity (Kenny 2011). Underactivity of reward circuitry likely contributes
to the anhedonia (inability to experience pleasure) and behavioral inertia that charac-
terize depression (Ferenczi et al. 2016).
 483

Reward circuitry 483

Dopamine release in reward circuitry does not serve as the internal representation of
pleasure as once was hypothesized, but as a learning signal that shapes behavior to max-
imize further rewards and thus the likelihood of survival (Schultz et al. 1997; Schultz
2006). In their basal (unstimulated) state, dopamine neurons exhibit a pattern of slow
tonic firing. When a reward is encountered unexpectedly, these neurons fire a brief phasic
burst of action potentials, producing a transient increase in synaptic dopamine in the
forebrain. For example, an encounter with natural rewards such as palatable foods or
mating opportunities causes VTA neurons to fire phasically (Kelley & Berridge 2002).
Important insights into the function of dopamine came from electrophysiologic record-
ings of dopamine-​releasing neurons in nonhuman primates, and later from rats and
mice undergoing classical (Pavlovian) conditioning (Schultz et al. 1997; Schultz 2006).
Animals readily learn to associate a previously neutral stimulus (e.g., a light) with delivery
of reward when the stimulus reliably precedes reward over several trials. In the monkey
studies by Schultz et al. (1997, 2006), appearance of highly palatable juice or food (an
unconditioned stimulus—​a natural reward) elicits phasic dopamine neuron firing and
thus a transient increase in dopamine release. Once the animal—​or as was later estab-
lished a human subject studied by noninvasive neuroimaging—​learns that the new stimu-
lus (e.g., light) predicts reward, the dopamine neurons no longer fire phasically when
the reward (unconditioned stimulus) appears, but rather at the appearance of the light,
which has become a conditioned stimulus (i.e., predictive of reward). If an new stimulus is
introduced (e.g., a tone), that reliably precedes the light, which in turn predicts the juice,
dopamine neurons fire phasically in response to the tone, but no longer to the light or to
reward delivery (Schultz et al. 1997; Schultz 2006). If the reward is omitted at the time
when it was predicted by learned cues, there is a pause in dopamine neuron firing (i.e., a
punishment signal). There is convergent evidence from many experiments (together with
computational models), which make a strong case that dopamine neurons respond to
errors in prediction about the availability of reward (Schultz 2006). They fire phasically at
the first and therefore unpredicted appearance of a conditioned stimulus or reward. They
fire only at their basal tonic rate when a cue or reward is encountered that has been fully
predicted (i.e., when there is nothing more to learn) and pause when an expected reward
is less than expected or omitted. The effect of increased synaptic dopamine is to initiate
a set of molecular and cellular processes that consolidate learning about the predictive
significance of cues and produce long-​lived alterations in behavioral responses to reward-​
associated cues. A critical mechanism by which dopamine alters functional outputs of the
forebrain is by facilitating long-​term changes in the strength of synaptic communication
between target neurons with the result that neural circuitry is altered long term (Berke &
Hyman 2000; Hyman et al. 2006; Luescher & Malenka 2011).
Acting in the NAc, dopamine binds reward-​associated stimuli to motivation, thus
imbuing the cue with what has been called incentive salience (Robinson et al. 2005). The
result is that the cue gains the ability to motivate pursuit and consummatory behavior.
Within orbital prefrontal cortex, dopamine updates the representation of rewards and
their relative valuation; neural processes within the orbital prefrontal cortex establish a
48

484 The neurobiology of addiction

common currency that permits an organism to choose among possible goals that may
differ both qualitatively and quantitatively (Gallagher et al. 1999; Montague et al. 2004;
Schoenbaum et al. 2006; Xie & Padoa-​Schioppa 2016). In the caudate and putamen, pha-
sic dopamine release supports motor learning that binds cues predictive of reward to
action. Motor learning involving the caudate and putamen requires repetition (i.e., prac-
tice), but eventually becomes highly efficient, smooth, automatic, and resistant to forget-
ting. Examples include learning to ride a bike, learning to touch-​type, or a baseball player
learning to throw a fastball. In the case of direct pursuit of rewards, such as obtaining food
under conditions of scarcity or intense competition, automatic recognition of predictive
cues and speedy, efficient engagement in hunting, or foraging might make the difference
between survival and starvation. While this last description may call up visions of animals
in the wild, they apply also to modern humans when, because of crop failure, conflict, or
extreme economic mismanagement, shops are empty and food is unavailable.
Well-​learned action repertoires typically remain goal directed, but become automatized,
highly efficient, and largely independent of conscious control. For example, fluent deliv-
ery of a well-​rehearsed lecture by a professor or a well-​practiced gymnastic routine during
an athletic competition are initiated in a goal-​directed manner but, once begun, unfold
without conscious consideration of each word, gesture, or bodily movement. Under path-
ological conditions, however, behaviors of varying complexity from tics to extended rou-
tines may be activated by environmental or internal cues independently of, and even in
contravention of a person’s goals. Such deeply ingrained habits, which may become quite
stereotyped, are highly resistant to conscious control (Graybiel 2008). Examples of com-
mon, relatively simple, stereotyped habits include compulsive nail biting and compulsive
hair pulling (trichotillomania). Automatized behaviors and even deeply ingrained habits
can be interrupted by a salient, unexpected event or a failure such as losing one’s place
while delivering a lecture or speech or falling during a well-​practiced gymnastic routine;
this results in a marked increase in arousal and attention, and a transient gain in behav-
ioral flexibility (e.g., to find one’s place or right oneself) before returning to the routine.
Thus the addicted person who sees a uniformed policeman standing where he expects to
see his drug dealer does not zombie-​like try to buy drugs from the policemen, but aborts
the plan and seeks out drugs elsewhere. Under such circumstances, the addicted person
often suffers intense drug craving (Tiffany 1990).
It may seem counterintuitive based on what we think we know about ourselves, but the
actions of dopamine in tuning motivation, cognition, and behavior toward future rewards
are unavailable to conscious introspection. The basis of consciousness remains a deep
scientific mystery, but the properties of conscious cognition are well studied. Among its
attributes, consciousness is a remarkable, but capacity limited, serial processor of infor-
mation. Conscious deliberative decision-​making is slow and effortful relative to uncon-
scious decision-​making processes. In a complex, rapidly moving world in which survival
often depends on speed and efficiency, it is unsurprising that decision-​making and con-
trol of behavior are served by rapid, massively parallel unconscious processing that has
access to multiple sources of relevant information (Dayan 2007; Cisek & Kalaska 2010).
 485

Addictive drugs 485

Addictive drugs
Addictive drugs are chemically diverse and interact with different molecular targets in
the nervous system (Nestler et al. 2015). Based on their chemical differences, these drugs
exert diverse physiological and behavioral effects. For example, amphetamines are stim-
ulants, that is, they increase arousal. At lower doses, amphetamines enhance cognitive
performance; and at higher doses they produce euphoria, but may also cause anxiety and
insomnia. Alcohol, in contrast, is a depressant; it is anxiolytic at low doses, and degrades
cognitive and motor performance with higher, intoxicating doses. Despite their differ-
ences in mode of action in the brain, all addictive drugs share the property of causing
dopamine release from VTA neurons and thus activating reward circuitry. Psychotropic
drugs such as selective serotonin reuptake inhibitor antidepressants that do not cause sig-
nificant dopamine release are not addictive. Even drugs that produce physical withdrawal
symptoms (physiological dependence) are not considered addictive unless they produce
compulsive behavior.
In a metaphorical sense, addictive drugs can be likened to Trojan horses in the brain.
All addictive drugs mimic one or another endogenous neurotransmitter that can directly
or indirectly increase synaptic dopamine. Cocaine is structurally similar enough to dopa-
mine itself that it binds the dopamine transporter that normally clears dopamine from
synapses. However, cocaine is different enough structurally from dopamine that it blocks
the transporter without entering it. The result of cocaine blockade of the dopamine trans-
porter is a buildup of dopamine in synapses to very high levels. Opiates, nicotine, alcohol,
and cannabinoids mimic different neurotransmitters and act on different receptors in the
brain, but by diverse mechanisms, all of them indirectly cause dopamine release (and in
the case of opiates also exert independent rewarding effects) (Nestler et al. 2015).
Why do addictive drugs have an advantage over natural rewards, and, in vulnerable indi-
viduals, crowd out other, more adaptive goals? It is because addictive drugs activate reward
circuits directly by pharmacologic action, independently of experience and despite their lack
of any homeostatic or reproductive benefit. Such drugs reliably cause significant dopamine
release and thus a positive reward prediction signal. As drug use is repeated under the initial
influence of pleasure seeking, relief of distress, or social forces, the resulting grossly abnormal
dopamine signal potently consolidates the motivational power of drug-​associated cues, patho-
logically excessive valuation of drug taking, and drug seeking and consummatory behavioral
repertoires (Montague et al. 2004; Schoenbaum et al. 2006; Everitt & Robbins 2016).
An additional advantage that addictive drugs have over natural rewards is that phar-
macologically induced dopamine release masks the results of disappointing or aversive
experiences. Thus biting into a rotten fruit would create, among other effects, a dopa-
mine pause, which might devalue that kind of fruit. This is not the case for drugs that
directly release dopamine. For example, if the inhalation of tobacco smoke causes painful
coughing or shortness of breath in a chronically ill smoker, nicotine still causes dopamine
release as a pharmacologic action mediated by nicotinic acetylcholine receptors. Despite
the smoker’s actual aversive experience, forebrain circuits still receive a signal that rein-
forces tobacco use (Redish 2004).
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486 The neurobiology of addiction

As individuals progress from repetitive drug use to addiction, action patterns involved
in drug seeking and drug taking become habitual: drug-​associated cues gain the ability
to activate automatized drug-​seeking behaviors in a manner that is increasingly indepen-
dent of the person’s goals (Berke & Hyman 2000; Everitt & Robbins 2005, 2016). Cue-​
dependent activation of ingrained drug-​seeking habits helps explain why an addicted
person continues to take drugs, even when late in the course of addiction, tolerance to
drugs and damage to health may have sapped all pleasure from the experience of using
them and may even be aversive. When such habitual drug seeking is delayed or foiled
(e.g., by unavailability or by attempts to cut down), intense drug craving often occurs,
increasing the motivation to find and use drugs (Tiffany 1990). Craving is so characteris-
tic of addicted individuals as to be listed among the DSM-​5 diagnostic criteria (American
Psychiatric Association 2013).

Control systems and their limitations

Given that pursuit of rewards requires investment of energy and entails potential risks
(e.g., exposure of prey species to predation when they leave shelter to seek food or water),
diverse mechanisms have evolved to regulate reward seeking. For example, the drive to
seek certain rewards, such as food and water, is regulated by homeostatic needs (e.g., hun-
ger or thirst), the value of the reward, its proximity, and the dangers involved in obtaining
it. Regions of the prefrontal cortex, such as the dorsolateral prefrontal cortex, subserve
cognitive control mechanisms (Miller & Cohen 2001) that can support or suppress reward
seeking in accordance with circumstances. For homeostatic functions such as balancing
caloric intake and energy utilization, other specialized circuits are also involved (Kenny
2011). Control of feeding and energy balance involves not only reward circuitry, but also
complex hypothalamic projection systems and both hormonal and neural signals involv-
ing the gastrointestinal system. Other specialized regulatory circuits in the hypothalamus
and peripheral hormonal systems are involved in thirst and in sexual behaviors.
Research that has compared chronic drug users with healthy comparison subjects has
found impairments in the ability of drug users to perform tasks that demand significant
cognitive control of thought or behavior. These performance failures correlate with failure
to activate prefrontal cortex in functional neuroimaging studies compared with healthy
subjects (Goldstein & Volkow 2011). The implication is that the ability to exert execu-
tive control over impulses is weakened just at the time when an addicted person is also
experiencing powerful drives to seek and consume drugs. This research suggests that in
addiction, not only is the drug wanting, valuation, and drug-​seeking behavior extremely
potent, as a result of neural plasticity that occurred in response to repeated, pathological
dopamine signals (Berke & Hyman 2000; Everitt & Robbins 2005, 2016), but the ability
to exert top-​down control over behavior may also be undermined. The result is a person
whose drug seeking is increasingly unrelated to goals and resistant to devaluation by neg-
ative consequences even when the person (as in the two opening vignettes) is well aware
of the situation (Hyman 2007; Ersche et al. 2016)
 487

The persistence of addiction 487

The persistence of addiction

One of the most challenging features of drug addiction for families, clinicians, and society
is the lifelong persistence of relapse risk that characterizes a significant subset of addicted
individuals (Hser et al. 2001). Even among individuals who recover, with or without treat-
ment, successful achievement of abstinence often follows after many prior attempts have
failed as a consequence of cue-​activated drug seeking or drug craving or, as has been well
studied, in the face as a result of a significant stress (Shaham et al. 2000; Koob 2008).
The grudgingly persistent nature of relapse risk is thought to reflect several biologi-
cal processes that are known to be long-​lived (Hyman et al. 2006; Wolf 2016). Among
the most persistent alterations in the structure and function of the nervous system are
forms of synaptic plasticity that underlie formation of associative memories—​in the case
of addiction, associations that bind specific drug cues to drug seeking. Drug-​induced
synaptic plasticity such as long-​term potentiation (LTP) and long-​term depression (LTD)
that produce persistent changes in information processing within neural circuits have
been well documented in VTA, and NAc in response to administration of addictive drugs
(Hyman et al. 2006; Luescher & Malenka 2011). Measurements of LTP and LTD are phys-
iological proxies for long-​lived, most often structural changes in synaptic connections
that can include the number and size of synaptic spines on the dendrites of the princi-
pal neurons of the NAc, caudate and putamen, and cerebral cortex. Activity-​dependent
changes in synapses and in synaptic spines alter information processing in the circuits in
which they participate. Dopamine acts in the forebrain to regulate plasticity in synapses
relevant to motivation, valuation, and reward-​related behavior (Nestler et al. 2015). The
persistence of alterations in synaptic connections that may be measured experimentally
as LTP and LTD, is mediated by such biological processes as changing patterns of gene
expression and protein translation in relevant neurons which might result, for example, in
structural alterations in synapses and spines. There are many mechanisms of gene regula-
tion influenced by addictive drugs including epigenetic modification of chromatin, the
protein scaffolding that makes regions of DNA more or less available to be transcribed
(Walker et al. 2015).
The foregoing review of mechanisms that contribute to addiction, perforce has limita-
tions both with respect to its brevity and with respect to the still advancing state of the
science. There is, however, a reasonable consensus that in individuals made vulnerable
by genetic, developmental, and environmental risk factors, repetitive use of drugs that
release dopamine in reward circuitry—​a survival system conserved across mammalian
evolution—​produces the severe behavioral syndrome of addiction. Because addictive
drugs reliably cause dopamine release, independently of any benefit, they have an advan-
tage over natural rewards, ultimately producing profound pathologies of decision-​making
and behavior. Over time, as drugs shape behavior and crowd out the rewards of fam-
ily, social interactions, and work, the addicted person’s life is progressively narrowed to
obtaining, using, and recovering from drugs. Despite these and other profoundly nega-
tive consequences, drug seeking and drug use, which has become stimulus bound and
48

488 The neurobiology of addiction

unrelated to a person’s goals, becomes extremely difficult to interrupt for any extended
period of time.

Some implications of the scientific model for understanding

the behavior of addicted people
I began this chapter with two vignettes, one of a smoker who does not stop despite his
understanding of the risks, experience of negative health consequences, and an intention
to quit. The other described a person addicted to opioids who relapses despite having made
it through severe withdrawal in a rehabilitation facility, and despite putting his marriage
and job at risk. The neural mechanisms of addiction provide a basis for understanding the
maladaptive behavior of such individuals. Both vignettes describe individuals who exhibit
compulsive drug use despite negative consequences, and would thus be diagnosed with
addiction by current, widely accepted DSM-​5 criteria (American Psychiatric Association
2013). Both vignettes illustrate the limitations of an addicted person’s knowledge of harms
and of goals of the person might hold for abstinence and recovery.
Even for healthy people attempting to cut down on calories or certain classes of foods,
homeostatic processes that drive hunger and reward-​associated cues that activate wanting
typically foil long-​term success. The conscious use of willpower (i.e., exertion of cogni-
tive control to inhibit prepotent impulses) is effortful and depletes cognitive resources
over time. For addicted individuals, for whom drug seeking has become stimulus bound
and dissociated from goals, awareness of harms and consciously held intentions typically
yield little progress toward abstinence. Indeed, drug craving is perversely likely to arise
from attempts to cut down because such attempts are an impediment to automatized drug
seeking. To make matters worse, as suggested by neuroimaging studies, prefrontal cortical
circuits may be impaired in addicted people, thus diminishing their ability to exert cogni-
tive control compared with healthy people (Goldstein & Volkow 2011).
Now in the second decade of the twenty-​first century the United States is experiencing
an epidemic of deaths from opiate overdoses; even short of death, many addicted people
continue to relapse over their lifespan (Hser et al. 2001). The situation for addicted peo-
ple is not hopeless. Despite the neural mechanisms of addiction reviewed here, humans
exhibit significant differences in their responses to drugs and to the addicted state. Some
stop drug use on their own—​often succeeding after many attempts; in the remarkable
case of US soldiers returning from Vietnam, a pervasive change in circumstance per-
mitted recovery for many without formal treatment (Robins et al. 1975). Of the many
addicted people who seek treatment, the results are variable in terms of overall outcome,
the number of episodes of high-​quality treatment that are needed, and the overall length
of time to a sustained recovery (during which harms unfortunately accrue). This essay is
not the place to discuss the strengths and weaknesses of existing treatments, but overall,
existing evidence-​based treatments have been shown to be better than no treatment. That
said, more effective treatments are much in need. Currently, some individuals gain sig-
nificant benefit from existing psychosocial, pharmacologic, or combined treatments, but
 489

Some implications of the scientific model for moral responsibility and legal culpability 489

large numbers obtain only modest benefits, if any. As in the case of many severe chronic
and relapsing human ills, especially those that affect the brain, progress has been slow. In
the case of addiction, the search for better treatments has been hampered by low levels
of interest on the part of pharmaceutical companies based, in part, on concerns about
retaining addicted people in clinical trials and in part about the likelihood of reimburse-
ment given the often tenuous state of health insurance for this stigmatized population.
The most important reason to investigate neurobiological mechanisms of addiction is
to gain deeper understandings that will yield biomarkers and effective treatments. One
early example of a treatment that has come from research on basic mechanisms is the
use of long-​acting opiate antagonists that diminish drug craving across multiple classes
of addictive drugs (Lee et al. 2016). These are proving a useful tool in treatment, but as
noted, much more is needed.
A challenging problem is how to convince addicted individuals to accept treatment—​a
problem that is exacerbated by the dearth of drug treatment slots in most countries and
the limitations on insurance payments. The foregoing discussion is consistent with the
experience of many families and many clinicians. Information alone is rarely adequate;
rather, sustained efforts at persuasion and some level of coercion are often required. Given
the power of cues and stress to elicit drug seeking, opportunities to succeed in getting an
addicted person to treatment may be transient—​thus the limitation of treatment slots and
insurance coverage are particularly unfortunate. Challenging and frustrating in addition,
as in the second of the opening vignettes, are relapses after treatment. Given what we
know of addiction, relapses are not surprising, nor should they be the occasion to give
up on the addicted person. Based on what we know of the power and persistence of the
underlying neural mechanisms, many attempts are often needed before an addicted per-
son can achieve a sustained remission.

Some implications of the scientific model for moral

responsibility and legal culpability
In most modern systems of justice, legal culpability is based both on commission of a
criminal act (actus reus) and criminal intent (mens rea). Possession of certain drugs is a
crime in most jurisdictions, and drug dealing universally so. A moral model of addiction
imputes to the addicted drug user the capacity for deliberative choice and the ability to
inhibit drug use, and thus both moral and legal responsibility for such illegal acts. The
medical model of addiction, in contrast, problematizes the application of mens rea to
addicted individuals, most clearly for crimes such as possession of illegal drugs intended
for the person’s use—​and perhaps even low-​level drug dealing when it is employed solely
as a mode of obtaining resources to maintain a drug habit. Understanding addiction as
compulsive behavior refutes the simple attribution of free choice and action assumed by
the moral model and thus calls into question the imputation of criminal intent to most
addicted individuals charged with drug possession, and to some degree other nonviolent
drug offenses that are committed directly in the service of obtaining drugs.
490

490 The neurobiology of addiction

Application of the medical model does not mean, however, that all sanctions would be
inappropriate. Rationales for punishment in most systems of justice include a combina-
tion of retributivist and consequentialist goals. Retribution expresses the moral outrage
of society about a crime and is meant to assuage the moral emotions of victims and of
society more broadly. Consequentialist goals include deterrence of future crime by the
perpetrator and by setting an example, deterrence of other potential perpetrators; inca-
pacitation of dangerous individuals; and rehabilitation of the person being punished. The
medical model of addiction does not militate against consequentialist goals of punish-
ment, but explains why punishment often fails to end drug use. Moreover, if one goal of
punishment is to protect society from the considerable harms wrought by drug use and
addiction (including the profoundly negative effects of black markets), it can be asked
whether incarceration in prison, which has been so common in the United States in
recent decades, is beneficial to society, or whether alternative sanctions—​a complex mat-
ter that cannot be discussed within the limits of this chapter—​might better serve society’s
pragmatic goals. The medical model suggests that retribution makes no sense with respect
to addicted individuals given the constraints its underlying pathologies put on volitional
control, and on the ability of addicted persons to respond to moral condemnation. The
moral model in systems of criminal justice, combined with stigmatization of addicted
people and outrage against them, has produced a period of harsh punishment, notably in
the United States, which has a significant percentage of its population serving long prison
sentences for drug-​related crimes, even when nonviolent.
Some legal scholars argue that moral responsibility and legal culpability can almost
always be determined at the level of psychological evidence and that neuroscience has
nothing to add (Morse 2006). This is because the factors that matter for determinations
of mens rea are the capacities and especially the rationality of accused persons at the
time that they committed an illegal act, and, they argue, facts about brain anatomy or
brain function do not directly address these issues (Morse 2006). Such views create some-
thing of an impasse between the law and neuroscience, since the neuroscience view would
argue that the apparent rationality of the addicted person is illusory: the person can plan
to gain and take drugs, but is not in control of his or her motives.
Significant challenges remain if neuroscience is to effectively influence systems of jus-
tice and social policy more broadly. The mechanistic picture of addiction, which I have
reviewed here, has ultimately been constructed out of many hundreds of individual stud-
ies. The majority of these studies are based on animal models rather than humans because
of the inviolability of the human brain to intrusive experimentation in life. In addition,
given the serious limitations of current noninvasive imaging and neurophysiological
technologies, neural correlates of addiction—​assuming these were better defined from
basic studies—​cannot be convincingly demonstrated for any given individual to a court,
parole officer, or medical personnel. Even if published neuroimaging studies were more
convincingly replicated than at the present time, it would still not be possible to deter-
mine the degree to which any specific person had been deprived by addiction of volitional
control—​and courts must deal with individuals, not with diagnostic classes. Perhaps at
 491

If the addicted person has significantly impaired agency 491

some future time, there will be convincing biomarkers that will provide a clear measure of
the severity of a given person’s loss of volitional control, but none exist today.
That might be the end of the matter for now, except that many scientists share the view
that the moral model of addiction has often tilted courts and especially their sentencing
practices toward injustice by overstating the degree to which addicted people can control
their actions in accordance with the law. Certain courts and legal scholars—​those more
anxious about letting the guilty go free than about punishing the innocent—​may also be
concerned that symptoms of addiction, like symptoms of all physically invisible disabili-
ties and disorders, such as mental illnesses and early-​stage neurodegenerative disorders,
might be feigned and impairments of decision-​making and behavioral control overstated
by defendants. These concerns notwithstanding, and understanding full well that today
the severity of compulsion in any individual person cannot be objectively determined, it
is still the case that mainstream scientific understandings converge on the view that drug
seeking and drug taking by addicted individuals reflects severely impaired volitional con-
trol and markedly diminished ability to conform behavior to rational goals. Indeed, the
moral model of addiction, based in folk psychological intuition, is inconsistent with scien-
tific understandings both of normal decision-​making (Dayan 2007; Glockner 2007; Gold
& Shadlen 2007; Koechlin & Hyafil 2007; Kable & Glimcher 2009; Cisek & Kalaska 2010;
Custers & Aarts 2010) and the pathological decision-​making and behavior of addicted
people (Berke & Hyman 2000; Redish 2004; Montague et al. 2004; Everitt & Robbins 2005;
Hyman et al. 2006; Hyman 2007; Ersche et al. 2016; Everitt & Robbins 2016). The only
way out of this impasse at this point in history is for the scientific investigation of addic-
tion to continue to advance, with greater focus on humans, as opposed to animal models,
and to engage more effectively with judges, legal scholars, and policymakers—​both to
understand their concerns and constraints, and to provide honest views of the state of the
science. The most to hope for and energetically pursue are effective treatments that inter-
rupt the progression of addiction and provide realistic and reliable alternatives to systems
of criminal justice.

If the addicted person has significantly impaired agency,

might coerced treatment be warranted?
The neuroscience-​based claim that addiction is characterized by impaired decision-​mak-
ing and diminished behavioral control argues against attribution of moral responsibility
to addicted people and for mitigation of legal culpability for crimes that flow directly from
the addicted state. The neurobiological model of reduced agency supports arguments
against punishment for nonviolent crimes that have been driven by the need to obtain
drugs. However, given the personal and societal harms of addiction, the neurobiological
view does not imply that society should take no action. Indeed, an implication of reduced
decisional capacity in critical matters of health, and behavior and impaired ability to
control behavior, including the ability to obey the law, invites the question of whether
and under what circumstances involuntary treatment, if safe and effective, is ethical and
492

492 The neurobiology of addiction

warranted. Coerced treatment, especially of addicted individuals found guilty of nonvio-

lent crimes has already engendered debate (Caplan 2008; Hall et al. 2008; Carter & Hall,
Chapter 25, this volume). In addition to ethical analysis, however, far more data is needed
from well-​designed studies of particular societal interventions, for example, supervision
by effective drug courts and of coerced treatments, including medications such as long-​
acting opiate blockers. Without safe and effective interventions that can be implemented
in real-​world settings, ethical analyses will remain too abstract to have utility.
A more difficult question is posed for addicted individuals who have never been
convicted of a crime, but who are suffering significant health-​related and other harms.
Implementation of paternalistic medical treatment for brain disorders has a very dark his-
tory, including the widespread use of prefrontal lobotomy in the 1950s (Valenstein 1986).
Thus as both an ethical and pragmatic matter there would have to be a high bar for deter-
mining the point at which an addicted person had so little decisional capacity or agency
as to be a candidate for paternalistic treatment. There would also have to be stringent
standards for the safety of a proposed intervention as well as its efficacy, and provision
for interventions to be closely monitored by a qualified, disinterested observer. The high
value placed on autonomy in bioethics and a history of many well-​meant but ultimately
damaging involuntary treatments (Valenstein 1986) militates against paternalism. Yet an
argument for relaxing punitive sanctions because of lost rationality and control strongly
entails open-​minded consideration of paternalism under tightly regulated circumstances.

Conclusion
In this chapter I have described a scientific model of addiction that, while still incomplete,
captures evidence-​based views of many neurobiologists and psychologists. Understandings
of neurobiological mechanisms that underlie both healthy functioning and pathological
conditions such as addiction will deepen over time, especially with recent technological
advances that, inter alia, have made analysis of genetic risk factors feasible. I have probed
the implications of a neurobiological model of addiction for attributions of moral respon-
sibility and legal culpability, contrasting it with a widely influential moral model that is
grounded in folk psychology. The moral model lacks a scientific basis, but given its origin
in the potent, if misleading, human intuition of a self that is free to make decisions and
exert agency, this model has enormous persuasive power. In contrast, scientific formula-
tions that appeal to complex and invisible neural mechanisms do not automatically influ-
ence public views of addiction or other neural pathologies that affect behavior; nor do
they necessarily change the views lawmakers or courts, who are often sensibly skeptical
of moving too rapidly on such claims. If scientific understandings of behavior are to con-
tribute to more just societies, it is not enough for the science to advance. More specifically,
understandings that are grounded in animal models must be convincingly translated to
the human situation, and the disease state must be made “visible” through well-​validated
and convincing markers. As noted, perhaps most convincing to important lay audiences
 493

References 493

would be significant advances in treatment. Nothing would destigmatize more effectively

than an ability to successfully reverse the addicted state.

References
American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders
(5th edn.). Arlington, VA: American Psychiatric Association.
Belin, D., Berson, N., Balado, E., Piazza, P.V., and Deroche-​Gamonet, V. (2011). High-​novelty preference
rats are predisposed to compulsive cocaine self-​administration. Neuropsychopharmacology, 36,
569–​579.
Berke J.D. and Hyman, S.E. (2000). Addiction, dopamine, and the molecular mechanisms of memory.
Neuron, 25, 515–​532.
Breiter, H.C., Gollub, R.L., Weisskoff, R.M., et al. (1997). Acute effects of cocaine on human brain
activity and emotion. Neuron, 19, 591–​611.
Caplan, A. (2008). Denying autonomy in order to create it: the paradox of forcing treatment upon
addicts. Addiction, 103, 1919–​1921.
Cisek, P. and Kalaska, J.F. (2010). Neural mechanisms for interacting with a world full of action choices.
Annual Review of Neuroscience, 33, 269–​298.
Conrad, P. and Schneider, J.W. (1992). Deviance and Medicalization: From Badness to Sickness,
Expanded Ed. St. Louis, MO: Mosby.
Custers, R. and Aarts, H. (2010). The unconscious will: how the pursuit of goals operates outside of
conscious awareness. Science, 329, 47–​50.
Dagher, A. and Robbins T.W. (2009). Personality, addiction, dopamine: insights from Parkinson’s
disease. Neuron, 61, 505–​510.
Dayan, P. (2007). The role of value systems in decision making. In: Engel, C. and Singer, W. (Eds.) Better
Than Conscious? Decision Making, the Human Mind, and Implications for Institutions, pp.51–​70.
Cambridge, MA, The MIT Press.
Diederen, K.M., Spncer, T., Vestergaard, M.D., Fletcher, P.C., and Schultz, W. (2016). Adaptive
prediction error decoding in human midbrain and striatum facilitates behavioral adaptation and
learning efficiency. Neuron, 90, 1127–​1138.
Dunham, Y., Chen, E.E., and Banaji, M.R. (2013). Two signatures of implicit intergroup
attitudes: developmental invariance and early enculturation. Psychological Science, 24, 860–​868.
Ersche, K.D., Gillian, C.M., Simon Jones, P., et al. (2016). Carrots and sticks fail to change behavior in
cocaine addiction. Science, 352, 1468–​1471.
Everitt, B.J. and Robbins, T.W. (2005). Neural systems of reinforcement for drug addiction: from
actions to habits to compulsion. Nature Neuroscience, 8, 1481–​1489.
Everitt, B.J. and Robbins, T.W. (2016). Drug addiction: updating actions to habits to compulsions ten
years on. Annual Review of Psychology, 67, 23–​50.
Fenno, L., Yizhar, O., and Deisseroth, K. (2011). The development and application of optogenetics.
Annual Review of Neuroscience, 34, 389–​412.
Ferenczi, E.A., Zalocusky, K.A., Liston, C., et al. (2016). Prefrontal cortical regulation of brainwide
circuit dynamics and reward-​related behavior. Science 351, 42–​54.
Gallagher, M., McMahan, R.W., and Schoenbaum, G. (1999). Orbitofrontal cortex and representation
of incentive value in associative learning. Journal of Neuroscience, 19, 6610–​6614.
Glockner, A. (2007). How evolution outwits bounded rationality. The efficient interaction of automatic
and deliberate processes in decision making and implications for institutions. In: Engel, C. and
49

494 The neurobiology of addiction

Singer, W. (Eds.) Better Than Conscious? Decision Making, the Human Mind, and Implications for
Institutions, pp 259–​284. Cambridge, MA: The MIT Press.
Gold, J.I. and Shadlen, M.N. (2007). The neural basis of decision making. Annual Review of
Neuroscience, 30, 535–​574.
Goldstein, R.Z. and Volkow, N.D. (2011). Dysfunction of the prefrontal cortex in addiction: neuroimaging
findings and clinical implications. Nature Reviews Neuroscience, 12, 652–​669.
Graybiel, A.M. (2008). Habits, rituals, and the evaluative brain. Annual Review of Neuroscience, 31,
359–​387.
Haggard, P. (2008). Human volition: towards a neuroscience of will. Nature Reviews Neuroscience, 9,
934–​946.
Hall, W., Capps, B., and Carter, A. (2008). The use of depot naltrexone under legal coercion: the case
for caution. Addiction, 103, 1922–​1924.
Heyman, G.M. (2010). Addiction: A Disorder of Choice. Cambridge, MA: Harvard University Press.
Hser, Y.I., Hoffman, V., Grella, C.E., and Anglin, M.D. (2001). A 33-​year follow-​up of narcotics addicts.
Archives of General Psychiatry, 58, 503–​508.
Hyman, S.E. (2007). The neurobiology of addiction: implications for voluntary control of behavior.
American Journal of Bioethics, 7, 8–​11.
Hyman, S.E., Malenka, R.C., and Nestler, E.J. (2006). Neural mechanisms of addiction: the role of
reward-​related learning and memory. Annual Review of Neuroscience, 21, 565–​598.
Kable, J.W. and Glimcher, P.W. (2009). The neurobiology of decision: consensus and controversy.
Neuron, 24, 733–​745.
Kelley, A.E. and Berridge, K.C. (2002). The neuroscience of natural rewards: relevance to addictive
drugs. Journal of Neuroscience, 22, 3306–​3311.
Kenny, P.J. (2011). Reward mechanisms in obesity: new insights and future directions. Neuron, 69,
664–​679
Koechlin, E. and Hyafil A. (2007). Anterior prefrontal function and the limits of human decision-​
making. Science, 318, 594–​598.
Koob G. (2008). A role for brain stress systems in addiction. Neuron, 59, 11–​14.
Lee, J.D., Friedman, P.D., Kinlock, T.W., et al. (2016). Extended-​release naltrexone to prevent opioid
relapse in criminal justice offenders. New England Journal of Medicine, 374, 1232–​1242.
Luescher, C. and Malenka RC. (2011). Drug-​evoked synaptic plasticity in addiction: from molecular
changes to circuit remodeling. Neuron, 69, 650–​63.
Merikangas, K.R., Stolar, M., and Stevens, D.E., (1998). Familial transmission of substance use
disorders. Archives of General Psychiatry, 55, 973–​979.
Miller E.K. and Cohen, J.D. (2001). An integrative theory of prefrontal cortex function. Annual Review
of Neuroscience, 24, 167–​202.
Montague, P.R., Hyman, S.E., and Cohen, J.D. (2004). Computational roles for dopamine in
behavioural control. Nature, 431, 760–​767.
Moreno, M., Economidou, D., Mar, A.C., et al. (2013). Divergent effects of D2/​3 receptor activation
in the nucleus accumbens core and shell on impulsivity and locomotor activity in high and low
impulsive rats. Psychopharmacology (Berlin), 228, 19–​30.
Morse, S.J. (2006). Brain overclaim syndrome. Ohio State Journal of Criminal Law, 3, 397–​412.
Morse, S.J. (2008). Determinism and the death of folk psychology: two challenges to responsibility from
neuroscience. Minnesota Journal of Law, Science, and Technology, 9, 1.
 495

References 495

Nestler, E.J., Hyman, S.E., Holtzman, D., and Malenka, R.J. (2015). Molecular
Neuropharmacology: Foundation for Clinical Neuroscience. New York: McGraw Hill.
Pascoli, V., Terrier, J., Hiver, A. and Luscher, C. (2015). Sufficiency of mesolimbic dopamine neuron
stimulation for the progression to addiction. Neuron, 88, 1054–​1066.
Redish, A.D. (2004). Addiction as a computational process gone awry. Science, 306, 1944–​1947.
Robbins, T.W. and Clark, L. (2015). Behavioral addictions. Current Opinion in Neurobiology, 30, 66–​72.
Robins, L.N., Helzer, J.E., and Davis, D.H. (1975) Narcotic use in southeast Asia and afterward. An
interview study of 898 Vietnam returnees. Archives of General Psychiatry, 32, 955–​961.
Robinson, S., Sandstrom, S.M., Denenberg, V.H., and Palmiter, R.D. (2005). Distinguishing whether
dopamine regulates liking, wanting, and/​or learning about rewards. Behavioral Neuroscience, 199,
336–​341.
Satel, S.L. (1999). What should we expect from drug abusers? Psychiatric Services, 50, 861.
Satel, S. and Lillienfeld, S.O. (2013). Brainwashed: The Seductive Appeal of Mindless Neuroscience.
New York: Basic Books.
Schoenbaum, G., Roesch, M.R., and Stalnaker, T.A. (2006). Orbitofrontal cortex, decision-​making and
drug addiction. Trends in Neurosciences, 29, 116–​124.
Schultz, W. (2006). Behavioral theories and the neurophysiology of reward. Annual Review of
Psychology, 57, 87–​115.
Schultz W., Dayan P., and Montague, P.R. (1997). A neural substrate of prediction and reward. Science,
275, 1593–​1599.
Shaham, Y., Erb, S., and Stewart, J. (2000). Stress-​induced relapse to heroin and cocaine seeking in
rats: a review. Brain Research. Brain Research Reviews, 33, 13–​33.
Stolier, R.M. and Freeman, J.B. (2016). Neural pattern similarity reveals the inherent intersection of
social categories. Nature Neuroscience, 19, 795–​797.
Sullivan, P.F., Daly, M.J., and O’Donovan, M. (2012). Genetic architectures of psychiatric disorders: the
emerging picture and its implications. Nature Reviews Genetics, 13, 537–​551.
Thorgeirsson, T.E., Gudbjartsson, D.F., Surakka, I., et al. (2010). Sequence variants at CHRNB3-​
CHRNA6 and CYP2A6 affect smoking behavior. Nature Genetics, 42, 448–​453.
Tiffany, S.T. (1990). A cognitive model of drug urges and drug-​use behavior: role of automatic and
nonautomatic processes. Psychological Review, 97,147–​168.
Traynor v. Turnage and McKelvey v. Turnage (1988). 485 US 535; 108 S. Ct. 1372.
Tsuang, M.T., Lyons, M.J., Eisen, S.A., et al. (1996). Genetic influences on DSM-​III-​R drug abuse and
dependence: a study of 3,372 twin pairs. American Journal of Medical Genetics, 67, 473–​477.
Valenstein, E. (1986). Great and Desperate Cures: The Rise and Decline of Psychosurgery and Other
Radical Treatments for Mental Illness. New York: Basic Books.
Volkow, N.D., Wang, G.J., Tomasi, D., and Baler, R.D. (2013). The addictive dimension of obesity.
Biological Psychiatry, 73, 811–​818.
Walker, D.M., Cates, H.M., Heller, E.A., and Nestler, E.J. (2015). Regulation of chromatin states by
drugs of abuse. Current Opinion in Neurobiology, 30, 112–​121.
Wallis, J.D. (2007). Orbitofrontal cortex and its contribution to decision-​making. Annual Review of
Neuroscience, 30, 31–​56.
Wegner, D.M. (2002). The Illusion of Conscious Will. Cambridge, MA: MIT Press.
Wegner, D.M. (2003). The mind’s best trick: how we experience conscious will. Trends in Cognitive
Science, 7, 65–​70.
496

496 The neurobiology of addiction

Wolf, M.E. (2016). Synaptic mechanisms underlying persistent cocaine craving. Nature Reviews
Neuroscience, 17, 351–​365.
World Health Organization (1992). The ICD-​10 Classification of Mental and Behavioural Disorders.
Geneva: World Health Organization.
Xie, J. and Padoa-​Schioppa, C. (2016). Neuronal remapping and circuit persistence in economic
decisions. Nature Neuroscience, 19, 855–​861.
 497

Chapter 25

Looking to the future: Clinical and

policy implications of the brain
disease model of addiction
Adrian Carter and Wayne Hall

Introduction
It has been two decades since Alan Leshner, then director of the US National Institute on
Drug Abuse (NIDA), published his seminal paper in Science declaring that “addiction is
a brain disease, and it matters” (emphasis added) (Leshner 1997). According to Leshner,
the chronic use of addictive substances flicked a neurochemical switch in the brain that
made it very difficult for addicted people to stop using drugs. The brain disease model of
addiction (BDMA) professed to explain the high rates of relapse among people treated
for addiction.
Leshner was not simply outlining the empirical case for why drug addiction is a brain
disease; he was laying the groundwork for a clinical and policy agenda to transform the
way in which addiction was treated by healthcare professionals, policymakers and leg-
islators, and the general public. He argued that the BDMA would deliver more effective
medical treatments for addiction that would be covered by health insurance and thereby
be more readily accessible to addicted people (Leshner 1997). The brain disease view was
also intended to convince a skeptical public that addiction was a real psychiatric disorder
and that addicted people suffered from a condition that warranted more humane medi-
cal treatment, rather than being morally weak or bad people who should be punished
either via incarceration or informally through stigmatization and social discrimination.
These changes in public understanding, he argued, would lead to a greater investment in
addiction treatment services and less reliance on punitive approaches to drug use and
addiction.
Over the last 20 years, Nora Volkow, current NIDA director, and others have expanded
this agenda. They have appealed to a growing body of neuroimaging research that argues
that the brains of people with an addiction have been hijacked by their drug (Dackis &
O’Brien 2005; Baler & Volkow 2006). This view has been very influential, particularly in
the United States, given that NIDA funds over 85% of addiction research. In 2014, Michael
Botticelli, then acting and now director of the US Office on National Drug Control Policy,
declared “decades of research have demonstrated that addiction is a brain disorder—​one
498  4

498 Looking to the future

that can be prevented and treated” (Botticelli 2014). The BDMA has also been widely
promoted in leading science journals (Volkow & Li 2004; Volkow et al. 2016a) and was
endorsed in an editorial in the UK journal, Nature (Editorial 2014). The American Society
of Addiction Medicine has also recently redefined addiction as a “primary, chronic dis-
ease of brain reward, motivation, memory, and related circuitry” (American Society of
Addiction Medicine 2011).
The notion that the brains of addicted individuals have been so altered to prevent them
from choosing not to use their drug of addiction has significant ethical implications. It
has been used to:
◆ justify the use of greater coercion or mandated treatment to support those who lack
the autonomy to make decisions to support themselves (Caplan 2008)
◆ suggest that addicted people lack the decision-​making capacity to freely consent to
research or treatment that involves the administration of their drug of addiction
(Charland 2002; Cohen et al. 2002), or its agonist (Carter & Hall 2008a)
◆ support the use of invasive and high-​risk interventions such as brain surgery (e.g.,
deep brain stimulation or ablative psychosurgery) to correct the brain dysfunction that
is believed to underpin addiction (Krack et al. 2010; Luigjes et al. 2012).
We have addressed these important ethical implications of a brain disease model else-
where (Carter & Hall 2008a, 2008b, 2011; Hall et al. 2008; Carter et al. 2011). In this chap-
ter, we examine the evidence supporting the claim that addiction is a brain disease and
we assess whether this view has lived up to its promises. We also examine recent research
on the impact that a BDMA has had on (1) public views of people with an addiction, and
specifically whether it has reduced addiction-​related stigma; (2) the way that people with
an addiction view their own behavior and drug use, or engage in treatment; and (3) public
health policies to reduce the harms of drug use. We explore a reframing of neuroscience
research of addiction that takes into account the impact that the repeated use of addictive
drugs has on the brain while ensuring that we apply these insights in ways that optimize
public health policies to reduce the harms of drug use and addiction.

Evidence for the brain disease model of addiction

Animal models of addiction have been central to the development of the BDMA (Koob &
Le Moal 2006; Feltenstein & See 2008; Ahmed 2012). Electrical stimulation and lesioning
studies in animals have enabled researchers to identify the neural circuitry through which
major drugs of addiction act. This is commonly referred to as the brain reward pathway
and includes the ventral striatum, nucleus accumbens, amygdala, and frontal cortices (see
Figure 25.1) (Hyman et al. 2006). Studies of drug use in animals, including rats, mice, and
nonhuman primates, have shown that animals will repeatedly self-​administer (by pressing
a lever) the same drugs that are addictive in humans (Koob & Le Moal 2006; Feltenstein
& See 2008); they will continue to do so despite the presence of aversive stimuli (such
as an electrical footshock); and that self-​administration of drugs is reduced by electri-
cally stimulating the brain’s reward center (Feltenstein & See 2008; Ahmed 2012). The
 49

Evidence for the brain disease model of addiction 499

Cingulate gyrus
Striatum

Prefrontal
cortex

Substantia nigra

Nucleus
accumbens
Ventral tegmental area

Figure 25.1  Projections from the midbrain to the nucleus accumbens (NAcc) and forebrain.
Dopaminergic neurons from the ventral tegmental area (VTA) and substantia nigra project to
the central reward area, the NAcc, and to the cortical areas primarily responsible for making
decisions, such as whether to use drugs (e.g., the prefrontal cortex (PFC), and the anterior
cingulate gyrus (aCG)). 
Reproduced with permission of Annual Review of Neuroscience, Volume 29, Issue 1, Steven E. Hyman, Robert C.
Malenka, Eric J. Nestler, ’Neural Mechanisms of Addiction: Role of Reward-​Related Learning and Memory’,
pp. 565–​598, DOI: 10.1146/​annurev.neuro.29.051605.113009 © by Annual Reviews, http://​www.annualreviews.org.

neurotransmitter, dopamine, plays a key role in addiction, although other neurotrans-

mitters such as endogenous opioids and cannabinoids, glutamate, gamma-​aminobutyric
acid, corticotropin-​releasing hormone, and the orexins are increasingly understood to
play critical roles in the development and maintenance of different types of addiction
(Feltenstein & See 2008).
Neuroimaging studies in normal and addicted human brains are broadly supportive
of the findings from animal studies. These studies have identified changes in dopamine-​
regulated activity in key regions of the reward pathway, notably the nucleus accumbens
and prefrontal cortices (Volkow et al. 2007, 2009, 2012). These changes in brain function
correlate with impaired decision-​making and poor impulse control (Volkow & Li 2004;
Volkow & Baler 2014). The persistence of many of these changes after long periods of
abstinence have been invoked to explain the high rates of relapse in people treated for
addiction, even after years of abstinence (Reske & Paulus 2011).
The tendency for addictions to run in families is well known. Genetic factors are
estimated to contribute between 40% and 60% of the risk of developing an addiction
to a range of substances, including alcohol, nicotine, opioids, stimulants, and cannabis
(Kendler et al. 2012). Genome-​wide association studies have identified risk alleles that
influence drug metabolism and the effects that drugs have on the brain, suggesting that
50  5

500 Looking to the future

chronic drug use acting on the brains of genetically vulnerable individuals produces
addiction (Kendler et al. 2012).

How strong is the evidence for a brain disease model

of addiction?
Volkow and Koob (2015) recently published an article where they again argue for the
positive consequences of a BDMA. This article failed to outline prominent criticisms of
the model (Buchman et al. 2010; Satel & Lilienfeld 2013; Satel & Lilienfeld 2014; Hall et al.
2015; Lewis 2015), although the authors did provide a brief response that was published
as an online supplementary appendix (Volkow et al. 2016a, 2016b). We have provided a
more detailed critique of the evidence against a BDMA elsewhere (Hall et al. 2015), and
we summarize the argument here.
First, as a number of prominent social scientists have pointed out, the vast majority of
people who have met the diagnostic criteria for dependence in epidemiological surveys
are not drug dependent at the time of their interview. In contrast to the view that addic-
tion is an inescapably chronic disease, the majority of individuals meeting a diagnosis of
addiction mature out of their condition, stopping drug use often without seeking treat-
ment (Robins 1993; Bachman et al. 1997; Heyman 2009; Satel & Lilienfeld 2014).
Second, the strong view of the BDMA where people with an addiction have been
hijacked by their drug and unable to control their drug use is inconsistent with evidence
that small financial rewards or avoiding 24 hours in jail for providing clean urine samples
substantially reduces drug use in severely dependent individuals (Heyman 2009; Kleiman
2009; Kilmer et al. 2013; Satel & Lilienfeld 2013). The changes in drug use in response to
such small incentives is hard to reconcile with the claim that such drug use is a compul-
sive behavior over which addicted people have little or no control (Hall et al. 2015).
Volkow and colleagues tacitly acknowledge these points in a rejoinder (Volkow et al.
2016b) to our critique of the BDMA (Hall et al. 2015). On our reading, they concede that
the majority of individuals with an addiction do not fit with the BDMA and that the loss
of control over their behavior is not complete, nor have they been hijacked by the drug
(as NIDA colleagues have argued elsewhere, e.g., Dackis & O’Brien (2005)), and maintain
some capacity to weigh up choices about whether to use a drug or not.
The BDMA may be more relevant if we acknowledge that addiction is a condition that
varies significantly in severity with the majority of individuals with mild to moderate
conditions not experiencing the chronic and relapsing version of the disorder who will
overcome their condition without engaging in significant treatment (Hall et  al. 2015).
Volkow and colleagues acknowledge this point in their rejoinder. A chronic and relapsing
account of addiction would only be applicable to a minority of addicted people who use
drugs into their early thirties despite adverse health and social consequences and who
are most likely to seek treatment after failing to control their drug use and most likely
to show altered brain function. It is regrettable that these responses are not made more
prominently and explicitly within the body of their numerous articles in support of the
 501

Does neurobiological evidence support a more modest version 501

BDMA (e.g., Volkow & Li 2004; Dackis and O’Brien 2005; Volkow & Koob 2015; Volkow
& Morales 2015; Volkow et  al. 2016a). In these articles they assert that addiction is a
chronic, relapsing brain disease that hijacks behavior; any qualifications are relegated to
supplementary material (Volkow et al. 2016b).
This acknowledgment has important implications for how clinicians, healthcare profes-
sionals, and policymakers discuss addiction and argue for its treatment and policies. We
believe that advocates of the BDMA cannot continue to equate the lifetime prevalence of
addictive disorders with the prevalence of the severe and chronic addictive disorders that
appear to fit the BDMA. Nor can they argue for policy initiatives and treatment interven-
tions that assume that the majority of addicted individuals are suffering from a chronic
and relapsing disease that robs them of their ability to control their drug use. Although
they state that the BDMA only applies to a minority of individuals with the most severe
forms of addiction (Volkow et al. 2016b), Volkow and colleagues still cite estimates of the
prevalence of lifetime and past year addiction from epidemiological surveys as if these
were estimates of the prevalence of addiction of sufficient severity to make a brain disease
a plausible hypothesis (Volkow et al. 2016a).

Does neurobiological evidence support a more modest

version of the brain disease model of addiction?
Even if we accept that the BDMA may be relevant to a small fraction of addicted people
with severe, chronic, and relapsing forms of addiction, a critical analysis of neurobio-
logical research on addiction raises doubts about how compelling the evidence is for this
more modest version of the BDMA.
Addictive patterns of behavior are not the invariable outcome of chronic drug self-​
administration in animals. Popular accounts of compulsive lever pressing and drug self-​
administration in animal studies of addiction diminish the context-​dependent nature
of these findings and the impact that the environment has on the behavior of animals.
Animal studies often employ specifically bred strains of rats that have a heightened pro-
pensity to develop addictive behaviors. The results are also critically influenced by the
very constrained conditions in which animal studies are conducted (Ahmed et al. 2013).
Animals housed in more naturalistic environments with a range of additional activities to
engage in and access to litter mates do not display the same extent of addictive behavior
(Alexander et al. 1978; Xu et al. 2007; Ahmed 2010). This could be interpreted as evidence
for the impact of impoverished environments and limited social opportunities on highly
social animals, including humans.
Animal models of addiction also have little to say about the high rates of recovery in
addiction in the absence of specific interventions (Kincaid & Sullivan 2010). Recovery
is absent from Koob and LeMoal’s analysis of the fit between animal models and the
stages of human addiction (Koob & Le Moal 2006). Their assumption seems to be that
an addicted animal or person will remain so unless treated. This is inconsistent with the
502  5

502 Looking to the future

epidemiological evidence reviewed in the previous section (“How strong is the evidence
for a brain disease model of addiction?”).
Neuroimaging studies of addiction are typically case–​control studies that report
statistically significant differences in brain function and structure between groups of
severely addicted and nonaddicted people. These averaged differences do not reflect all
addicted people—​many addicted individuals will not display these deficits while some
nonaddicted controls will. These studies also do not tell us whether addiction is a cause
or a consequence of differences in brain structure (Ersche et al. 2013). Differences in
patterns of activation in brain scans between addicted and nonaddicted people also
do not prove that drug use in people with an addiction is compulsive (Hyman 2007).
The fact that reduced activity in frontal brain regions is modestly correlated with self-​
reported craving does not demonstrate that drug use is driven by impulses that are
irresistible.
Volkow and colleagues acknowledge that neuroimaging technologies have been unable
to distinguish between addicted and nonaddicted individuals, but optimistically place
this failure at the feet of current technological limitations, a lack of understanding of how
the human brain works, and the complexity of the neurobiological changes triggered by
drugs and the heterogeneity of substance use disorders (Volkow et al. 2016b). However,
this failure may also reflect the fact that there are other important psychological and social
factors at play in addiction. In the absence of acknowledgment of this failure, the role
played by the brain in individual outcomes is overestimated.
While we know from twin and adoption studies that addiction runs in families and that
genetics accounts for a significant portion of this risk, this pattern of risk is not explained
by a small number of specific genetic or molecular pathways. Very large numbers of alleles
are involved in the susceptibility to addiction and individually they are weak predictors
of addiction risk (Kendler et al. 2012). Risk scores based on multiple risk alleles do not
predict addiction risk any better than simple family history information (e.g., number of
smoking parents) (Gartner et al. 2009). Risk involves a complex and unpredictable inter-
action between genetics and environmental events, as well as a possible constellation of
gene–​gene and epigenetic effects.
Our analysis suggests that the neuroscience research does not uncritically support the
more modest version of the BDMA. We next examine whether the BDMA has delivered
the clinical, social, and policy benefits promised and propose an alternative account of the
relevance of neuroscience research to addiction.

Twenty years on: Has the brain disease model of addiction

delivered?
When Leshner declared that addiction is a brain disease, he promised a range of ther-
apeutic, social, and policy benefits. These benefits have continued to be promoted
in support of treating and framing addiction as a brain disease (McLellan et  al. 2000;
Dackis & O’Brien 2005; Volkow & Li 2005; Volkow & Koob 2015). Given the important
 503

Twenty years on: Has the brain disease model of addiction delivered? 503

role that these outcomes have played in garnering support for the BDMA, it is worth ask-
ing whether the BDMA has lived up to its promise.

Improved medical treatments for addiction

Among the new treatments being trialed to treat addiction are novel drugs that aim to
weaken the ability of cues associated with drug use or stress to trigger drug use; anti-
craving medications; drugs to reverse epigenetic changes produced by chronic drug
use; invasive and noninvasive brain stimulation devices to directly modulate aberrant
brain activity; vaccines and implantable antagonists to protect against a relapse to drug
use; and genomic and neurocognitive tests to match patients to the treatments that are
most likely to be effective for them (Volkow & Li 2005; Nutt & Lingford-​Hughes 2008).
Despite significant investment by NIDA and other funders in the search for effective
medical interventions, the promise of treatments that significantly improve upon the
currently poor outcomes remain largely unfulfilled (Kalant 2010). The most widely used
treatments for addiction are those that were developed prior to the considerable invest-
ment in neuroscience research and precede the BDMA by over three decades. These are
primarily substitution treatments that attempt to replace commonly abused drugs of
addiction, such as heroin and nicotine, with safer alternatives, such as methadone and
nicotine replacement therapy.
There are ample claims that medications are among the most effective interventions
for which they are available (Volkow et  al. 2016b) but, in reality, few drugs derived
from neurobiological research (e.g., naltrexone and varenicline) provide better results
than older forms of treatment, such as disulfiram and nicotine replacement therapy
(Lingford-​Hughes et al. 2012). These represent a very small return from a large and sus-
tained research investment in drug development in which the failures of a long list of
promising new drugs have been quickly forgotten and attention and investment shifted
to the next great hopes. Research on vaccines for nicotine and cocaine dependence have
also been disappointing, with one of the leading developers of a nicotine vaccine with-
drawing from clinical trials due to its limited effectiveness (Hall & Gartner 2011; Kosten
et al. 2014).
There are significant challenges to the development of effective drug treatments for
addiction, many of which are shared with development of pharmacological treatments
in biomedicine more broadly (Koob et al. 2009). The development of drug treatments in
addiction also raises additional challenges. Pharmaceutical companies have been reluc-
tant to invest in addiction treatments due to doubts over the profitability of the medica-
tions when the majority of consumers will not be able to afford them. There is a concern
that the stigma of addiction will discourage other potentially more profitable uses of these
drugs, such as drugs to treat chronic pain.

Public views of addiction, stigma, and discrimination

Stigma can have serious deleterious effects on the health and well-​being of individu-
als with mental illnesses such as addiction (Corrigan et al. 2014). Stigma is a complex
504  5

504 Looking to the future

construct that involves several elements. Structural stigma can lead to institutionalized
discrimination that deprives individuals with certain disorders of effective healthcare.
Social stigma involves the interpersonal victimization or discrimination against an indi-
vidual that may discourage someone from seeking treatment. It can also exacerbate inter-
nalized or self-​stigma, a collection of negative attitudes toward oneself that can lead to a
loss of self-​esteem and poorer health behaviors, such as continued or escalated drug use
to escape negative thoughts and feelings.
A major benefit claimed for the BDMA is that its public acceptance will reduce
stigma and discrimination against people with addictions. A  similar hope has long
been expressed in mental health more generally (Pescosolido et  al. 2010; Sartorius
2010). The optimistic assumption is that the public will be more accepting of people
with mental illnesses, such as depression and addiction, if they can be convinced that
these are the result of biological, specifically neurobiological changes that produce
the aberrant behavior, and hence that their sufferers have real diseases (Pescosolido
et al. 2010).
Proponents of the BDMA do not provide sufficient evidence to support this claim and
have ignored a growing body of social science survey evidence that suggests otherwise.
Numerous social science surveys have found that increased acceptance of a biological
basis for schizophrenia and alcohol dependence has had minimal impact on stigmatiza-
tion, and may in fact increase rather than decrease stigma (Angermeyer & Matschinger
2005; Pescosolido et al. 2010; Reavley & Jorm 2011; Kvaale et al. 2013). One large study of
the attitudes of US citizens over a 10-​year period found that while acceptance of neuro-
biological and genetic causes of addiction and schizophrenia, two of the most highly stig-
matized mental illnesses, increased substantially over this period, stigmatizing attitudes
were unchanged. Some research suggests that addicted individuals often see the BDMA as
adding to the stigma that they experience by reinforcing public fears that their behavior is
an uncontrollable consequence of permanent changes in their brains. We have also found
mixed support for the BDMA among Australian clinicians who treat addiction (Bell et al.
2014; Carter et al. 2014).
Reduced stigmatization and discrimination against people with an addiction is a desir-
able outcome, but we doubt that acceptance of a BDMA will achieve this. Stigma is a
complex construct that involves a range of different stakeholders (e.g., clinicians, policy-
makers, the public, and the individual), each of whom will require a specific and targeted
approach to reduce stigma and its negative consequences (Corrigan et al. 2014). There
is a growing realization that alternative approaches are needed to reduce the stigma of
mental illness, such as those employed by the nonprofit organization Bring Change 2
Mind, that target emotional processes to reduce social distance and fear (Corrigan et al.
2007; Corrigan & Shapiro 2010; Sartorius 2010). Future campaigns will need to identify
evidence-​based ways of reducing social distance and fear, rather than relying on plausible
but misplaced suppositions that simply educating the public about the impact of drug use
on the brain will reduce stigma.
 50

Twenty years on: Has the brain disease model of addiction delivered? 505

Impact of brain disease explanations on addicted individuals

To date, the assertion that BDMA will increase treatment-​seeking by people with drug
addictions because it will increase acceptance of drug addiction as a persistent neurobio-
logical change has been made in the absence of any research on its impact on addicted
people. Satel, for example, believes that the BDMA rhetoric encourages addicted indi-
viduals to believe that they can never fully free themselves of their drug and alcohol prob-
lems (Satel 1998, 1999; Satel & Lilienfeld 2013). Davies (1998) argues that the BDMA
exculpates the addicted person from taking responsibility for their condition: “it’s not me,
it’s my disease” (Bell et al. 2014). Critics are concerned that biological understandings of
addiction and other mental disorders may suggest that these disorders are incurable or
untreatable, and will therefore reduce willingness to seek treatment (Phelan et al. 2006;
Bell et al. 2014). Some critics suggest that the BDMA may in fact deter quit attempts by
making quitting seem harder than it actually is (Chapman & MacKenzie 2010).
The empirical evidence, as limited as it is on these issues, is mixed. In a survey of pub-
lic attitudes toward the treatability of mental illnesses, those who accepted psychologi-
cal explanations were more likely to see mental illnesses as curable, less debilitating, and
less likely to require professional assistance or hospitalization than those who supported
biological explanations (Lam et  al. 2005). Brain-​based biological explanations also led
people with these disorders to believe that their condition was harder to overcome than if
they attributed them to psychological causes. If these findings are also true for addiction,
the BDMA could discourage rather than encourage treatment-​seeking and quit attempts.
By contrast, Walker (2010) has argued that if people accept that they have a disease that
is beyond their control, they may be prompted to seek medical assistance rather than rely
on willpower. Individuals who see their addiction as arising from a character flaw rather
than a medical condition are less likely to seek treatment (Cunningham et al. 1993; Moyers
& Miller 1993; Varney et al. 1995). Similarly, endorsement of genetic or neurochemical
causes of mental illness, including alcohol dependence, has been associated with greater
public support for medical treatment and the use of medication (Pescosolido et al. 2010).
Our own studies with addiction clinicians and people with various drug addictions
have also produced mixed results (Meurk et  al. 2013, 2016a, 2016b; Bell et  al. 2014).
Many interviewees were receptive to the findings of neuroscience research but their opin-
ions varied on whether they believed that addiction constituted a brain disease and on
what they thought the likely effects would be on addicted individuals. Many believed the
BDMA could help addicted individuals to understand their own behavior and facilitate
behavior change by reducing guilt about their personal responsibility for their condition
(Meurk et al. 2013, 2016a, 2016b). Insofar as this happened, it could empower them to
seek treatment and remain abstinent. The BDMA was also seen as potentially reducing
what many interviewees believed to be the damaging effects of moralistic views of addic-
tion (Meurk et al. 2013, 2016a, 2016b), and as a useful rhetorical device for improving
treatment and reducing the punishment of individuals who need treatment for their
addiction (Bell et al. 2014).
506  5

506 Looking to the future

These positives were offset by views about the potentially adverse impacts of the BDMA
on the treatment and drug use of a subpopulation of addicted individuals. The concern
was that it could hinder addicted individuals’ behavior change, reduce their willingness
to enter treatment, undermine their ability to reduce drug use, and provide them with an
excuse for not changing their behavior (Bell et al. 2014). These results are consistent with
findings from a recent study of opioid-​dependent individuals receiving opioid substitu-
tion treatment (Netherland 2011).

Policy consequences of the neuromedicalization of addiction

Another criticism of the BDMA is that it will focus on neurobiological solutions to treat-
ing addiction at the expense of more intensive psychosocial approaches. The majority
of people with an addiction still do not receive minimal treatment or social support to
improve their quality of life and reduce harmful drug use. The eminent pharmacologist,
Harold Kalant, has argued that addiction neuroscientists have not critically reflected
on their failure to deliver the promised advances in treatment of the addictions (Kalant
2010). We believe that the research focus of National Institutes of Health agencies on the
neurobiology of severe addiction has deflected attention from population-​based policies
that are effective in reducing the harm from tobacco and alcohol use, namely, high rates
of taxation, strategies to reduce drug availability, and smoke-​free policies. This point was
well made over a decade ago by Merikangas and Risch (2003).
In this context, the narrow focus on the neurobiological causes of severe cases of addic-
tion has led to an over allocation of research and health resources toward neurobiological
solutions that will benefit few addicted people. It also largely neglects the psychosocial
drivers of drug use and addiction, such as poverty, homelessness, domestic violence, lack
of access to quality education and employment, and social isolation. Indeed, the BDMA
pays scant attention to social, cultural, and ethnic factors in addiction risk and severity
or social obstacles to recovery. It gives little attention to the value of public health policies
that have been the most successful in reducing cigarette smoking, gambling, and alcohol-​
related harm, such as increased taxation, reduced availability, and controls on the promo-
tion of addictive products by the industries that profit from them. For example, taxes
on cigarettes, advertising bans, and restrictions on where people can smoke have halved
cigarette smoking rates in Australia (White et al. 2003) and the United States (Pierce et al.
1998) in the last 30 years. These strategies are much more efficient than high-​risk strate-
gies aimed at treating individual smokers or people at risk of smoking (Rose G. 1992; Hall
et al. 2002). Similar evidence supports the greater efficiency of population-​based strate-
gies in reducing the societal harms of alcohol misuse (Doran et al. 2010). However, there
is a real concern that an overemphasis on the BDMA may undermine population-​level
approaches, particularly when misused by the alcohol and tobacco industries to oppose
public health policies and promote preventive policies that target at risk drug users or the
treatment of addicted people (Miller et al. 2012).
The BDMA prioritizes treatment over public health policy. For example, of the 2014
NIDA and National Institute on Alcohol Abuse and Alcoholism $1065.24 million USD
 507

Reframing neurobiological accounts of addiction 507

research budget, 41% was allocated to basic and clinical neuroscience and 17% to phar-
macotherapies (NIDA 2014). Social and public health research forms a small part of the
24% allocated to epidemiological research (NIDA 2014). A National Academy of Science
committee highlighted in 2001 that the National Institutes of Health had seriously under-
invested in drug policy evaluation (National Research Council 2001). In a recent response
to criticisms of the policy payoffs of the BDMA, Volkow and colleagues explicitly stated
the greater need for even further investment in the search for medical treatments of
addiction, despite acknowledging the failure to develop new effective treatments (Volkow
et al. 2016b). No mention was made of increasing investment in public policy research.
It is important to emphasize that clinical treatment and population-​level approaches
are not mutually exclusive; we are not arguing for either one or the other. The obser-
vation that science should not ignore the very significant benefits of population-​level
approaches does not preclude the need to identify more effective treatments for addicted
people. Society can, and should, look for more effective medical treatments of addiction.
But this should not be at the expense of maintaining attention to more broadly effective
population-​level approaches for reducing drug use and preventing harm (Hall et al. 2015).
We would like to see greater advocacy for increasing access to existing treatments rather
than for a BDMA that is of uncertain utility and acceptability to the people who are sup-
posedly its chief beneficiaries.
Volkow and colleagues claim that the BDMA has contributed to at least two policy
milestones in recent years: (1) passing of the Mental Health Parity and Addiction Equity
Act as part of the Patient Protection and Affordable Care Act that ensures that addiction
treatment is covered by medical insurance; and (2) justification for increasing the drink-
ing age to 21 years (Volkow et al. 2016b). It is difficult to assess whether the BDMA led to
the Patient Protection and Affordable Care Act as part of US nationalized healthcare per
se, however. A fair appreciation of the factors that contributed to the passage of this Act
would require social and historical research on the drivers of this policy change.

Reframing neurobiological accounts of addiction

There is considerable scientific value in neurobiological and genetic research on addic-
tion. Neuroscience research has uncovered the neurochemical and neurocognitive mech-
anisms that are associated with drug use. It helps to explain why those who have used
addictive drugs over longer periods of time can find it difficult to refrain from drug use
despite significant personal and social harms.
However, this research does not justify the simplified BDMA that dominates official
discourse about addiction in the United States. Evidence that drugs alter brain function in
a profound way is not new. The question is, what does neurobiology mean for the present
or future of diagnosis and treatment? Our understanding of addiction, and the policies
we adopt to treat and prevent problem drug use, should give biology its due, but no more
than its due. Evidence from research in economics, epidemiology, and the social sciences
shows that neurobiology is not the overriding factor when formulating policies toward
508  5

508 Looking to the future

drug use and addiction, and is not a major influence on our concern for people with an
addiction (Meurk et al. 2016a).
Originators and current proponents of the BDMA uphold the forced choice of the
1990s, namely, that rejection of addiction as a chronic, relapsing brain disease equates
to an acceptance of the moral view of addiction according to which addicted people can
simply stop using (Leshner 1997; Volkow & Koob 2015). Critics can accept that there is
value in neurobiological and genetic research on addiction but still reject the narrow view
that addiction is a brain disease and be skeptical that promoting this view will overcome
many of the limitations in the treatment of addicted individuals in society. As we have
outlined already, we do not believe that telling people with an addiction that they have a
brain disease that involves persistent rewiring of their brain that drives them to drug use
will necessarily lead to better health outcomes.
It has recently been claimed that there is a consensus view among scientists and clini-
cians that addiction is a brain disease (American Society of Addiction Medicine 2011;
Editorial 2014). There has been little empirical research to test this claim. In a small study
of Australian neuroscientists and clinicians, less than one-​third strongly endorsed the
BDMA. A  more reasonable and modified argument for the relevance of neurobiology
to addiction would involve arguing that addiction can be, but is not always, a chronic,
relapsing disorder; that people who develop chronic forms of addiction often require sus-
tained treatment to become and remain abstinent; that this treatment often has to address
the biological effects of sustained heavy drug use on brain and body; and that drug treat-
ments can certainly assist in withdrawing from drugs and in maintaining abstinence after
cessation of use. This view makes it clearer that the drug treatment of addiction is often
only the beginning in addressing the many challenges that addicted people face in recov-
ering and remaining abstinent, namely, securing useful employment, making friends who
are not drug users, repairing damaged family relationships, and overcoming the stigma
and social consequences of having a criminal record.

Neural plasticity: The forgotten science in addiction

Neuroplasticity is surprisingly absent from neurobiological accounts of addiction, par-
ticularly given the attention it has received in the academic and popular media. The
BDMA rarely, if ever, discusses the relevance of neural plasticity to addiction treatment;
it emphasizes instead the persistence of the changes produced by chronic drug use. One
can only speculate that the view that chronic use of addictive drugs produces long-​lasting
or permanent changes in brain function provides a more morally and politically accept-
able message, namely, that some forms of drug use damage the brain. While this message
may deter some young people from experimenting with drugs of addiction, it may have
a negative effect on those who develop an addiction, for example, by undermining their
self-​efficacy and treatment-​seeking, thereby promoting fatalism and learned helplessness.
A more effective, and accurate, application of neuroscience research on addictive drug
use would take account of the ability of the brain to recover from drug-​induced changes
through abstinence and reduced drug use, therapy, and prosocial lifestyle choices, such as
 509

Conclusion 509

exercise, brain training, or cognitive exercises, to rewire and relearn more adaptive habits
(Lewis 2015).

Conclusion
The chronic, relapsing brain disease model seems most plausible when used to describe
the minority of severely addicted people who fail to quit using drugs and who present
themselves, or are coerced by others, into treatment in middle adult life. These individu-
als comprise a minority of those who meet diagnostic criteria for addiction. The BDMA
cannot be used to describe the vast majority of individuals who receive an addiction diag-
nosis at some point during their lives.
We conclude that the BDMA has also not delivered on its promises. We are yet to see
substantially more effective treatments for drug addictions and the impact of the BDMA
in reducing stigma and improving access and funding to appropriate treatment services
has been modest. We share many of the hopes of those who advocate for the BDMA, such
as the delivery of more effective treatment and less punitive responses to addicted people.
But addiction is a complex biological, psychological, and social disorder that requires
a combined clinical and public health approach (Carter & Hall 2012). The search for
technological cures of addiction should not distract from increasing access to currently
available psychosocial and drug treatments for addiction, which the majority of addicted
individual are still unable to access, or developing simpler, cheaper, and more efficient
population-​based policies that discourage the whole population from smoking tobacco,
drinking heavily, or abusing illicit drugs.
Our rejection of the BDMA should not be misinterpreted as a defense of the moral
model of addiction (Carter & Hall 2012)  or the denial of the value of neuroscience.
Neuroscience research on addiction has provided useful insights into the neurobiology of
decision-​making, motivation, and behavioral control. These insights help to understand
how chronic use of addictive drugs can impair cognitive and motivational processes and
may partially explain why some people are more vulnerable than others to developing
an addiction. The challenge for all addiction researchers is to incorporate the emerging
insights of neuroscience research into those provided by economics, epidemiology, soci-
ology, psychology, and political science so the harms caused by drug misuse and all forms
of addiction can be reduced.
Neuroscience research can be extremely persuasive. It can influence expectations of
the clinical effectiveness of treatments (Racine et al. 2007) and the understanding of the
self in health and disease (Racine et  al. 2010; Rose N.S. & Abi-​Rached 2013). Care is
needed in how clinicians, policymakers, and other relevant stakeholders communicate
the results of neuroscience research on addiction (Satel & Lilienfeld 2013). It should not
be assumed that messages about diseased brains will always lead to increased treatment-​
seeking and reduced drug use. Messages about neuroscience research must be tailored to
individuals to foster better choices and health outcomes and avoid negative consequences.
This requires evidence on how addicted individuals interpret this research. More work is
510  5

510 Looking to the future

needed to understand how addicted individuals understand and respond to neuroscience

research of addiction, and how best to present this research to optimize treatment and
reduce unintended adverse consequences.

References
Ahmed, S.H. (2010). Validation crisis in animal models of drug addiction: beyond non-​disordered drug
use toward drug addiction. Neuroscience & Biobehavioral Reviews, 35, 172–​184.
Ahmed, S.H. (2012). The science of making drug-​addicted animals. Neuroscience, 211, 107–​125.
Ahmed, S.H., Lenoir, M., and Guillem, K. (2013). Neurobiology of addiction versus drug use driven by
lack of choice. Current Opinion in Neurobiology, 23, 1–​7.
Alexander, B.K., Coambs, R.B., and Hadaway, P.F. (1978). The effect of housing and gender on
morphine self-​administration in rats. Psychopharmacology, 58, 175–​179.
American Society of Addiction Medicine (2011). Public Policy Statement: Definition of Addiction (Long
Version). Chevy Chase, MD: American Society of Addiction Medicine.
Angermeyer, M.C. and Matschinger, H. (2005). Labeling–​stereotype–​discrimination. An investigation
of the stigma process. Social Psychiatry and Psychiatric Epidemiology, 40, 391–​395.
Bachman, J.G., Wadsworth, K.N., O’Malley, P.M., Johnston, L.D. and Schulenberg, J. (1997). Smoking,
Drinking, and Drug Use in Young Adulthood: The Impacts of New Freedoms and New Responsibilities.
Mahwah, NJ: Lawrence Erlbaum.
Baler, R.D. and Volkow, N.D. (2006). Drug addiction: the neurobiology of disrupted self-​control.
Trends in Molecular Medicine, 12, 559–​566.
Bell, S., Carter, A., Mathews, R., Gartner, C., Lucke, J., and Hall, W. (2014). Views of addiction
neuroscientists and clinicians on the clinical impact of a “brain disease model of addiction”.
Neuroethics, 7, 19–​27.
Botticelli, M. (2014). National Blueprint for Drug Policy Reform Released Today in Roanoke, VA. Office
of National Drug Control Policy Media Release.
Buchman, D.Z., Skinner, W., and Illes, J. (2010). Negotiating the relationship between addiction, ethics,
and brain science. AJOB Neuroscience, 1, 36–​45.
Caplan, A. (2008). Denying autonomy in order to create it: the paradox of forcing treatment upon
addicts. Addiction, 103, 1919–​1921.
Carter, A. and Hall, W. (2008a). Informed consent to opioid agonist maintenance
treatment: recommended ethical guidelines. International Journal of Drug Policy, 19, 79–​89.
Carter, A. and Hall, W. (2008b). The issue of consent in research that administers drugs of addiction to
addicted persons. Accountability in Research, 15, 209–​225.
Carter, A. and Hall, W. (2011). Proposals to trial deep brain stimulation to treat addiction are
premature. Addiction, 106, 235–​237.
Carter, A. and Hall, W. (2012). Addiction Neuroethics: The Promises and Perils of Neuroscience Research
on Addiction. London: Cambridge University Press.
Carter, A., Bell, E., Racine, E., and Hall, W. (2011). Ethical issues raised by proposals to treat addiction
using deep brain stimulation. Neuroethics, 4, 129–​142.
Carter, A., Mathews, R., Bell, S., Lucke, J., and Hall, W. (2014). Control and Responsibility in Addicted
Individuals: What do Addiction Neuroscientists and Clinicians Think? Neuroethics, 7, 205–​214.
Chapman, S. and MacKenzie, R. (2010). The global research neglect of unassisted smoking
cessation: causes and consequences. PLoS Medicine, 7, e1000216.
Charland, L.C. (2002). Cynthia’s dilemma: consenting to heroin prescription. American Journal of
Bioethics, 2, 37–​47.
 51

References 511

Cohen, M.J.M., Jasser, S., Herron, P.D., and Margolis, C.G. (2002). Ethical
perspectives: opioid treatment of chronic pain in the context of addiction. Clinical Journal
of Pain, 18, S99-​S 107.
Corrigan, P.W. and Shapiro, J.R. (2010). Measuring the impact of programs that challenge the public
stigma of mental illness. Clinical Psychology Review, 30, 907–​922.
Corrigan, P.W., Larson, J., Sells, M., Niessen, N., and Watson, A. C. (2007). Will filmed presentations
of education and contact diminish mental illness stigma? Community Mental Health Journal, 43,
171–​181.
Corrigan, P.W., Druss, B.G., and Perlick, D.A. (2014). The impact of mental illness stigma on
seeking and participating in mental health care. Psychological Science in the Public Interest,
15, 37–​70.
Cunningham, J.A., Sobell, L.C., and Chow, V.M. (1993). What’s in a label? The effects of substance
types and labels on treatment considerations and stigma. Journal of Studies on Alcohol, 54, 693–​699.
Dackis, C. and O’Brien, C. (2005). Neurobiology of addiction: treatment and public policy
ramifications. Nature Neuroscience, 8, 1431–​1436.
Davies, J.B. (1998). Pharmacology versus social process: competing or complementary views on the
nature of addiction? Pharmacology & Therapeutics, 80, 265–​275.
Dejong, W. and Blanchette, J. (2014). Case closed: research evidence on the positive public health
impact of the age 21 minimum legal drinking age in the United States. Journal of Studies on Alcohol
and Drugs, Supplement, 108–​115.
Doran, C.M., Hall, W.D., Shakeshaft, A.P., Vos, T., and Cobiac, L.J. (2010). Alcohol policy reform in
Australia: what can we learn from the evidence. Medical Journal of Australia, 192, 468–​470.
Editorial (2014). Animal farm. Nature, 506, 5.
Ersche, K.D., Williams, G.B., Robbins, T.W., and Bullmore, E.T. (2013). Meta-​analysis of structural
brain abnormalities associated with stimulant drug dependence and neuroimaging of addiction
vulnerability and resilience. Current Opinion in Neurobiology, 23, 615–​624.
Feltenstein, M.W. and See, R.E. (2008). The neurocircuitry of addiction: an overview. British Journal of
Pharmacology, 154, 261–​274.
Gartner, C.E., Barendregt, J.J., and Hall, W. (2009). Multiple genetic tests for susceptibility to smoking
do not outperform simple family history. Addiction, 104, 118–​126.
Hall, W., Madden, P., and Lynskey, M. (2002). The genetics of tobacco use: methods, findings and
policy implications. Tobacco Control, 11, 119–​124.
Hall, W., Capps, B., and Carter, A. (2008). The use of depot naltrexone under legal coercion: the case
for caution. Addiction, 103, 1922–​1924.
Hall, W. and Gartner, C. (2011). Ethical and policy issues in using vaccines to treat and prevent cocaine
and nicotine dependence. Current Opinion in Psychiatry, 24, 191–​196.
Hall, W., Carter, A., and Forlini, C. (2015). The brain disease model of addiction: is it supported by the
evidence and has it delivered on its promises? The Lancet Psychiatry, 2, 105–​110.
Heyman, G. (2009). Addiction: A Disorder of Choice. Cambridge, MA: Harvard University Press.
Hyman, S.E. (2007). The neurobiology of addiction: implications for voluntary control of behavior.
American Journal of Bioethics, 7, 8–​11.
Hyman, S.E., Malenka, R.C., and Nestler, E.J. (2006). Neural mechanisms of addiction: the role of
reward-​related learning and memory. Annual Review of Neuroscience, 29, 565–​598.
Kalant, H. (2010). What neurobiology cannot tell us about addiction. Addiction, 105, 780–​789.
Kendler, K.S., Chen, X., Dick, D., et al. (2012). Recent advances in the genetic epidemiology and
molecular genetics of substance use disorders. Nature Neuroscience, 15, 181–​189.
512  5

512 Looking to the future

Kilmer, B., Nicosia, N., Heaton, P., and Midgette, G. (2013). Efficacy of frequent monitoring with swift,
certain, and modest sanctions for violations: insights from South Dakota’s 24/​7 sobriety project.
American Journal of Public Health, 103, e37–​e43.
Kincaid, H. and Sullivan, J.A. (2010). Medical models of addiction. In: Ross, D., Kincaid, H., Spurrett,
D., and Collins, P. (Eds.) What is Addiction?, pp.353–​376. Cambridge, MA: MIT Press.
Kleiman, M. (2009). When Brute Force Fails: How to Have Less Crime and Less Punishment. Princeton,
NJ: Princeton University Press.
Koob, G.F. and Le Moal, M. (2006). Neurobiology of Addiction. New York: Academic Press.
Koob, G F., Lloyd, G.K., and Mason, B.J. (2009). Development of pharmacotherapies for drug
addiction: a Rosetta Stone approach. Nature Reviews Drug Discovery, 8, 500–​515.
Kosten, T.R., Domingo, C.B., Shorter, D., et al. (2014). Vaccine for cocaine dependence: a
randomized double-​blind placebo-​controlled efficacy trial. Drug and Alcohol Dependence,
140, 42–​47.
Krack, P., Hariz, M.I., Baunez, C., Guridi, J., and Obeso, J.A. (2010). Deep brain stimulation: from
neurology to psychiatry? Trends in Neurosciences, 33, 474–​484.
Kvaale, E.P., Haslam, N., and Gottdiener, W. H. (2013). The “side effects” of medicalization: a meta-​
analytic review of how biogenetic explanations affect stigma. Clinical Psychology Review, 33,
782–​794.
Lam, D.C.K., Salkovskis, P.M., and Warwick, H.M.C. (2005). An experimental investigation of the
impact of biological versus psychological explanations of the cause of “mental illness”. Journal of
Mental Health, 14, 453–​464.
Leshner, A.I. (1997). Addiction is a brain disease, and it matters. Science, 278, 45–​47.
Lewis, M. (2015). The Biology of Desire: Why Addiction is Not a Disease. New York: Scribe Publications.
Lingford-​Hughes, A.R., Welch, S., Peters, L., and Nutt, D.J. (2012). BAP updated guidelines:
evidence-​based guidelines for the pharmacological management of substance abuse, harmful
use, addiction and comorbidity: recommendations from BAP. Journal of Psychopharmacology, 26,
899–​952.
Luigjes, J., van den Brink, W., Feenstra, M., et al. (2012). Deep brain stimulation in addiction: a review
of potential brain targets. Molecular Psychiatry, 17, 572–​583.
McLellan, A.T., Lewis, D.C., O’Brien, C.P., and Kleber, H.D. (2000). Drug dependence, a chronic
medical illness: implications for treatment, insurance, and outcomes evaluation. JAMA, 284,
1689–​1695.
Merikangas, K.R. and Risch, N. (2003). Genomic priorities and public health. Science, 302, 599–​601.
Meurk, C., Hall, W., Morphett, K., Carter, A., and Lucke, J. (2013). What does “acceptance” mean?
Public reflections on the idea that addiction is a brain disease. Biosocieties, 8, 491–​506.
Meurk, C., Fraser, D., Weier, M., Lucke, J., Carter, A., and Hall, W. (2016a). Assessing the place of
neurobiological explanations in accounts of a family member’s addiction. Drug and Alcohol Review,
35(4), 461–​469.
Meurk, C., Morphett, K., Carter, A., Weier, M., Lucke, J., and Hall, W. (2016b). Scepticism and hope in
a complex predicament: people with addictions deliberate about neuroscience. International Journal
of Drug Policy, 32, 34–​43.
Miller, P., Carter, A., and De Groot, F. (2012). Investment and vested interests in neuroscience research
of addiction: Why research ethics requires more than informed consent. In: Carter, A., Hall, W., and
Illes, J. (Eds.) Addiction Neuroethics: The Ethics of Addiction Research and Treatment, pp. 278–​301.
New York: Elsevier.
Moyers, T.B. and Miller, W.R. (1993). Therapists’ conceptualizations of alcoholism: Measurement and
implications for treatment decisions. Psychology of Addictive Behaviors, 7, 238.
 513

References 513

National Institute on Drug Abuse (2014). Fiscal Year 2015 Budget information—​Congressional
justification for National Institute on Drug Abuse. Rockville, MD: National Institute on Drug Abuse.
National Research Council (2001). Informing America’s Policy on Illegal Drugs: What We Don’t Know
Keeps Hurting Us. Washington, DC: National Academy Press.
Netherland, J. (2011). “We haven’t sliced open anyone’s brain yet”: Neuroscience, embodiment and the
governance of addiction. In: Pickersgill, M. and Van Keulen, I. (Eds.) Sociological Reflections on the
Neurosciences (Advances in Medical Sociology, Volume 13), pp. 153–​177. Bingley, UK: Emerald
Group Publishing Limited.
Nutt, D. and Lingford-​Hughes, A. (2008). Addiction: the clinical interface. British Journal of
Pharmacology, 154, 397–​405.
Pescosolido, B.A., Martin, J.K., Long, J.S., Medina, T.R., Phelan, J., and Link, B. (2010). “A disease
like any other?”: a decade of change in public reactions to schizophrenia, depression, and alcohol
dependence. American Journal of Psychiatry, 167, 1321–​1330.
Phelan, J.C., Yang, L.H., and Cruz-​Rojas, R. (2006). Effects of attributing serious mental illnesses to
genetic causes on orientations to treatment. Psychiatric Services, 57, 382–​387.
Pierce, J.P., Gilpin, E.A., Emery, S.L., White, M.M., Rosbrook, B., and Berry, C. C. (1998). Has the
California tobacco control program reduced smoking? JAMA, 280, 893.
Racine, E., Waldman, S., Palmour, N., Risse, D., and Illes, J. (2007). “Currents of
hope”: neurostimulation techniques in U.S. and U.K. print media. Cambridge Quarterly of Healthcare
Ethics, 16, 312–​316.
Racine, E., Waldman, S., Rosenberg, J., and Illes, J. (2010). Contemporary neuroscience in the media.
Social Science and Medicine, 71, 725–​733.
Reavley, N.J. and Jorm, A.F. (2011). Stigmatizing attitudes towards people with mental
disorders: findings from an Australian National Survey of Mental Health Literacy and Stigma.
Australian and New Zealand Journal of Psychiatry, 45, 1086–​1093.
Reske, M. and Paulus, M.P. (2011). A neuroscientific approach to addiction: ethical issues. In: Illes,
J. and Sahakian, B. (Eds.) Oxford Handbook of Neuroethics, pp. 177–​202. Oxford: Oxford
University Press.
Robins, L.N. (1993). Vietnam veterans’ rapid recovery from heroin addiction: a fluke or normal
expectation? Addiction, 88, 1041–​1054.
Rose, G. (1992). The Strategy of Preventive Medicine. Oxford: Oxford University Press.
Rose, N.S. and Abi-​Rached, J.M. (2013). Neuro: The New Brain Sciences and the Management of the
Mind. Princeton: Princeton University Press.
Sartorius, N. (2010). Short-​lived campaigns are not enough. Nature, 468, 163–​165.
Satel, S. (1998). For addicts, force is the best medicine. Wall Street Journal, January 6.
Satel, S. (1999). The fallacies of no-​fault addiction. Public Interest, 99, 52–​67.
Satel, S. and Lilienfeld, S.O. (2013). Brainwashed: The Seductive Appeal of Mindless Neuroscience.
New York: Perseus Books Group.
Satel, S. and Lilienfeld, S.O. (2014). Addiction and the brain-​disease fallacy. Frontiers in Psychiatry,
4, 141.
Varney, S.M., Rohsenow, D.J., Dey, A.N., Myers, M.G., Zwick, W.R., and Monti, P.M. (1995). Factors
associated with help seeking and perceived dependence among cocaine users. American Journal of
Drug and Alcohol Abuse, 21, 81–​91.
Volkow, N. and Baler, R. (2014). Addiction science: uncovering neurobiological complexity.
Neuropharmacology, 76, 235–​249.’
Volkow, N.D. and Koob, G. (2015). Brain disease model of addiction: why is it so controversial? The
Lancet Psychiatry, 2, 677–​679.
514

514 Looking to the future

Volkow, N.D. and Li, T.-​K. (2004). Drug addiction: the neurobiology of behaviour gone awry. Nature
Reviews. Neuroscience, 5, 963–​970.
Volkow, N.D. and Li, T.-​K. (2005). Drugs and alcohol: treating and preventing abuse, addiction and
their medical consequences. Pharmacology & Therapeutics, 108, 3–​17.
Volkow, N.D. and Morales, M. (2015). The brain on drugs: from reward to addiction. Cell, 162,
712–​725.
Volkow, N.D., Fowler, J.S., Wang, G.J., Swanson, J.M., and Telang, F. (2007). Dopamine in drug abuse
and addiction: results of imaging studies and treatment implications. Archives of Neurology, 64,
1575–​1579.
Volkow, N.D., Fowler, J.S., Wang, G.J., Baler, R., and Telang, F. (2009). Imaging dopamine’s role in drug
abuse and addiction. Neuropharmacology, 56(Suppl. 1), 3–​8.
Volkow, N.D., Wang, G.-​J., Fowler, J.S. and Tomasi, D. (2012). Addiction circuitry in the human brain.
Annual Review of Pharmacology and Toxicology, 52, 321.
Volkow, N.D., Koob, G.F., and McLellan, A.T. (2016a). Neurobiologic advances from the brain disease
model of addiction. New England Journal of Medicine, 374, 363–​371.
Volkow, N.D., Koob, G.F., and McLellan, A.T. (2016b). Supplement to: Neurobiologic advances from
the brain disease model of addiction. New England Journal of Medicine, 374(4), 363–​371. Available
from: http://​www.nejm.org/​doi/​suppl/​10.1056/​NEJMra1511480/​suppl_​file/​nejmra1511480_​
appendix.pdf [accessed February 9, 2017].
Vrecko, S. (2010). Birth of a brain disease: science, the state and addiction neuropolitics. History of the
Human Sciences, 23, 52–​67.
Walker, M.J. (2010). Addiction and self deception: a method for self control? Journal of Applied
Philosophy, 27, 305–​319.
White, V., Hill, D., Siahpush, M. and Bobevski, I. (2003). How has the prevalence of cigarette smoking
changed among Australian adults? Trends in smoking prevalence between 1980 and 2001. Tobacco
Control, 12, ii67.
Xu, Z., Hou, B., Gao, Y., He, F. and Zhang, C. (2007). Effects of enriched environment on morphine-​
induced reward in mice. Experimental Neurology, 204, 714–​719.
 51

Chapter 26

Concussion, neuroethics, and sport:

Policies of the past do not suffice for
the future
Brad Partridge and Wayne Hall

Introduction
Concussion is a short-​term disturbance in neurological function that is the result of a
traumatic impact to the head. The term is sometimes used interchangeably with mild
traumatic brain injury (MTBI). The Concussion in Sport Group has called concussion
“a complex pathophysiological process affecting the brain, induced by traumatic biome-
chanical forces,” which reflects a “functional” disruption to the brain rather than “struc-
tural” damage (McCrory et al. 2013).
The Centers for Disease Control has estimated that up to 3.8  million sports-​related
concussions occur in the United States alone each year, but these events are significantly
under-​reported (Daneshvar et  al. 2011). It is a common injury in many body contact
sports and its prevalence in this arena has recently garnered attention because of concerns
about the possible long-​term effects of these injuries. The focus of this chapter is on con-
cussion injuries in body collision sports. It addresses ethical issues that arise in the diag-
nosis of concussion, debates about the longer-​term consequences of repeated concussion
injuries, and the design and implementation of policies that aim to prevent and manage
concussion injuries that occur in the course of sporting matches.

Concussion in football codes
Some football codes exhibit high levels of risk of concussion because they involve repeated
heavy collisions between participants who are running at speed directly at each other. The
prevalence of concussion in amateur and professional Australian Rules football (Makdissi
et al. 2009) and rugby league (Hinton-​Bayre et al. 2004) are among the highest of any con-
tact sports. At the high school and collegiate level in the United States, American football
has the highest participation rate among sports and the highest rate of concussion per
thousand playing hours (Daneshvar et al. 2011).
Concussion management policies have become a major priority worldwide for sports
that involve frequent collisions between participants because repeated head trauma has
been associated with long-​term cognitive impairments (Guskiewicz et al. 2005), mental
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516 Concussion, neuroethics, and sport

health problems (Guskiewicz et al. 2007), and some forms of neurological degeneration
(Omalu et al. 2005; McKee et al. 2009, 2013, 2014). Traumatic brain injury (TBI) is the
leading cause of death and disability among children and young adults worldwide, and
approximately one-​fifth of all TBI cases occur during sports participation.
Concussion management guidelines have been developed by a number of groups in
an effort to either prevent concussion or to improve its management. These include the
American Academy of Neurology (Giza et  al. 2013)  and Concussion in Sport Group
(McCrory et al. 2009, 2013). Although procedures for identifying concussion have been
formally implemented in many sports, clinicians are still confronted with conceptual,
empirical, and ethical uncertainty in diagnosing and managing concussion (McNamee
et al. 2016).

Challenges in diagnosis
Diagnosis can be a challenge because there is a long list of potential symptoms and signs
of concussion that reflect disruptions to normal cognition, motor functioning, or affect.
These include, for instance, amnesia, loss of balance, blurred vision, confusion, dizziness,
feeling “in a fog,” or being more emotionally labile. There is no consensus on when a
diagnosis of concussion should be made and there are no specified necessary and suf-
ficient symptoms for the diagnosis, not even the seemingly obvious loss of consciousness
(McNamee et al. 2016).
Brief diagnostic tools have been developed to identify concussion but there is no defini-
tive “concussion test” and so a concussion diagnosis always reflects a clinician’s judgment.
These conceptual uncertainties have the potential to undermine the reliability and valid-
ity of a diagnosis of the presence or absence of concussion. They also affect the validity of
epidemiological data on the prevalence of concussion in different sports, with the likeli-
hood that many cases of concussion go unrecognized.

Debates about the long-​term effects of concussion

Most cases of concussion appear to resolve themselves without the need for medical inter-
vention although there is individual variation in how long it may take for this resolution to
occur. Some symptoms may be very brief and many of the symptoms of mild concussion
will completely resolve within 7–​10 days (McCrory et al. 2013). A minority of affected
people may experience more lingering effects, such as headaches and mental fogginess
that may last for weeks, months, or even longer. Deficits in functioning on cognitive tasks
may also be evident in people with post-​concussion syndrome.
Epidemiological studies in the general population have found that self-​reported TBI
in early life or midlife increases the risk of mild forms of cognitive impairment as well as
dementia and Alzheimer’s disease later in life (Graves et al. 1990; Molgaard et al. 1990;
Salib and Hillier 1997; Guo et al. 2000; Lye & Shores 2000; Fleminger et al. 2003; Shively
et al. 2012). A history of TBI has also been associated with an earlier onset of Alzheimer’s
dementia (Nemetz et al. 1999). Systematic reviews of these studies have concluded that
 517

Debates about the long-term effects of concussion 517

there is sufficient evidence for a causal relationship between moderate to severe TBI and
Alzheimer’s and Parkinson’s-​related dementia. There is also an association between these
conditions and mild TBI when there has been a loss of consciousness (Bazarian et  al.
2009). This includes evidence from a large-​scale prospective study which found that mild
TBI was an independent risk factor for dementia (Lee et  al. 2013). Prospective cohort
studies also find that severe, moderate, and mild TBI are associated with an increased risk
of developing depression (Fann et al. 2004).
There are fewer studies of the specific risks of concussion in athletes but epidemio-
logical studies of players of collision sports have reported similar findings to the studies
of TBI in the general population. Former American footballers who have suffered three
or more concussions reported more mild cognitive impairment, memory problems, and
depression than players without such a history. Retired football players also have an ear-
lier age of onset of Alzheimer’s disease than peers in the general population (Guskiewicz
et al. 2005, 2007) and are three times more likely to die prematurely from neurodegenera-
tive diseases than the general population (Lehman et al. 2012).
The available epidemiological evidence is sufficient to justify prudential policies to
reduce the incidence of concussion in body collision sports. Instead, in the United States,
these policies have been delayed by a narrow debate on whether the cumulative effects of
repeated concussion cause a specific condition known as chronic traumatic encephalopa-
thy (CTE)—​a degenerative brain disease in which neurofibrillary tangles of tau protein
are deposited in the brain—​that was first described in boxers in the 1920s. Interest in
CTE among American footballers increased after a 2005 postmortem neuropathological
study of a former National Football League (NFL) player found evidence of the condition
(Omalu et al. 2005). Since then, several groups have reported signs of CTE in postmortem
studies of the brains of several dozen former American footballers and a smaller number
of former rugby players and wrestlers (Omalu et al. 2010; McKee et al. 2014).
People who show neuropathological evidence of CTE often reported dementia-​like
symptoms, disturbed memory and mood, increased impulsiveness and aggression, and
an increased risk of suicide (McKee et al. 2014). The prevalence of CTE in football players
and other collision sport athletes is unknown but the seriousness of the condition and
high public profile of some of its sufferers have placed the condition at the center of a con-
tentious debate in the United States that has echoes in other countries such as Australia.
The evidence for the hypothesis that repeated head trauma causes CTE comes from
postmortem evidence of the disorder in players with a history of repeated head trauma.
Proponents of the CTE hypothesis assume that the disorder is so rare and so clearly
related to repeated head trauma that these cases are sufficient to establish a causal rela-
tionship. Critics (Gardner et al. 2014) counter that there is no epidemiological evidence
that CTE is more common among football players than in the general population and no
evidence to rule out the role of factors other than concussion, such as genetic vulnerability
to dementia, alcohol and other drug use, and risky behavior outside football. The most
recent consensus statement about such injuries by the 4th International Conference on
Concussion in Sport held in Zurich, November 2012 (McCrory et al. 2013) stated that: “a
518  5

518 Concussion, neuroethics, and sport

cause and effect relationship has not as yet been demonstrated between CTE and concus-
sions or exposure to contact sports.”
Well-​designed, independent, and credible research studies are essential to decide
whether CTE is caused by repeated concussions and head injuries in athletes. But this
shortcoming in the literature on CTE should not detract attention from the larger epide-
miological literature that strongly suggests that repeated head injuries increase the risk of
cognitive impairment, depression, and dementia, whatever the underlying pathological
mechanism.

Responses to concussion from professional sporting bodies

The governing bodies of many collision sports have struggled in how to appropriately
manage concussion in the face of public controversy about the effects of repeated con-
cussions and head injuries. In 2012, a class action lawsuit against the NFL was filed on
behalf of more than 4500 former players which alleged that the NFL had:
◆ hidden and misrepresented evidence about the long-​term neurological effects of
football-​related head injuries
◆ been aware of the neurological risks of playing football but deliberately failed to warn
players
◆ funded a falsified body of scientific research that was conducted by its concussion
advisory committee with the intention of raising doubts about independent evidence
of the long-​term effects of head injuries.
After failing to have the lawsuit dismissed, the NFL settled the case before trial. This
unfortunately meant that the NFL was able to avoid admitting liability or that plain-
tiffs’ injuries were caused by football and avoided a forensic examination of their alleged
deception. The players also had good reasons to settle. The payout meant that players with
“cognitive injuries” (yet to be defined) could access compensation and funding for medi-
cal examinations sooner than if the case had gone to trial. If the case had proceeded to a
jury trial, the players may have received more money but they could also have lost and
received nothing.
In Australia, the Australian Football League (AFL) and National Rugby League (NRL)
claim that player safety and player welfare are key priorities in concussion management.
The NRL has claimed that it will do “everything possible” to ensure the game is safe for
all players (NRL 2012). The former Chief Medical Officer of the NRL has argued that
“we have to protect players from themselves” (Crawley 2014). Taken together, these state-
ments imply that these sporting bodies accept an ethical obligation to make their colli-
sion sports safer for participants and perhaps even paternalistically protect players from
injuring themselves.
There is an alternative position that collision sports have not chosen to publicly advo-
cate, namely, that adult athletes are autonomous agents who are free to participate in
collision sports, if they choose to do so, and so should accept the risks of participation
 519

Responses to concussion from professional sporting bodies 519

including concussion. If this stance were taken, then collision sports could argue that
participants play at their own risk and therefore must accept responsibility for any future
health problems that may arise (Partridge & Hall 2015).
If the “play at your own risk” stance were adopted then sporting bodies would need to
ensure that players autonomously decide whether or not to play after being fully informed
about the risks of participation. This would require (1) management of the potential for
coerced consent and the conflicts of interest among players, coaches, trainers, and doctors
that may lead them to circumvent concussion management; and, (2) full acknowledgment
and disclosure of the risks of repeated head injuries by sports governing bodies.
The implicit assumption of current management policies seems to be that the risk of
concussion cannot be eliminated from American football, rugby league, and Australian
Rules football. The goal of these policies is therefore on managing specific instances
of concussion. There are no policies to prevent players from suffering repeated head
trauma during their playing careers. This stance is arguably at odds with the professed
claims of the governing bodies of these sports that they give a high priority to protect-
ing players.
These minimalist policies have often been justified by skepticism about the claim that
concussions can cause serious long-​term neurological harm in general and CTE in par-
ticular. Sporting officials have used uncertainty about the causal relationship to delay act-
ing on their professed ethical obligation to protect players from repeated head injuries.
For instance, some medical officers employed by, and researchers with professional links
to, the AFL have described the evidence on the long-​term risks of multiple concussions as
“anecdotal” and overhyped by the media (Lane 2012, 2016). In 2012, for example, when
the Chief Medical Officer of the International Rugby Board (IRB) was asked whether
repeated concussions could cause long-​term brain damage, he responded (McDermott
and Hichens 2012):  “The answer is:  it is possible. But at the moment there is no clear
evidence—​there are some isolated cases suggesting it could—​but there is no clear evi-
dence that repeated concussions lead to long term brain damage.”
In 2014 the Director of the AFL Medical Officers Association (Dr. Hugh Seward) also
characterized evidence on the link between sports-​related concussions and brain injury
as circumstantial (Carlisle 2014).
If there was proof that repeated head trauma caused a degenerative condition such as
CTE this would be a strong reason for collision sports to implement policies to prevent
repeated head injuries. But uncertainty about whether a causal relationship between CTE
and repeated concussion has been used to delay “major changes in the play or manage-
ment of sports” (McKee et al. 2014). By avoiding acting until there is proof of causation
for CTE, sports governing bodies have ignored the epidemiological evidence that justifies
prudent measures to prevent repeated head injuries. In doing so, they have arguably failed
to honor their professed commitment to protecting the health and safety of their players.
There are probably a number of reasons for these delaying tactics, namely, that concus-
sion is seen as an inherent feature of many collision sports because many fans enjoy see-
ing fit athletes engage in bodily collisions; and that no sports administrator or fan would
520  5

520 Concussion, neuroethics, and sport

like to believe that repeated concussions can produce brain injuries because accepting
this would require major changes in the way their sports are played. As with similarly
motivated reasoning about the evidence on climate change, skepticism about the evidence
for CTE has been used to justify inaction. This may be changing. In March 2016, an NFL
executive was prepared to concede for the first time a “link between football and CTE”
(Bieler 2016)—​it remains to be seen how this change of mind will influence concussion
management in collision sports around the world.

Proposed policies to manage concussion

It is common for players of collision sports to report repeated head trauma over their
playing careers. An increasing number of players who have such a history have retired,
or been advised to retire, because their medical advisors were concerned that additional
head injuries could compromise their cognitive and mental health. Various policies have
been proposed to deal with these concerns in the popular media, academic discourse, and
by major sporting bodies in Australia and overseas.
Some examples of these proposals include:
◆ having concussion management in professional football codes overseen by indepen-
dent doctors rather than team affiliated doctors
◆ legislating to prohibit junior athletes from returning to play after concussion without
being given medical clearance
◆ the mandatory use of neuroimaging in football players who suffer a concussion
◆ genetic screening of athletes for genes implicated in the development of chronic neu-
rological problems (e.g., APOE4 allele) that may increase their risk of developing cog-
nitive impairment from head injuries
◆ mandatory “sit-​out” periods after concussion, or mandatory retirement after a speci-
fied number of concussions.
The effectiveness of these proposals is unknown and there has been little analysis of the
ethical issues raised in implementing them.

Ethical issues in current policies to manage concussion

Several major position statements on concussion management have been published in
the last 15 years by professional groups in the neurosciences (McCrory et al. 2009, 2013),
neurology (Giza et al. 2013), and sports medicine (Harmon et al. 2013). Many of these
guidelines on concussion management are regularly breached in sports at the professional
and community levels (Price et al. 2012; Partridge 2014; White et al. 2014).
A popular recommendation, adopted by many sports organizations, is that concussed
participants should be excluded from play on the day of injury—​the “concussion exclu-
sion rule” or “no same-​day return-​to-​play” rule. The concussion exclusion rule represents
a significant rule change that is specific to concussion because there are no analogous
rules that prohibit players from continuing to play after receiving any other type of injury.
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Ethical issues in current policies to manage concussion 521

For example, neither the NRL nor the AFL prohibits same-​day return to play for muscu-
loskeletal injuries.
Previously in both leagues, team doctors were only encouraged not to allow concussed
players to return to the field if they still had symptoms of concussion. It is clear that in the
past, many players who suffered concussion continued to play for the remainder of the
match even after being examined by a team doctor. Given recent concerns about the long-​
term implications of repeated head trauma, it is worrying that some former players have
reported suffering multiple concussions in the same match on several occasions during
their career (McDermott & Hichens 2012).
Efforts to improve compliance with this rule have focused on increasing awareness
of the injury and educating coaching and medical staff on how to manage it. Important
ethical and social issues pose significant barriers to the proper identification and man-
agement of concussion in many sports at the professional and community level (ama-
teurs and juniors) (Partridge 2014; Partridge & Hall 2014). Lack of awareness may
only be one reason for noncompliance with concussion guidelines. Conflicts of inter-
est between doctors, players, and teams may be a more substantial obstacle to their
adherence.
The decision to allow a concussed athlete to return to play is one of the most con-
tentious in sports medicine (Kaye & McCrory 2012). Autonomy in decision-​making,
informed consent to participate in risky activities, coercion, and competing interests of
key decision-​makers all present difficulties when diagnosing and managing concussion—​
particularly in the case of junior athletes (Dunn et al. 2007). And there is little guidance
on how key stakeholders should navigate these ethical issues.
In professional sports, the emergence of the “team doctor” (Polsky 1998)  has trans-
formed the doctor–​patient relationship into a triad:  doctor–​patient–​team (Dunn et  al.
2007). A  team’s interest in winning may conflict with the welfare of an injured player
when decisions are made about whether he is fit to play after injury. These issues are not
confined to professional sport: they may present even greater difficulties in community
level sport where other key stakeholders (e.g., coaches, parents) also have a duty of care
toward junior athletes (Gilbert & Johnson 2011).
Severe concussion usually renders a player unable to continue playing but footballers
may recover from many of the symptoms of milder cases during a match. Without a “con-
cussion exclusion rule” these players have been allowed to stay on, or go back onto the
field, and play at the risk of incurring further injury and complications. Some coaches
may not want a player to continue after suffering a concussion, but there are examples of
coaches allowing players to continue playing despite suspected concussion. In some cases,
it may be in the team’s interests of winning to prevent a potentially concussed player from
being assessed (e.g., if there are no other substitute players available), if the match is very
close, or if a particularly important team player is involved.
In surveys, sports physicians often report pressure from coaches (and injured players)
to clear the injured players for a rapid return to play despite the risks to their welfare
(Anderson & Gerrard 2005; Price et al. 2012). For example, Anderson and Gerrard (2005)
52  5

522 Concussion, neuroethics, and sport

interviewed sports physicians in New Zealand and found that conflicts of interest were
one of the ethical issues team doctors had the most trouble managing.
Team doctors also report pressure from coaches to return concussed players to the field
on the same day. The implementation of a concussion exclusion rule would reduce this
pressure because it would require players to remain on the sideline for the remainder of
the match after receiving a diagnosis of concussion. However, this rule could affect team
doctors’ clinical decisions as to whether a played has been concussed. A revealing insight
into these tensions was given by a rugby league team doctor early in 2012 on the British
Journal of Sports Medicine blog after the Australian NRL instigated a “concussion exclu-
sion rule” (see Box 26.1) (Orchard 2012).
In this case, the team coaching staff prioritized team goals over player health by tell-
ing the doctor that if he “didn’t examine the player, then the rules would allow him to
continue.” In practice, a team doctor could be prevented from examining a potentially
concussed player if the sports trainer who initially assesses the player fails to refer him to
a doctor at a coach’s direction. The attitude of the coaching staff described in the blog post
describes this situation.
The first point in Box 26.1 describes the tension created between the team doctors, the
team, and the NRL by the concussion guideline. When the doctor says that “I am going
to be pulling players out of the game who I have been comfortable letting continue for

Box 26.1  BJSM Blog post by a NRL team doctor

I told the coaching and training staff that the new official rule was that if I examined a
player and determined that he had been concussed that day that, under the new rules,
I couldn’t let him return to the field and the club couldn’t overrule me. However, it was
quickly pointed out, if I didn’t examine the player, then the rules would allow him to
continue. I think everyone can see where this is heading. I am either going to be put in
one of the 3 uncomfortable positions very soon:
1. That I am going to be pulling players out of the game who I have been comfort-
able letting continue for many years, and possibly hurting our team’s chances of
winning games.
2. That I am going to turn a blind eye and not examine or fully assess a player who
looks as though he is fit to continue.
3. That I am going to re-​name something I used to call “mild transient concussion”
something different like “traumatic migraine” so the player can be allowed to con-
tinue, even though deep down I think that the player has probably had a very mild
concussion that has quickly recovered.
Reproduced with permission from Orchard, J. ‘Concussion: how do we reconcile risk-​averse policies with risk-​
taking sports?’ BJSM Blog. Retrieved May 14, 2016 from http://​blogs.bmj.com/​bjsm/​2012/​03/​15/​concussion-​
how-​do-​we-​reconcile-​risk-​averse-​policies-​with-​risk-​taking-​sports/​, Copyright © 2012 The British Medical Journal
Publishing Group.
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Ethical issues in current policies to manage concussion 523

many years,” he refers to the previous policy of allowing concussed players to continue
playing, if their symptoms had resolved. Under the most recent guidelines, the NRL has
taken this clinical judgment out of the hands of team doctors. While this may accord
with the views of some sports physicians, others may see it as an unwelcome intrusion
into their clinical practice that reflects a lack of confidence in their management of their
players. Concussion can sometimes be difficult to identify and there is still uncertainty
about the threshold for diagnosing concussion, but the team doctor in Box 26.1 was aware
that the concussion exclusion rule may “hurt our team’s chances of winning” and so felt
uncomfortable.
The second point raised in Box 26.1 is the worrying possibility that team doctors may
avoid assessing players if a diagnosis of concussion may hurt their team’s chances of win-
ning. If this happens, then concussed players could be put at risk of further injuries—​the
very outcome the guidelines were intended to prevent.
The third point in Box 26.1 is that team doctors may re-​label concussion as “being
dazed” or “traumatic migraine” to enable a concussed player to continue playing.
This runs the serious risk of delaying appropriate and timely treatment of concussion.
Furthermore, because their injury would not be recorded as a concussion, the footballer
would not be included in prospective epidemiological studies of how concussed players
fare. Good data about the long-​term consequences of concussion is essential for better
management. Ironically, before the “concussion exclusion rule” there was less pressure to
re-​label concussion as something more benign because concussed players whose symp-
toms had resolved were permitted to continue (Orchard 2012).
Important questions remain about how to implement concussion management guide-
lines in ways that avoid nonadherence by team doctors. These questions include the
following:
◆ What are the implications of concussion management guidelines for autonomy in
decision-​making by athletes, clinicians, parents, and coaches?
◆ How is decision-​making about concussion affected by coercive influences to continue
playing exerted on athletes by coaches, clinicians, parents and other stakeholders?
◆ How do we reconcile the competing ethical obligations among athletes, coaches, and cli-
nicians when making decisions about the diagnosis and management of concussion?
◆ Does simply informing athletes (or parents of junior athletes) about the short-​and
long-​term risks of suffering concussion make the athlete (or parent) responsible for any
future adverse health outcomes?
◆ Is there still a moral obligation on team doctors or sports governing bodies to prescribe
how concussions must be managed, and to make paternalistic decisions for athletes in
their own best interests in some cases?
◆ Can athletes (or parents of junior athletes) give full and informed consent in accepting
the risks of participating in sports with high rates of concussion when the evidence
about the long-​term harms of such injuries is incomplete?
524  5

524 Concussion, neuroethics, and sport

◆ How can emerging neurotechnologies (e.g., neuro-​and psychological diagnostic tests)

be ethically incorporated into concussion management guidelines?
◆ What issues are raised by financial links between concussion experts (clinicians and
researchers) and professional sporting bodies with high rates of concussion?
◆ How do competing interests among concussion policymakers and commercial entities
affect the independence of concussion management guidelines?

Ethical, social, and policy implications of emerging

neurotechnologies
Neuroscience promises to provide superior ways to diagnose and treat concussion that
may be incorporated into future concussion management guidelines. This desirable goal
will need to be achieved in ways that address the ethical, social, and policy impacts of
proposed concussion management strategies.
Issues of conflict of interest are raised by a burgeoning market (what is now known as
“Concussion Inc.”) for neurogadgets, tests, devices, and other tools that claim to diagnose
concussion, protect athletes from concussion, monitor the cognitive/​neurological effects
of concussion, and enable team doctors to make decisions about an athlete’s fitness to
return to play.
Over the last decade, a number of companies have marketed computerized products
that they claim can assess the neuropsychological (NP) effects of concussion and assist
physicians to manage these problems. These products include ImPACT, and CogState/​
Axon. A  series of global protocols for dealing with sports-​related concussions—​the
Consensus Statements on Concussion in Sport (Aubry et al. 2002; McCrory et al. 2005,
2009, 2013)—​have recommended that organized sports should make use of computerized
NP tests to protect athletes.
In 2011, for example, the AFL and NRL adopted concussion policies that were based on
the Consensus Statements. These policies made it compulsory for teams to use computer-
ized NP tests when determining if a concussed athlete has recovered from their injury
and can safely return to play. Players were required to undertake a pre-​concussion assess-
ment (e.g., at the start of a football season) so that post-​concussion functioning could be
compared to the athlete’s “baseline” functioning. These tests were first sold to professional
teams but are increasingly being used by amateur and youth participants in contact sport
across the globe (often funded by sports sponsors). In Australia, the AFL and NRL both
specifically mandated the use of the CogState product, and in a 2012 letter to the Medical
Journal of Australia, the Chief Medical Officer of the NRL at the time stressed the central
role that this test played: “[Concussed] players are not allowed to return to training until
they are asymptomatic and their results have returned to baseline on CogState testing”
(Muratore 2012).
The prominent role played by these tests in professional sports can be linked to the posi-
tion statements on concussion—​otherwise called the Consensus Statements—​published
 52

Ethical, social, and policy implications of emerging neurotechnologies 525

by the self-​appointed Concussion in Sport Group some of whose members have serious
ethical issues of conflicts of interest.
First, the companies that market these tools, particularly ImPACT and CogState, have
funded or undertaken many of the studies that have been published in the academic lit-
erature in support of the clinical utility of their products. Often these studies have been
coauthored by owners or employees of the company, by researchers who have received
research funding from the company, or by consultants to the company. Second, some of
these researchers have been authors of the guidelines recommending the routine use of
these tests. In the Consensus Statements on Concussion in Sport that have supported NP
testing:
◆ only industry-​funded studies were cited in support of the value of NP tests for
concussion
◆ the industry funding of these studies was not disclosed in the consensus document
◆ some panel members have had direct links to the companies that own these NP tests
but these links have not always been declared
◆ these documents do not cite research undertaken by independent researchers that
raise doubts about the reliability and utility of these NP tests.
Some of the authors of the Consensus Statements who have links to NP testing companies
have advised professional sporting leagues in the United States and Australia to adopt
these tests. These leagues have subsequently mandated the use of these NP tests for all
players—​most notably, the NFL, the AFL, and, the NRL.
Major conflicts of interest arise when recommendations are made by a panel that
includes members with financial and professional links to companies that sell computer-
ized NP tests for concussion management. Without regulations to declare and manage
conflicts of interest, it may be difficult to ascertain when special interests have improperly
influenced a decision. Could we be confident that a panel without any links to the com-
panies that market computerized NP tests would have made the same recommendations?
A major concern about their reliance on evidence from industry-​linked research is
that companies may simply not report studies that fail to support their products, as has
happened in the past with the reporting of clinical trials by pharmaceutical companies.
For example, systematic reviews that have compared neutrally sponsored drug trials with
those sponsored by the pharmaceutical industry have found that the latter are much more
likely to favor the company’s product (Lexchin et al. 2003). Investigator bias may be even
more likely when the investigators include owners and employees of the company.
Industry funding may also determine the questions that are asked and answered, often
with the future marketing of the product in mind. This may bias the literature toward
publication of results that are favorable to the funder’s product, again as has been noted in
the pharmaceutical field with selective publication of the results of clinical trials. The fact
that the Consensus Statements relied on industry-​sponsored evaluations of NP testing
raises concerns that recommendations to use particular products have not been based on
an unbiased appraisal of the evidence. The same concerns apply when sporting leagues
526  5

526 Concussion, neuroethics, and sport

establish their own concussion advisory groups whose members have links to computer-
ized NP testing companies. How can sports governing bodies be sure that they received
unbiased advice about the use of these products?
If independent assessment of these tests support the claims made by their designers,
then no harm will have been done. But if these tests are not as useful in evaluating and
managing concussion as their proponents claim, then athletes could be mistakenly diag-
nosed as “fit” to return to play and suffer additional concussions that produce longer-​
lasting forms of cognitive impairment.
In 2013, Resch and colleagues published a review of computerized NP tests for con-
cussion including the ImPACT and CogState tools (Resch et al. 2013). They concluded
that:  “Although many of the studies reviewed demonstrate suboptimal reliability and
validity, computerized testing is widely used in concussion management at all competi-
tive levels … development, marketing and sales appear to have outpaced the clinical
evidence base.”
A high priority should be given to developing evidence-​informed policies to manage
concussions in sports. This should be done in ways that reduce the potential effects of
conflicts of interest when those who design these tests make recommendations about
their use and can by virtue of their positions also control the research that evaluates their
effectiveness in reducing concussion.

Conclusion
Ethical issues can be important obstacles in the proper identification and manage-
ment of concussion in sport. And yet despite the proliferation of published concus-
sion management guidelines by professional groups over the last decade, there has
been little guidance for stakeholders in how to navigate and resolve many of these
issues. In the past, concussions in collision sports were often overlooked by players,
coaches, team doctors, fans, and administrators. Describing a concussed player as
having “gone to Disneyland” or “having their bell rung” reflects how concussion
has often been spoken about in a nonserious way that downplays the potentially
serious nature of the injury. The legacy of past policies and attitudes is a culture
within many sports that sees concussion as a trivial injury, with participants who
succumb to concussion being viewed as weak or not team players. In the past it
was not uncommon for coaches, doctors, teammates, and the players themselves to
continue playing after a concussion if it were physically possible—​a stark contrast
to the “no same-​d ay return-​to-​play” policy adopted by many sports today. Despite
increasing evidence that repeated concussions are associated with long-​term cogni-
tive and neurological sequelae, this legacy is not easily erased. Participants com-
monly encounter covert and overt forms of coercion to continue playing after a
concussion at all levels of competition. What is best for the concussed player (sit-
ting out) may not be what is best for the team (winning). In professional sports in
particular, the lucrative rewards on offer mean that players, coaches, team doctors,
 527

References 527

and sports governing bodies may find that they have competing loyalties when it
comes to concussion management. These conflicts of interest have often been over-
looked or tolerated, and vigilance is required to ensure that conflicts of interest do
not undermine the health and welfare of athletes. Sporting leagues would do well to
explore managing some of these issues through the use of independent doctors who
are not affiliated with particular teams.
Experts in sports medicine, neurology, and the neurosciences may also find they have
conflicts of interest when it comes to concussion. The need to find better ways of identi-
fying and managing concussion has presented a large commercial opportunity for clini-
cians and researchers, and led to a preponderance of neurogadgets aiming to address
these issues. But we need to ensure that in the pursuit of commercial opportunity, the
marketing of these products does not outpace the evidence for their utility, reliability, and
validity. Furthermore, there are professionally lucrative opportunities to consult for, or
conduct research for, multimillion (or multibillion)-​dollar sports leagues. Clinicians and
researchers should ensure that they properly disclose these affiliations when publishing
work in the area or treating athletes.

Acknowledgments
Sincere thanks to Sarah Yeates for her assistance in formatting this chapter.

References
Anderson, L.C. and Gerrard, D.F. (2005). Ethical issues concerning New Zealand sports doctors.
Journal of Medical Ethics, 31(2), 88–​92.
Aubry, M., Cantu, R., Dvorak, J., et al. (2002). Summary and agreement statement of the first
International Conference on Concussion in Sport, Vienna 2001. British Journal of Sports Medicine,
36(1), 6–​7.
Bazarian, J.J., Cernak, I., Noble-​Haeusslein, L., Potolicchio, S., and Temkin, N. (2009). Long-​term
neurologic outcomes after traumatic brain injury. Journal of Head Trauma Rehabilitation, 24(6),
439–​451.
Bieler, D. (2016, March 14). In stunning admission, NFL official affirms link between football and CTE.
Washington Post. Available from: https://​www.washingtonpost.com/​news/​early-​lead/​wp/​2016/​03/​14/​
in-​stunning-​admission-​nfl-​official-​affirms-​link-​between-​football-​and-​cte/​ [accessed May 14, 2016].
Carlisle, W. (2014, June 22). Concussion games. ABC Radio National Background Briefing. Available
from: http://​www.abc.net.au/​radionational/​programs/​backgroundbriefing/​-​v2/​5497562#transcript
[accessed May 14, 2016].
Crawley, P. (2014, March 13). Wake-​up call: rugby league concussion culture “has to change” says
head doctor. The Daily Telegraph. Available from: http://​www.dailytelegraph.com.au/​sport/​nrl/​
wakeup-​call-​rugby-​league-​concussion-​culture-​has-​to-​change-​says-​head-​doctor/​story-​fni3fbgz-​
1226852942110 [accessed May 14, 2016].
Daneshvar, D.H., Nowinski, C.J., McKee, A.C., and Cantu, R.C. (2011). The epidemiology of sport-​
related concussion. Clinics in Sports Medicine, 30(1), 1–​17.
Dunn, W.R., George, M.S., Churchill, L., and Spindler, K.P. (2007). Ethics in sports medicine.
American Journal of Sports Medicine, 35(5), 840–​844.
528  5

528 Concussion, neuroethics, and sport

Fann, J.R., Burington, B., Leonetti, A., Jaffe, K., Katon, W.J., and Thompson, R.S. (2004). Psychiatric
illness following traumatic brain injury in an adult health maintenance organization population.
Archives of General Psychiatry, 61(1), 53–​61.
Fleminger, S., Oliver, D.L., Lovestone, S., Rabe-​Hesketh, S., and Giora, A. (2003). Head injury as a risk
factor for Alzheimer’s disease: the evidence 10 years on; a partial replication. Journal of Neurology,
Neurosurgery and Psychiatry, 74(7), 857–​862.
Gardner, A., Iverson, G.L., and McCrory, P. (2014). Chronic traumatic encephalopathy in sport: a
systematic review. British Journal of Sports Medicine, 48(2), 84–​90.
Gilbert, F. and Johnson, L.S.M. (2011). The impact of American tackle football-​related concussion in
youth athletes. AJOB Neuroscience, 2(4), 48–​59.
Giza, C.C., Kutcher, J.S., Ashwal, S., et al. (2013). Summary of evidence-​based guideline
update: evaluation and management of concussion in sports: report of the Guideline
Development Subcommittee of the American Academy of Neurology. Neurology, 80(24),
2250–​2257.
Graves, A.B., White, E., Koepsell, T.D., et al. (1990). The association between head trauma and
Alzheimer’s disease. American Journal of Epidemiology, 131(3), 491–​501.
Guo, Z., Cupples, L.A., Kurz, A., et al. (2000). Head injury and the risk of AD in the MIRAGE study.
Neurology, 54(6), 1316–​1323.
Guskiewicz, K.M., Marshall, S.W., Bailes, J., et al. (2005). Association between recurrent concussion
and late-​life cognitive impairment in retired professional football players. Neurosurgery, 57(4),
719–​726.
Guskiewicz, K.M., Marshall, S.W., Bailes, J., et al. (2007). Recurrent concussion and risk of depression
in retired professional football players. Medicine and Science in Sports and Exercise, 39(6), 903–​909.
Harmon, K.G., Drezner, J.A., Gammons, M., et al. (2013). American Medical Society for Sports
Medicine position statement: concussion in sport. British Journal of Sports Medicine, 47(1), 15–​26.
Hinton-​Bayre, A.D., Geffen, G., and Friis, P. (2004). Presentation and mechanisms of concussion in
professional rugby league football. Journal of Science and Medicine in Sport, 7(3), 400–​404.
Kaye, A.H. and McCrory, P. (2012). Does football cause brain damage? Medical Journal of Australia,
196(9), 547–​549.
Lane, S. (2012). US Concussion Study May Not Apply to AFL: Doctor. Available from: http://​www.smh.
com.au/​afl/​afl-​news/​us-​concussion-​study-​may-​not-​apply-​to-​afl-​doctor-​20120603-​1zq6h.html
[accessed May 14, 2016].
Lane, S. (2016). Concussion Problem Overblown: AFL Expert Paul McCrory. Available from: http://​www.
theage.com.au/​afl/​afl-​news/​nfl-​concussion-​problem-​overblown-​afl-​expert-​paul-​mccrory-​20160406-​
go0ctx.html#ixzz45CM8W9VA [accessed May 14, 2016].
Lee, Y.K., Hou, S.W., Lee, C.C., Hsu, C.Y., Huang, Y.S., and Su, Y.C. (2013). Increased risk of dementia
in patients with mild traumatic brain injury: a nationwide cohort study. PloS One, 8(5), e62422.
Lehman, E.J., Hein, M.J., Baron, S.L., and Gersic, C.M. (2012). Neurodegenerative causes of death
among retired National Football League players. Neurology, 79(19), 1970–​1974.
Lexchin, J., Bero, L.A., Djulbegovic, B., and Clark, O. (2003). Pharmaceutical industry sponsorship
and research outcome and quality: systematic review. BMJ (Clinical Research Ed.), 326(7400),
1167–​1170.
Lye, T.C. and Shores, E.A. (2000). Traumatic brain injury as a risk factor for Alzheimer’s disease: a
review. Neuropsychology Review, 10(2), 115–​129.
Makdissi, M., McCrory, P., Ugoni, A., Darby, D., and Brukner, P. (2009). A prospective study of
postconcussive outcomes after return to play in Australian football. American Journal of Sports
Medicine, 37(5), 877–​883.
 529

References 529

McCrory, P., Johnston, K.M., Meeuwisse, W., et al. (2005). Summary and agreement statement of
the 2nd International Conference on Concussion in Sport, Prague 2004. British Journal of Sports
Medicine, 39(4), 196–​204.
McCrory, P., Meeuwisse, W., Johnston, K.M., Dvorak, J., Aubry, M., Molloy, M., and Cantu, R. (2009).
Consensus Statement on Concussion in Sport: the 3rd International Conference on Concussion in
Sport held in Zurich, November 2008. British Journal of Sports Medicine, 43(Suppl 1), i76-​i84.
McCrory, P., Meeuwisse, W.H., Aubry, M., et al. (2013). Consensus Statement on Concussion in
Sport: the 4th International Conference on Concussion in Sport held in Zurich, November 2012.
British Journal of Sports Medicine, 47(5), 250–​258.
McDermott, Q. and Hichens, C. (2012, May 14). Hard knocks. ABC TV Four Corners. Available
from: http://​www.abc.net.au/​4corners/​stories/​2012/​05/​10/​3499950.htm [accessed May 14, 2016].
McKee, A.C., Cantu, R.C., Nowinski, C.J., et al. (2009). Chronic traumatic encephalopathy in
athletes: progressive tauopathy after repetitive head injury. Journal of Neuropathology and
Experimental Neurology, 68(7), 709–​735.
McKee, A.C., Stein, T.D., Nowinski, C.J., et al. (2013). The spectrum of disease in chronic traumatic
encephalopathy. Brain, 136(1), 43–​64.
McKee, A.C., Daneshvar, D.H., Alvarez, V.E., and Stein, T.D. (2014). The neuropathology of sport. Acta
Neuropathologica, 127(1), 29–​51.
McNamee, M.J., Partridge, B., and Anderson, L. (2016). Concussion ethics and sports medicine. Clinics
in Sports Medicine, 35(2), 257–​267.
Molgaard, C.A., Stanford, E.P., Morton, D.J., et al. (1990). Epidemiology of head trauma and
neurocognitive impairment in a multi-​ethnic population. Neuroepidemiology, 9(5), 233–​242.
Muratore, R. (2012). The need to tackle concussion in Australian football codes. Medical Journal of
Australia, 197(3), 146.
Nemetz, P.N., Leibson, C., Naessens, J.M., et al. (1999). Traumatic brain injury and time to onset of
Alzheimer’s disease: a population-​based study. American Journal of Epidemiology, 149(1), 32–​40.
NRL (2012). NRL Mailbox: Player Safety and Concussions. Available from: http://​www.nrl.com/​nrl-​
mailbox-​player-​safety-​and-​concussions/​tabid/​10874/​newsid/​66477/​default.aspx [accessed May
14, 2016].
Omalu, B.I., Dekosky, S.T., Minster, R.L., Kamboh, M.I., Hamilton, R.L., and Wecht, C.H. (2005).
Chronic traumatic encephalopathy in a National Football League player. Neurosurgery, 57(1), 128–​
134; discussion 128–​134.
Omalu, B.I., Hamilton, R.L., Kamboh, M.I., Dekosky, S.T., and Bailes, J. (2010). Chronic traumatic
encephalopathy (CTE) in a National Football League Player: Case report and emerging medicolegal
practice questions. Journal of Forensic Nursing, 6(1), 40–​46.
Orchard, J. (2012). Concussion: how do we reconcile risk-​averse policies with risk-​taking sports? BJSM
Blog. Available from: http://​blogs.bmj.com/​bjsm/​2012/​03/​15/​concussion-​how-​do-​we-​reconcile-​risk-​
averse-​policies-​with-​risk-​taking-​sports/​ [accessed May 14, 2016].
Partridge, B. (2014). Dazed and confused: sports medicine, conflicts of interest, and concussion
management. Journal of Bioethical Inquiry, 11(1), 65–​74.
Partridge, B. and Hall, W. (2014). Conflicts of interest in recommendations to use computerized
neuropsychological tests to manage concussion in professional football codes. Neuroethics,
7(1), 63–​74.
Partridge, B. and Hall, W. (2015). Repeated head injuries in Australia’s collision sports highlight ethical
and evidential gaps in concussion management policies. Neuroethics, 8(1), 39–​45.
Polsky, S. (1998). Winning medicine: professional sports team doctors’ conflicts of interest. Journal of
Contemporary Health Law and Policy, 14(2), 503–​529.
530

530 Concussion, neuroethics, and sport

Price, J., Malliaras, P., and Hudson, Z. (2012). Current practices in determining return to play following
head injury in professional football in the UK. British Journal of Sports Medicine, 46(14), 1000–​1003.
Resch, J.E., McCrea, M.A., and Cullum, C.M. (2013). Computerized neurocognitive testing in the
management of sport-​related concussion: an update. Neuropsychology Review, 23(4), 335–​349.
Salib, E. and Hillier, V. (1997). Head injury and the risk of Alzheimer’s disease: a case control study.
International Journal of Geriatric Psychiatry, 12(3), 363–​368.
Shively, S., Scher, A.I., Perl, D.P., and Diaz-​Arrastia, R. (2012). Dementia resulting from traumatic
brain injury: what is the pathology? Archives of Neurology, 69(10), 1245–​1251.
White, P.E., Newton, J.D., Makdissi, M., et al. (2014). Knowledge about sports-​related concussion: is
the message getting through to coaches and trainers? British Journal of Sports Medicine, 48(2),
119–​124.
 531

Chapter 27

Security threat versus aggregated

truths: Ethical issues in the use of
neuroscience and neurotechnology for
national security
Michael N. Tennison, James Giordano,
and Jonathan D. Moreno

History

Introduction
The historical relationship between the brain and military spans many cultures, conti-
nents, and centuries. From the age-​old use of stimulants, depressants, intoxicants, and
hallucinogens—​including cannabis, coca, cocaine, and others—​to today’s pharmaceuti-
cals and sophisticated brain–​machine interfaces (BMIs), humankind has long studied and
altered neurological functions to enhance mental and physical performance in warfare.
Some of the same pharmacological and electronic neuroengineering breakthroughs that
are being developed for use in medicine, including military medicine to treat neurologi-
cal and psychiatric wounds of war, can also be employed within dual-​use initiatives to
facilitate or augment warfighter capabilities, or both. Additionally, in the United States at
least, security agencies are increasingly addressing ways to leverage findings from neu-
roscience to enhance intelligence operations, including the acquisition, analysis, and use
of diverse types and levels of information (Strategic Multilayer Assessment Group 2014,
2015; Giordano & Wurzman 2016).
Despite numerous success stories and persistently high hopes for the ways that brain
science can be used in national security and intelligence operations, fundamental ten-
sions between the goals of science and security riddle the history of US military and
intelligence neuroscience research with case studies in ethics, law, and policy. Whereas
national security relies on secrecy to maximize strategic, technological surprise, science
is an inherently public enterprise characterized by transparency and peer review. Security
agencies, moreover, focus on the ever-​present immediacy of security threats, while sci-
ence slowly tests and aggregates truths over time. History shows that an unfortunate
result of these conflicts of values can manifest as unethical experimentation on human
532  5

532 Security threat versus aggregated truths

subjects and the deployment of technologies before being scientifically and ethically vali-
dated as safe and effective. And yet, as described by the Collingridge dilemma, the prac-
tical and ethical consequences of technological innovation may be unpredictable until
widely deployed; by then, however, it may be too late to put the proverbial genie back in
the bottle (Collingridge 1980).
The dual-​use nature of national security neuroscience applications represents a funda-
mental tension in the science–​security relationship. In the context of scientific research
and the development and deployment of technology, scholars and policymakers use the
term “dual-​use” to refer to two separate, but interrelated, dichotomies. One meaning indi-
cates that the research and/​or use of a given technology may be intended to achieve either
benevolent or malevolent ends, whereas the second refers to science and technology with
both military and civilian uses (Evans 2014). Ongoing work, in both the United States
and the European Union, addresses the historical uses of the term “dual-​use” in order to
clarify its meaning and implications.
Numerous science and technological developments for medical and other civilian uses
have been adopted and incorporated for security and defense purposes (e.g., chemical and
biological agents, among others). Moreover, under what is referred to as reverse dual-​use,
many innovations used and taken for granted in civilian medicine—​and daily life—​have
trickled down from, or were developed in pursuit of, military applications (e.g., ther-
mographic medical imaging and the Internet). With increasing momentum of the brain
sciences, and growing interest in and dedication to the use of neurocognitive science for
national security purposes, researchers, regardless of nationality, should be aware of both
explicit dual-​use research of concern (DURC), and the potential for any brain science to
be viable and of value to security and defense agendas.
How should these tensions be managed and by whom? A 2003 Nature editorial admon-
ished applied neuroscientists to consider the intentions of their military funders and to
speak out (Editorial 2003). Does the “silence of the neuroengineers” that the editorial
alleged persist? Recently, a concerned group of neuroscientists developed a document to
establish a pledge to proscribe active participation in brain research that is explicitly to be
used for military purposes (Bell 2014).
But can the goals that stand behind such a pledge be realized? After all, any published
research could be utilized to develop information, techniques, and methods in military
settings and operations. A study published in 2015 suggests that neuroscientists are far
more likely to consider their colleagues’ work of dual-​use potential than their own (Kosal
& Huang 2015). Ethical, legal, and social analysis of the science–​security partnership
receives scant attention in the academic world and government bureaucracy, allowing the
military–​and intelligence–​industrial complex to churn along largely unfettered by the
concerns that make national security and neuroscience a prime target for neuroethical
critique. Perhaps a first question is: How did we get here?
Since the mid-​nineteenth century, government agencies and advisory bodies have been
periodically created to assess and direct science and technology policy issues as they
relate to military operations and national security. In the United States, President Lincoln
 53

History 533

established the National Academy of Sciences to advise the Union on weapons purchasing,
among other pressing technological issues. During World War I, the National Research
Council was formed in an attempt to apply civilian science to the preparation for and
waging of war. At that time, however, the military was reluctant to integrate findings from
the academy. World War II marked the transition of US foreign policy from isolation-
ism to a garrison state, a nation perennially militarized and engaged in conflict (Lasswell
1941). In 1945 the US presidential science advisor Vannevar Bush informed President
Harry S. Truman that science represented an essential component of US national defense,
one that the government must support, stating:  “it has become clear beyond all doubt
that scientific research is absolutely essential to national security” (Bush 1945). Bush went
on to cite the critical advantages provided by radar and then-​secret anti-​rocket devices.
Only a few months later, his point was bolstered by the results of the Manhattan Engineer
District, popularly known as the Manhattan Project, that caused the Japanese Imperial
Government to sue for peace. Implicit in Bush’s description of science as “an endless fron-
tier” was its dual-​use nature, crucial for civilian as well as military purposes. Notably,
in charging the former provost of the Massachusetts Institute of Technology (MIT) to
prepare his report, US President Franklin Delano Roosevelt wrote in 1944 that “[n]‌ew
frontiers of the mind are before us” (Roosevelt 1944).
Ever since the outset of the Cold War, US national security policy has called for techno-
logical superiority over all adversaries, not merely parity. In 1950, the National Security
Council officially recognized the importance of the science–​security partnership, declar-
ing:  “it is mandatory that in building up our strength, we enlarge upon our technical
superiority by an accelerated exploitation of the scientific potential of the Unites States
and our allies” (Nitze 1950). Following this recognition of the importance of innova-
tion and technological surprise, a full-​fledged military–​academic complex emerged
and remains an essential element of today’s university funding portfolio. Reacting to
the Soviet Union’s launch of Sputnik, the first Earth-​orbiting satellite, in 1958 President
Dwight Eisenhower founded the Advanced Research Projects Agency (now known as
the Defense Advanced Research Projects Agency (DARPA); one of a number of such
ARPAs), tasked with the development of rockets and weather satellites among its first
projects. DARPA’s mission was and remains that of “keeping the United States out front
when it comes to cultivating breakthrough technologies for national security rather than
in a position of catching up to strategically important innovations and achievements of
others” (DARPA 2016).
DARPA’s most celebrated achievement, the development of the Internet, is proving
useful in various BMI projects and integrating head-​mounted displays to web-​access
for augmented reality. Since at least the early 2000s, DARPA has contracted with many
university-​and medical school-​based neuroscientists to pursue projects of interest.
According to one estimate, by fiscal year 2011 DARPA was funding at least $240 million
USD in cognitive neuroscience studies (Kosal, quoted in Moreno 2012, p.53). In 2014, the
presidential administration proposed to double, in fiscal year 2015, the $100 million USD
federal investment in DARPA, the National Institutes of Health, and the National Science
534  5

534 Security threat versus aggregated truths

Foundation, key participants in the federal Brain Research through Advancing Innovative
Neurotechnologies (BRAIN) Initiative® (White House 2014).
Although DARPA has played a significant role in development and testing of innova-
tive neuroscience techniques and technologies that can be translated into both military
and civilian use, other US military agencies have also been, and are increasingly engaged
in brain research. The Office of Naval Research (ONR) has sponsored a number of proj-
ects that have focused on enhancing warfighter performance. Through such work, ONR
seeks to “[e]‌nhance individual and team decision-​making and combat effectiveness” by
optimizing biological efficiency and performance (Office of Naval Research: Science &
Technology n.d. a). Additionally, the agency’s Computational Neuroscience Program
supports the development of neurologically inspired microcircuitry (Office of Naval
Research:  Science & Technology n.d. b). Replicating in silico the structural and func-
tional bases of the algorithmic computations of the brain could enhance the scientific
understanding of the relationship between brain and cognition. In addition, the US
Department of Defense directly engages brain research through broad-​agency announce-
ments and contracts that solicit university-​based projects. For example, in 2003, MIT
received $500  million USD and Johns Hopkins University was awarded approximately
$300 million USD in Department of Defense grants and contracts. Of course, not all of
these efforts have proven to be fruitful. One especially colorful effort by the US Army in
the 1980s involved an attempt to determine whether extrasensory perception and psy-
chokinesis could aid in the training of “warrior monks” who could “remotely view” sites
without ever having been physically present in them or seen them in images, and even
cause animals to collapse at will (Druckhman & Swets 1988).
More sober efforts have been reflected in advisory reports from the National Research
Council commissioned by agencies including the Army and the Defense Intelligence
Agency during the early 2000s (National Research Council 2008; National Research
Council (US) Committee on Opportunities in Neuroscience for Future Army Applications
2009). These reports included recommendations for the military and intelligence com-
munity to identify and pursue neurotechnologies that could be developed for opera-
tional use. This was prescient, for while a 2008 US National Academies Report, Emerging
Cognitive Neuroscience and Related Technologies, was somewhat cautious in its view of the
operational utility of brain science, subsequent reports, including a number of Pentagon
white papers, have acknowledged that neuroscientific techniques and technologies have
high potential for operational use in a variety of security, defense, and intelligence enter-
prises (Air Force Studies Board, 2008; Strategic Multilayer Assessment Group 2010, 2012a,
2012b, 2012c, 2013, 2015). These papers also advocated the need to address current and
near-​term ethical, legal, and social issues (ELSI) generated by such use. A  subsequent
report by the National Academies in 2014, Emerging and Readily Available Technologies
and National Security:  A  Framework for Addressing Ethical, Legal, and Societal Issues,
reflected this view, and the importance of ethical engagement (Chameau et al. 2014). At
present, operationally viable products of brain science include microbiological agents,
toxins, drugs, and devices (Wurzman & Giordano 2014). Certain microbiological agents,
 53

History 535

toxins, and chemicals are regulated and restricted by international policies, conven-
tions, and treaties, such as DURC policies, and the Biological and Toxin and Weapons
Convention (BTWC), and Chemical Weapons Convention (CWC). Therefore, this chap-
ter will focus upon research and use of drugs and devices that are not constrained by
these regulations, and which have been, and remain viable for use in defense and security
initiatives on an international scale.

Enhancement/​therapy
Drugs
Warfighters have long used myriad substances both to fortify performance of military
tasks and to cope with the horrors of war. Alertness, wakefulness, and focus—​key decision-​
making capacities of a warfighter—​have been enhanced for centuries. An ephedrine-​
containing herb stimulated the senses of guards on China’s Great Wall, just as coca leaves
did for Incan fighters. Bavarian soldiers received cocaine from their officers, and amphet-
amines have been used by warfighters since World War II (Moreno 2012). Referred to as
“go pills,” amphetamines came to the attention of the public in 2003 when US Air National
Guard pilots, allegedly enhanced by go pills, accidentally bombed Canadian troops in
Afghanistan (Shanker & Duenwald 2003).
Warfighters have even used hallucinogens and intoxicating combinations of psychoac-
tive herbs to enhance their combat effectiveness, or at least the appearance of ferocity.
Turks reportedly used opium to enhance wartime bravery in the 1500s (Lewin 1998).
Consumption of Amanita muscaria, a psychoactive and hallucinogenic mushroom, may
have facilitated the “berserker” rage characteristic of Viking raids, though scholars remain
divided on the veracity of this claim (Fabing 1956; Høyersten 2015). South African tribal
warriors smoked dagga, a type of cannabis, in combination with the consumption of
other herbs to enhance fearlessness and insensitivity to pain (Kamienski 2016, pp.29–​30).
Not only have warfighters used substances to enhance capacities to engage in combat,
the history of warfare is rich with examples of warriors using substances to disengage from
combat. Homer’s Odyssey famously described the consumption of nepenthe by warriors
who quickly forgot their wartime sorrows (Kamienski 2016, pp.29–​30). During the US
Civil War, the term “soldier’s disease” became synonymous with opiate addiction, likely
as a result of the widespread use of opiate analgesics among warfighters (Miller 2013).
Deployment to Vietnam correlated with an uptick in warfighter narcotic use and addic-
tion, at least in part used for escapism (Robins et al. 1975). More recently, US warfighters
have used “no go pills” to calm the mind and induce rest in preparation for, or in recovery
from, combat (Golub & Bennett 2013). These interventions foreshadow ongoing research
on drugs like propranolol, which could ultimately enable warfighters to disengage from
combat without having formed traumatic memories (Donovan 2010).

Devices
The history of neuromodulation via electricity and magnetism also dates back centuries, if
not millennia. Scribonius Largus, an ancient Roman physician, wrote the earliest known
536  5

536 Security threat versus aggregated truths

account of neurostimulation (Fregni & Pascual-​Leone 2007). As a headache remedy he

described the application of an electric fish to the scalp. Much more recently, eighteenth-​
century scientists demonstrated the therapeutic potential of transcranial electric current
and the electrical stimulation of muscle contractions (Parent 2004). For the following two
centuries, researchers attempted to treat various mental conditions with electric current,
but their success varied. In the meantime, other electrical stimulation techniques gained
traction. Scientists successfully used electroconvulsive therapy (ECT) to treat depression
in the 1930s (UK ECT Review Group 2003). Another technique, deep brain stimulation
(DBS), emerged in the 1980s as a treatment for Parkinson’s and other movement disor-
ders. Delivering pulses of electricity, DBS can activate or block action potentials in spe-
cific brain regions (Coffey 2008).
As the twentieth century came to a close, researchers rediscovered the potential of
applying low-​level electrical current through the skull to affect the brain and its function.
Types of transcranial electrical stimulation (tES), including transcranial direct current
stimulation (tDCS), have been used to modulate cortical excitability (Nitsche & Paulus
2000; Priori et al. 2008). In contrast to DBS, tDCS does not stimulate neurons by forcing
or blocking their action potentials; rather, it modulates neurons by increasing or decreas-
ing their threshold to fire. Studies have focused on the effects of tDCS on neuroplasti-
city as well as the neurological substrates of cognition and motor activity. Transcranial
direct current stimulation has been shown to be safe, but the current understanding of
its efficacy for enhancement is incomplete (Horvath et  al. 2015). Some studies suggest
that “tDCS can enhance cognitive processes occurring in targeted brain areas,” but other
scientists have failed to replicate this finding (Ukueberuwa & Wassermann 2010; Horvath
et  al. 2015). Recent analyses reveal that context matters, and the type(s) and extent of
effects that can be elicited by tES strongly depend upon setting, and the neurocognitive
state of the subject. Recreational tDCS devices are available on the consumer market and
both clinical and direct-​to-​consumer tES technologies are of growing interest and poten-
tial utility to the military (Foc.us 2015; Kappenmann et al. 2016).
Magnetism is also used to manipulate neurological functions. Technologies include
magnetic seizure therapy and transcranial magnetic stimulation (TMS). Approved to treat
major depression, TMS may have additional applications for enhancement (Hamilton
et  al. 2011). In 2009, the US National Research Council identified TMS as a wakeful-
ness enhancement for the US Army (Committee on Opportunities in Neuroscience for
Future Army Applications, National Research Council of the National Academies 2009).
Similarly, DARPA and the US Army funded studies of wearable, helmet-​borne devices
to affect neurological function through the delivery of patterned ultrasound pulses
(Tyler 2010).
Brain–​machine interfaces (BMIs, also known as brain–​computer interfaces or BCIs)
constitute another major area of military neurological device research. BMIs either trans-
late neurological signals into inputs for computers or machines, or vice versa. BMIs have
potential for therapeutic breakthroughs in civilian and military medicine. They also have
a rich—​though short—​history of security applications.
 537

History 537

In 2002, Nature published results of a DARPA study that created the “roborat,” a
remote-​controlled rodent that utilized BMI technology. Scientists implanted electrodes in
the rat’s brain and in real time controlled its locomotion through complex mazes (Talwar
et al. 2002). Scientists equivocate on whether such research actually advances the aims
of medical prostheses, but DARPA’s interest was different: the roborat could be sent into
dangerous scenarios to detect mines, clear bombs, or identify survivors among rubble.
More recently, scientists have created “cyborg beetles” whose flight characteristics can be
remotely controlled (Sato et al. 2015). Such studies also raise ethical issues about the use
and purpose of animals in such research. There is a nuanced general consensus that the
public interest in animal studies performed for biomedical research may outweigh animal
autonomy, but such sentiments are less clear when biomedical research is directed toward
furthering military goals (Quigley 2007).
Other national security-​funded animal BMI studies are more directly oriented toward
therapeutic objectives. Around the same time as the roborat studies, scientists equipped
monkeys with BMIs attached to robotic arms and successfully trained the primates to
articulate and control the prostheses using neurological output from their brains (Lebedev
2006). This research could revolutionize prosthetics, both for warfighters and civilians.
Since then, BMIs have also facilitated human neurological control of a mouse cursor,
which could allow paraplegic patients to regain control and physical autonomy in their
lives (Simeral et al. 2011). Current DARPA research seeks to complete the feedback loop
between the brain and prostheses, not only granting the brain direct control over a robotic
limb but also returning tactile feedback, such as pressure and temperature, from sensors
in the prosthesis to the user’s brain (DARPA 2015).
An early twenty-​first century DARPA program, AugCog (short for “augmented cogni-
tion”), sought to fully integrate, at the neurological level, a warfighter’s cognitive capaci-
ties and sensory perceptions with his or her combat vehicle environment (Cummings
2010). As computers monitor working memory, attention, executive function, and sen-
sory input, the warfighter would be prompted in real time with information about cogni-
tive load. This kind of biofeedback could help a warfighter manage his or her neurological
resources; it might even bring into conscious awareness one’s own subconscious recogni-
tion of danger, prompting the warfighter’s attention to threats before they would have
been identified naturally (Szondy 2012). Though in name AugCog no longer exists, simi-
lar research continues. Giordano and Dando provide current overviews of neuroscience
and technology that is being studied, considered, developed, and used in national secu-
rity, intelligence, and defense (Giordano 2014c; Dando 2015).

Ethical issues in historical context

The bioethics literature on optimizing human neurological function and performance
tends to focus on cognitive enhancement via the use of drugs and devices and the implica-
tions for performance in school and in the workplace settings. Warfighter enhancement,
however, can manifest more grave, if not lethal stakes and may entail additional enhance-
ment modalities, including physical adaptions and modifications through wearable or
538  5

538 Security threat versus aggregated truths

implantable technologies, such as neurofeedback-​equipped helmets and biointegrated

BMIs, respectively. The ethics of civilian enhancement may be extrapolated and extended
to address the implications of warfighter enhancement. When approaching these ethi-
cal issues, it becomes important to evaluate the actual capabilities and limitations of the
technique(s) or technologies at hand, to assess if, and how any augmentation of function
is imparted, and to evaluate the impact that any such effects will have (Shook & Giordano
2014; Shook et al. 2014; Giordano 2015). On a fundamental level, human enhancement
raises ethical questions in at least two domains: (1) Does enhancement inherently trans-
gress fundamental moral boundaries? (2) Do the known and unknown risks of enhance-
ment interventions render them unethical?
In 2003, the then US President’s Council on Bioethics released a report on the ethical
issues associated with using ostensibly medical interventions to go beyond therapy into
the realm of human enhancement (The President’s Council on Bioethics & Kass 2003).
The Council pointed out that enhancements could undermine human nature by obvi-
ating the natural connection between actions and accomplishments, which underlies
human dignity. Enhancement may also represent a deeper transgression against what
some view as the natural, given world: it could be a hubristic attempt to “play God” or
master nature. These intuitions flag fundamental moral concerns about the normative
implications of altering one’s relationship to the world.
Assuming that performance enhancement is not intrinsically unethical, additional
issues arise related to the risks of enhancement. Enhancing performance in a competi-
tive endeavor is a zero-​sum game. Performance optimization increases one’s chance of
winning, thereby directly decreasing one’s opponent’s chances. This underlies the sense
of unfairness that, for example, gives rise to stringent drug testing in professional sports.
And yet, athletes may feel coerced to enhance in order to remain competitive, risking not
only getting caught but also potential short-​and long-​term health consequences as well as
conceding a robust sense of autonomy. The military, however, does not necessarily seek a
fair fight when entering combat. The entire purpose of the science–​security partnership is
to gain a technological advantage over the enemy, thereby enabling the accomplishment
of an objective while minimizing loss on both sides. But here derivative ethical issues
arise, including effects of enhancement on the health and status of an individual (and
what occurs if such enhancements are discontinued), and the possibility of escalating
development and use of neuroenhancements (and other applications of neuroscience and
neurotechnology) within and for military operations (Giordano 2014a, 2016a; McCreight
2014; Shook & Giordano in press).

Current and future use of neurocognitive science in security

operations
Although discussion thus far has focused upon efforts of the United States military and
Department of Defense to operationalize or engage dual-​use neuroscience, there is ongo-
ing investment of academic, commercial, and governmental resources in developing and
 539

Current and future use of neurocognitive science in security operations 539

testing tools and techniques of the brain sciences in and for security and defense agendas
around the world. As shown in Table 27.1, these include (but are not limited to) Australia,
Canada, China, consolidated efforts of the North Atlantic Treaty Organization (NATO)
member nations, India, and Russia.
In the main, brain science is primarily being used in international military and security
contexts:
◆ for medical purposes
◆ to optimize operational training and performance in military and intelligence
personnel
◆ to study (and perhaps develop) nonlethal and lethal weapons (e.g., chemical and
microbial agents and toxins, and neurotechnologic devices) (Giordano 2014b).
The 2014 report of the National Academies asserted that the research, development, and
use of brain science in international military and security scenarios represent a significant
and growing concern. In the United States and most Western nations, governmentally
funded neuroscience programs adhere to DURC policies, in keeping with the general
constructs of the BTWC and CWC. But such control can also create a dilemma: on the
one hand, it creates parameters for the conduct of brain science in participatory states;
on the other, it can create opportunities for other nations or even nonstate actors to
take advantage of these constraints to gain a competitive edge toward attaining power.
What’s more, international policies and treaties don’t guarantee cooperation, and studies
and applications of brain science don’t have to be covert. As previously noted, the cur-
rent BTWC and CWC do not restrict pharmaceutical formulations of neurotropic drugs
for medical use, or neurotechnologies (e.g., neurostimulatory or modulatory devices);
exemptions for biomedical experimental purposes and/​or shields of commercial propri-
etary interests and intellectual property can subvert inquiry into the dual-​use or military
applications of brain science (Giordano 2016).

Addressing ethical issues
Military medicine can generate particular ethical circumstances and implications (e.g.,
conflicting military and medical duties; exigencies of battlefield conditions). However,
brain research and the application of new techniques and technologies in military medi-
cine evoke many of the same ethical issues, questions, and steps toward resolution as in
civilian contexts. Also, several fundamental questions and issues about the type(s), extent,
limit(s) and effects of neurological assessment and augmentation of military personnel
can be viewed and addressed in much the same ways that these approaches are dealt with
in civilian settings. There is continued discussion about the potentially coercive nature
and non-​consented conduct of biomedical research in the military, discussions that stem
in large part from awareness of past ethical transgressions.
But, as matter of fact, illustration of such transgressions both in the military, and more
widely in biomedical research, have fortified the stringency of responsible practices in
the conduct of research in—​and for—​the military, at least in the United States, Canada,
 540
Table 27.1  Representative international research programs in neuroscience and neurotechnology for national security

Country Major research institutions and Research themes Example research projects and initiatives
funding resources
Australia Defense Science and Technology Group Transcranial direct-current ◆ Evaluating the index of cognitive activity as a measure of men-
(previously DSTO, now DSTG) stimulation (tDCS) tal workload.
◆ Transferring training for battle management systems: From
Land Human Services branch leads group on Artificial intelligence (AI)
Cognition and Behavior and machine cognition simulators to the real world.
◆ Evaluating longitudinal impacts of combat expo-
Centre for Cognitive Work and Safety Analysis Cognitive enhancement/
sure: Neurocognitive, psychological and biological outcomes.
Office of the Chief Defense Scientist performance
◆ Analyzing sleep characteristics of a small Australian Army popu-

Chemical Warfare Agent Laboratory Network Sleep deprivation studies lation and the effect of sleep deprivation on their simulated
driving performance.
Defense Materials Technology Centre
◆ Defining usability of command and control technology while
accumulating sleep loss.
◆ Reducing psychological dependency on ideological groups.
◆ Analyzing cognitive work beyond human factors and engineer-
ing: Application to military doctrine and strategy development.
◆ Evaluating non-invasive brain stimulation: Opportunities and
implications for the Australian Defense Force (ADF).
◆ Determining the importance of cognitive neuroengineering and
computational neuroscience for defense.

Canada National Research Council Canada Biotechnology Sleep and circadian cycles ◆ Novel ligands of prothrombin as inhibitors of blood and extra-
Research Institute (NRC-BRI) Working memory vascular coagulation.
◆ Human factors engineering (HFE) support to Canadian soldier
Defense Research and Development Canada Blood brain barrier-related
(DRDC), particularly the Toronto, Valcartier and systems.
topics
◆ Department of National Defense (DND) and SickKids work-
Suffield locations
Human factors, decision- ing together to better diagnose post-traumatic stress disorder
Defense and Security Research Institute making, and team/group (PTSD) and mild traumatic brain injury (mTBI).
Director General Military Personnel Research & behavior ◆ The future Canadian soldier and enhancement of human per-
Analysis Performance enhancement formance: Research meets policy.
◆ Inflammatory cytokine and chemokine profiles are associated
Pharmacokinetics
with patient outcome and the hyperadrenergic state following
PTSD acute brain injury.
  541
◆ Hyperbaric stress in divers and non-divers: Neuroendocrine and
psychomotor responses.
◆ Thromboelastographic study of psychophysiological
stress: A review.
◆ Do framing effects reveal irrational choice?

China National Natural Science Foundation of China “Bio-chips” and ◆ Determining how perceptual learning modifies the functional
Ministry of Science and Technology (MOST) biotechnology specializations of visual cortical areas.
◆ Evaluating minocycline ameliorates hypoxia-induced blood-
Institute of Neuroscience (ION) of the Chinese Trauma
brain barrier damage by inhibition of HIF-1α through SIRT-3/
Academy of the Sciences (CAS) Neurodegeneration
PHD-2 degradation pathway.
Chinese Society for Neuroscience Tumor biology ◆ Creating CGCG clinical practice guidelines for the management

Second Military Medical University Pain and analgesia of adult diffuse gliomas.
◆ Evaluating meCP2 plays an analgesic role in pain transmission
Third Military Medical University Drug abuse and addiction
through regulating CREB/miR-132 pathway.
Fourth Military Medical University in Xi’an ◆ Learning to memorize: Shedding new light on prefrontal
Institute of Neurosciences functions.
◆ Analyzing medial prefrontal activity during delay period contrib-
Zhujiang Hospital, Institute of Neuromedicine
utes to learning of a working memory task.
Partners
◆ Evaluating high-angular diffusion MRI in reward-based psychiat-
Beijing Society for Neuroscience ric disorders.
Neuroscience Research Institute, Peking University ◆ Determining if PKMζ might be a potential target for the treat-
ment of aging-related cognitive impairment, suggesting a
IDG/McGovern Institute for Brain Research at
potential therapeutic avenue.
Peking University
◆ Analyzing functions and mechanisms of microglia/macrophages
Beijing Normal University, National Key Laboratory in neuroinflammation and neurogenesis during stroke.
of Cognitive Neuroscience and Learning
East China Normal University – School of
Psychology and Cognitive Science
The Translational Neuroscience Center of West
China Hospital of Sichuan University

(continued)
 542
Table 27.1 Continued

Country Major research institutions and Research themes Example research projects and initiatives
funding resources

Germany Defense laboratories: Bundeswehr Institutes—part Biological agent research ◆ Developing methods and measures to identify relevant charac-
of a “Medical Academy” network PTSD teristic parameters in military workplaces with high cognitive
Institute of Microbiology (InstMikroBioBw) demands.
Cognitive performance
◆ Researching the pathophysiology of mild form of neurological
Center for Aerospace Medicine of the Airforce optimization
decompression sickness.
German Society for Cognitive Science ◆ Analyzing spatial and temporal phylogenesis for the verification
of biological agents using tick-borne encephalitis virus.
◆ Developing new therapies for nerve agent poisoning: From in
vitro models to clinical use.
◆ Evaluating brain activity in soldiers with combat-related PTSD.
◆ Detecting molecular markers in the cerebellum after traumatic
brain injuries (TBI).
India Defense Research and Development Organisation Effects of high altitude ◆ Differentiating neural activation for camouflage detection task
(DRDO) Effects of environmental in field-independent and field-dependent individuals: Evidence
Defense Institute of Psychological Research stress from fMRI
◆ Analyzing the neuroprotective role of L-NG-nitroarginine methyl
DIPAS –Defense Institute of Physiology and Allied Radiation neurobiology
ester (L-NAME) against chronic hypobaric hypoxia with crowd-
Sciences Biological/chemical agent ing stress (CHC) induced depression-like behaviour.
DRDE –Defense Research and Development research ◆ Analyzing the neuroprotective role of intermittent hypobaric
Establishment hypoxia in unpredictable chronic mild stress-induced depression
Institute of Nuclear Medicine and Allied Sciences in rats.
(INMAS) ◆ Evaluating the elevated pulmonary artery pressure and brain
natriuretic peptide in high-altitude pulmonary edema-suscepti-
ble non-mountaineers.
◆ Evaluating neural activation patterns in self deceivers.
◆ Comparing (11)C-methionine and (18)F-fluorodeoxyglucose
positron emission tomography-computed tomography scans in
evaluation of patients with recurrent brain tumors.
◆ Identifying critical path in strategic domains using fuzzy cogni-
tive maps.
  543
Israel Israel Institute for Biological Research (IIBR) Therapeutics for CNS/PNS ◆ Evaluating rapid brain MRI based on temporal sparsity
Subsidiary: Life Science Research Israel disorders exploitation.
◆ Analyzing novel bifunctional hybrid small molecule scavengers
Israel Ministry of Defense, Directorate of Defense Nanotechnology
for mitigating nerve agent toxicity.
R&D Neurodegeneration
◆ Evaluating solvent effects on the reactions of the nerve
Affiliates PTSD agent VX with KF/Al2O3: Heterogeneous or homogeneous
Israel National Nanotechnology Initiative Medical diagnostic decontamination?
techniques ◆ Analyzing the attenuation of sarin-induced brain damage in
Ministry of Science, Technology, and Space
rats by delayed administration of midazolam.
Ben-Gurion University of the Negev, Zlotowski Protein and enzyme synthe-
◆ Determining if rivastigmine is a safe pretreatment against nerve
Center for Neuroscience sis and engineering
agents poisoning? A pharmacological, physiological and cogni-
Vaccines and tive assessment in healthy young adult volunteers.
pharmaceuticals ◆ Acute and long-term ocular effects of acrolein vapor on the
eyes and potential therapies
◆ Improving functional recovery after experimental traumatic
brain injury via inosine.
North Korea Pyongyang Bio-Institute Anthrax (hypothesized) N/A
Biological agents,
neurotoxins
Russia Russian Foundation for Advanced Research Neurotechnology ◆ Evaluating whether intracortical microinjections may cause
Projects Integrated biosystems spreading depression and suppress absence seizures.
◆ Analyzing a Bayesian classifier for brain–computer interface
Laboratory of Neurotechnology Perception and Memory, perception, and
Recognition with focus areas based on mental representation of movements.
recognition
◆ Activating brain structures by fMRI data when viewing the
Russian Academy of the Sciences Public health and safety video clips and recall of shown actions.
Institute of Higher Nervous Activity Neurotrauma ◆ Determining whether two-faced nitric oxide is necessary for

30th Central Scientific Research Institute, Ministry both erasure and consolidation of memory.
of Defense ◆ Evaluating the influence of the working memory load on the
spatial synchronization of prestimulus cortical electrical activity
State Research Center of Virology and
during recognition of facial expression.
Biotechnology (VECTOR)
◆ Analyzing the mechanisms of orientation sensitivity of human
vision system. Part II: neural patterns of early processing of
information about line orientation.
◆ Evaluating stress reactivity and stress-resilience in the patho-
genesis of depressive disorders: Involvement of epigenetic
mechanisms.

(continued)
 54
Table 27.1 Continued

Country Major research institutions and Research themes Example research projects and initiatives
funding resources
United Defense Science and Technology Laboratory Next-generation neuro- ◆ Analyzing R-Cloud human capability SOR—From safety net to
Kingdom Porton Down pharmacology including augmented cognition: Using flexible autonomy levels for on-
nootropic agents line cognitive assistance and automation.
Centre for Defense Enterprise
◆ Initiatives on:
Transcranial stimulation (DC
University of Kent (academic partnership) • Adaptive technologies
and magnetic)
• Human factors
Synthetic biology
• Understanding and influencing human behavior
Machine-augmented • Human performance and protection
cognition • Evaluating the cognitive systems project
Neuro-prostheses
Also interests in: neurotox-
ins, virtual reality, trauma,
social and behavioral
influence
 54

Current and future use of neurocognitive science in security operations 545

United Kingdom, and European Union (Gross & Carrick 2013). There are still uncertain-
ties regarding responsible conduct of research in those countries that employ differing
codes of ethics, and what this portends both for research subjects and for the outcomes of
such research and the capabilities of power incurred. Further questions arise if and when
considering the use of brain science in settings and situations that are explicitly relevant to
warfare, such as warfighter augmentation and the development and use of neuroweapons,
and intelligence operations.
Casebeer has proposed a normative framework for neuroethical address of issues
fostered by neuroscience research and its translation, which although primarily ori-
ented toward military and civilian medicine, can be applied, and is nonetheless useful
to national security, intelligence, and defense agendas (Casebeer 2014). This has been
expanded to engage neuroethicolegal and social risk-​assessment and mitigation para-
digm, in which defined steps, queries, and framing constructs are employed to determine
if and how specific uses of neuroscience and neurotechnologies give rise to ethical issues
(Giordano et al. 2014; Giordano 2015). Critical to this approach is consideration of con-
texts of application. An undergirding question is whether neuroethical issues of brain
science in contexts of national security and defense are best addressed in accordance with
military ethics, ethics relevant to enterprises in the public domain, or some other system
or ethical toolkit. It could be argued that ethics are ethics, but ethics provide systematic
analysis and articulation of moral actions relevant to the specific goals, values, and tasks
defined by and within communities of use even though the underlying principles are the
same. This “telic” approach is not an attempt at veiled consequentialism, or mere ethical
relativism, but rather, is ethical realism. It asks: What are the ends (i.e., the telos) of the
profession, and how is the good to be attained and upheld in both end(s) and the means
entailed toward their achievement?
On this realist view, the professional ethics of the military should define the focus,
scope, and conduct of any and all its constituent scientific and technological enterprises.
Just war theory, jus ad bellum, may substantiate using neuroscience and neurotechnol-
ogy (or any science and technology) in national security, intelligence, and defense, in
accordance with ethical precepts that define the need for aggressive actions. The premise
is that war is a horror to be abhorred and avoided, but realistically may sometimes be nec-
essary. Defined criteria attempt to discern if and how such conflict might be prevented,
restrained, and made more humane.
In this latter regard, precepts for fair conduct of conflict (i.e., jus in bello) might define
whether and ways that neuroscience and technologies may be employed within warfare,
or to prevent warfare. But particular attention should be paid to the precept of no means
malum in se, which proscribes the use of methods and weapons that violate some con-
sensus construct of harm (e.g., chemical weapons), or that may be uncontrollable (e.g.,
biological and nuclear weapons), or both of these. This remains a gray zone: as noted pre-
viously, while some domains of brain science fall within the purview of the current BTWC,
CWC, and DURC policy, others such as neurotechnologies do not. Thus, as brain science
both continues to advance and to be assessed for use within national defense agendas,
546

546 Security threat versus aggregated truths

it will be important to address (1)  whether extant and new neuroscientific techniques
and technologies can incur harms relative to considerations of means malum in se, and
(2) whether neurotechnologies fall under mandate constraints of biological weaponry.
An underlying issue is the ethics of power, specifically power exercised to preserve
communal values and a way of life. The mission of national security and defense is to
protect the ideals, objectives, and integrity of a state. Like any cutting-​edge tool, brain
science can afford an actor’s defined advantage in leveraging relative balances of power
in deterrence and influence. Furthermore, although in a free state the values of the polis
are reflected in its politics, totalitarian regimes often inflict and enforce values of a power
estate upon the polis. This gives rise to questions of relative good: what one state deems to
be right and just may not necessarily be the same for other states. Formal, contemporary
constructs of jus ad bellum define grave, public evil such as “aggression or massive viola-
tion of the basic human rights of … populations” as substantive grounds to justify hostile
action (i.e., war). If this is the case, should neuroscientific techniques and technologies be
part of the armamentarium?
In light of these considerations, it is important to regard “the good” in a variety of
dimensions, as security and defense operations represent state-​level enterprises that are
executed and exert influence in an international milieu. Such a view moves beyond the
somewhat narrow confines of military ethics, and brings neuroethical and legal con-
sideration of brain science in national defense agendas into a broader social context.
Consistent with core precepts of other international deliberations upon the use of various
implements in military and defense operations, such consideration would need to evalu-
ate the ways that brain science should or should not be studied, developed, and employed.
In many ways, these considerations reflect more general concerns about both unknown,
unanticipated, and possibly uncontrollable effects of nascent science and technology, and
the sociocultural manifestations and responses generated by the use or misuse of such
techniques and technologies (Giordano & Benedikter 2012; Giordano 2014b). Key ques-
tions include whether the use of certain neuroscientific and technological approaches
incurs greater or lesser risks and harms than other methods of intelligence, security, and
defense, and what limits should be applied to any possible development and use of brain
science in defense initiatives (Tractenberg et al. 2014).
Based upon the activities and results of other international conventions (e.g., the
BTWC, CWC, and Geneva Convention) that have sought to govern military methods and
weapons, we have speculated that such deliberation could lead to two possible outcomes.
The first is a move to ban or restrict any research or use of brain science that is applicable
to military operations. However, this would be difficult, if not impossible, in that existing
brain research can be used for military purposes, and, as we have previously noted in this
chapter, many countries already have directly subsidized military and defense enterprises
of brain research. Thus, unless a ban was universal, restricted research and development
by some could afford opportunities for others to exploit scientific and technological bal-
ances of power (Forsythe & Giordano 2011). The second, and we believe more plausible,
possibility is to work to establish realistic criteria for development and use of specific
 547

Current and future use of neurocognitive science in security operations 547

types and extents of neuroscience and neurotechnological approaches within military

and defense operations in accordance with strictly defined and implemented ethicolegal
parameters, which would then require surveillance and enforcement on a variety of scales
and levels.
Still, questions arise as to whether these criteria should be based upon or grounded to
a particular philosophy, military ethics international law, or some other extant, new, or
combined approach (Ferguson 2000; Forsythe & Giordano 2011; Benedikter & Giordano
2012; Dando 2012; Lanzilao et al. 2013; Abney et al. 2014; Farwell 2014; Shook & Giordano
2014). To be sure, any such deliberations must be articulated by dedicated groups of mul-
tidisciplinary professionals, from government and civilian sectors, with experience and
expertise that is essential to making ethical decisions about the use, constraints, and out-
comes of brain science in national security and defense initiatives on the global stage
(Dando 2007; White 2008; Moreno 2012; Casebeer 2013). We have posited that these
individuals and groups must be task-​agile, scientifically and situationally knowledgeable,
and ethically responsible, and have proposed methods for training and executing the pro-
cess. Case-​based analysis informed partly by historical information as presented in this
chapter and elsewhere, provides a basis from which to assess the potential effects of cur-
rent and emerging developments in brain science that can be employed in national secu-
rity operations (Moreno 2012; Tabery 2014; Tractenberg et al. 2014). But ethical oversight
is not simply a matter of retrospection; rather it must be forward-​looking, descriptive,
predictive, and not simply proscriptive, but rather preparatory for contingencies and exi-
gencies that can occur as brain science and technology and global politics and military
operations evolve. Moreover, such ethical engagement should not be a merely academic
exercise: it must be conducted by groups that have credibility and capability to inform and
influence formulation of international policies, treaties, and laws.

Infrastructure: Building for the challenges and opportunities ahead

This conclusion speaks to the need to develop infrastructure(s) capable of the tasks at
hand, and to come. The 2014, the US National Research Council report on Emerging
and Readily Available Technologies and National Security addressed ELSI relative to
government agencies’ work in disruptive technologies of potential interest to both
state and nonstate actors. The committee’s recommendations included a five-​step
process:  initial screening of proposed research and development; further review of
proposals that raise ELSI concerns; project monitoring and midcourse corrections as
needed; public engagement; and periodic review of ELSI processes within an agency
(Chameau et al. 2014).
But which agency, agencies, or organizations should be charged with these duties, how
will their constituencies be decided, and what level and extent of interagency and pub-
lic discourse can and should be engaged? Differing groups may have distinct views and
goals, and, as with any approach to national defense, issues of security, operational readi-
ness, and power will need to be evaluated and weighed in light of global humanitarian
concerns. Axiomatically, defense and security operations require that some information
548

548 Security threat versus aggregated truths

remains classified, and so public discussion, while necessary, must be carefully engaged
(Giordano et al. 2010). We believe that it is vital to inform the public about the reality and
growing potential for brain science to be used in security, intelligence, and defense opera-
tions, so as to foster broad social awareness.
Indeed, it is the social impact of the use and misuse of brain science in military and
security operations that gives rise to ethical and legal issues. Thus, we do not see mili-
tary and civilian silos of ethicolegal deliberation and guidance as being wholly separate.
Current intramural efforts at various national agencies dedicated to examining current
and future ELSI are commendable. And while it is important to elucidate the ethical issues
that arise in and from such research and its use, ethics alone are not sufficient. Ethics must
inform and lead to the formulation of policies and regulations that guide and govern
what aspects of brain science are studied and employed in these contexts (Dando 2007;
Moreno 2012). The growing potential for the use of novel drugs and devices of brain
science will prompt re-​examination and revision of current categorizations, caveats, and
constraints. As we have stated in prior work, it is undeniable that neuroscience is, and
will be, employed in security and defense agendas (Moreno 2012; Wurzman & Giordano
2014). Our hope is that the knowledge and capabilities it confers will be used to prevent
or mitigate violence, reduce conflict, and foster peace.

Acknowledgments
The authors gratefully acknowledge the research and editorial assistance of Celeste Chen
and Kira Becker, and the ongoing collaboration of the Strategic Multilayer Assessment
Group of the Joint Staff of the Pentagon. Aspects of this this work were supported in part
by funding from the Lawrence Livermore National Laboratory (JG) and Office of Naval
Research (JG).

Disclaimer
The work presented in this chapter is solely that of the authors and does not necessarily
represent the perspectives of the United States Department of Defense, Defense Advanced
Research Projects Agency (DARPA), or Strategic Multilayer Assessment Group of the
Joint Staff of the Pentagon.

References
Abney, K., Lin, P., and Mehlman, M. (2014). Military neuroenhancement and risk assessment.
In: Giordano, J. (Ed.) Neurotechnology in National Security and Defense: Practical Considerations,
Neuroethical Concerns, pp.239–​248. Boca Raton, FL: CRC Press.
Air Force Studies Board (2008). Emerging Cognitive Neuroscience and Related Technologies. Washington,
DC: National Academies Press.
Bell, C. (2014). Why neuroscientists should take the pledge: a collective approach to the misuse of
neuroscience. In: Giordano, J. (Ed.) Neurotechnology in National Security and Defense: Practical
Considerations, Neuroethical Concerns, pp.227–​238. Boca Raton, FL: CRC Press.
 549

References 549

Benedikter, R. and Giordano, J. (2012). Neurotechnology: new frontiers for European policy. Pan
European Networks: Science & Technology, 3, 204–​207.
Bush, V. (1945). Science: the endless frontier. Transactions of the Kansas Academy of Science (1903–​),
48(3), 231–​264.
Casebeer, W.D. (2013). Plenary Testimonial Presented to US Presidential Commission for the Study of
Bioethical Issues. Available from: https://​bioethicsarchive.georgetown.edu/​pcsbi/​node/​2779.html
[accessed February 19, 2017].
Casebeer, W.D. (2014). A neuroscience and national security normative framework for the twenty
first century. In: Giordano, J. (Ed.) Neurotechnology in National Security and Defense: Practical
Considerations, Neuroethical Concerns, pp.279–​284. Boca Raton, FL: CRC Press.
Chameau, J.-​L, Balhaus, W.F., and Lin, H.S. (2014). Emerging and Readily Available Technologies and
National Security: A Framework for Addressing Ethical, Legal, and Societal Issues. Washington,
DC: National Academies Press.
Coffey, RJ. (2008). Deep brain stimulation devices: a brief technical history and review. Artificial
Organs, 33(3), 208–​220.
Collingridge, D. (1980). The Social Control of Technology. New York: St. Martin’s Press.
Committee on Opportunities in Neuroscience for Future Army Applications, National Research
Council of the National Academies (2009). Opportunities in Neuroscience for Future Army
Applications. Washington, DC: National Academies Press.
Cummings, M.L. (2010). Technology impedances to augmented cognition. Ergonomics in Design,
18(2), 25–​27.
Dando, M. (2007). Preventing the Future Military Misuse of Neuroscience.
New York: Palgrave-​Macmillan.
Dando, M. (2012). Bioterror and Biowarfare: A Beginner’s Guide. Oxford: OneWorld Publications.
Dando, M. (2015). Neuroscience and the Future of Chemical-​Biological Weapons.
New York: Palgrave-​Macmillan.
DARPA (2015, April 23). HAPTIX Starts Work to Provide Prosthetic Hands with Sense of Touch.
Available from: http://​www.darpa.mil/​news-​events/​2015-​04-​23 [accessed January 4, 2016] [accessed
January 4, 2016].
DARPA (2016). Where the Future Becomes Now. Available from: http://​www.darpa.mil/​about-​us/​
timeline/​where-​the-​future-​becomes-​now [accessed January 4, 2016].
Donovan, E. (2010). Propranolol use in the prevention and treatment of posttraumatic stress disorder
in military veterans: forgetting therapy revisited. Perspectives in Biology and Medicine, 53(1), 61–​74.
Druckman, D. and Swets, J.A. (Eds.) (1988). Enhancing Human Performance: Issues, Theories, and
Techniques. Washington, DC: National Academies Press.
Editorial (2003). Silence of the neuroengineers. Nature, 423(6942), 787. Available from: http://​www.
nature.com/​nature/​journal/​v423/​n6942/​full/​423787b.html [accessed January 11, 2016].
Evans, NG. (2014). Dual-​use decision making: relational and positional issues. Monash Bioethics
Review, 32, 268–​283.
Fabing, H.D. (1956). On going berserk: a neurochemical inquiry. American Journal of Psychiatry,
113(5), 409–​415.
Farwell, J. (2014). Issues of law raised by the developments and use of neuroscience and
neurotechnology in national security and defense. In: Giordano, J. (Ed.) Neurotechnology in National
Security and Defense: Practical Considerations, Neuroethical Concerns, pp.133–​166. Boca Raton,
FL: CRC Press.
Ferguson, J.R. (2000). Biological weapons and US law. In: Lederberg, J. (Ed.) Biological
Weapons: Limiting the Threat, pp.81–​91. Cambridge, MA: MIT Press.
50

550 Security threat versus aggregated truths

Foc.us (2015). Focus Take Charge®—​Foc.us Electrical Brain Stimulators. Available from: http://​www.foc.
us [accessed February 8, 2017].
Forsythe, C. and Giordano, J. (2011). On the need for neurotechnology in the national intelligence and
defense agenda: scope and trajectory. Synesis: A Journal of Science, Technology, Ethics and Policy,
2(1), 5–​8.
Fregni, F. and Pascual-​Leone, A. (2007). Technology insight: noninvasive brain stimulation in
neurology—​perspectives on the therapeutic potential of rTMS and tDCS. Nature Clinical Practice
Neurology, 3(7), 384.
Giordano, J. (Ed.) (2014a). Neurotechnology in National Security and Defense: Practical Considerations,
Neuroethical Concerns. Boca Raton, FL: CRC Press.
Giordano, J. (2014b). Neurotechnology, global relations and national security: Shifting contexts
and neurothical demands. In: Giordano, J. (Ed.) Neurotechnology in National Security and
Defense: Practical Considerations, Neuroethical Concerns, pp.1–​10. Boca Raton, FL: CRC Press.
Giordano, J. (2014c). The human prospect(s) of neuroscience and neurotechnology: domains of
influence and the necessity—​and questions—​of neuroethics. Human Prospect, 4(1), 1–​18.
Giordano, J. (2015). A preparatory neuroethical approach to assessing developments in
neurotechnology. AMA Journal of Ethics, 17(1), 56–​61.
Giordano, J. (2016, May). The neuroweapons threat. Bulletin of the Atomic Scientists. Available
from: http://​thebulletin.org/​neuroweapons-​threat9494 [accessed February 8, 2017].
Giordano, J. and Benedikter, R. (2012). An early—​and necessary—​flight of the Owl of
Minerva: neuroscience, neurotechnology, human socio-​cultural boundaries, and the importance of
neuroethics. Journal of Evolution and Technology, 22(1), 14–​25.
Giordano, J. and Wurzman, R. (2016). Integrative computational and neurocognitive science and
technology for intelligence operations: horizons of potential viability, value and opportunity.
STEPS: Science, Technology and Engineering Policy Studies, 4, 32–​37.
Giordano, J., Casebeer, W., and Sanchez, J. (2014). Assessing and managing risks in systems neuroscience
research and its translation: A preparatory neuroethical approach. Paper presented at 6th Annual
Meeting of the International Neuroethics Society, Washington, DC.
Giordano, J., Forsythe, C., and Olds, J. (2010). Neuroscience, neurotechnology and national
security: the need for preparedness and an ethics of responsible action. AJOB Neuroscience,
1(2), 1–​3.
Golub, A. and Bennett, A.S. (2013). Introduction to the special issue: drugs, wars, military personnel,
and veterans. Substance Use & Misuse, 48, 796.
Gross, M.L. and Carrick, D. (Eds.) (2013). Military Medical Ethics for the 21st Century.
New York: Ashgate.
Hamilton, R., Messing, S., and Chatterjee, A. (2011). Rethinking the thinking cap: ethics of neural
enhancement using noninvasive brain stimulation. Neurology, 76(2), 187–​193.
Horvath, J.C., Forte, J.D., and Carter, O. (2015). Quantitative review finds no evidence of cognitive
effects in healthy populations from single-​session transcranial direct current stimulation (tDCS).
Brain Stimulation, 8(3), 535–​550.
Høyersten, J.G. (2015). Manifestations of psychiatric illness in texts from the medieval and Viking era.
Archives of Psychiatry and Psychotherapy, 2, 57–​60.
Kamienski, L. (2016). Shooting Up: A Short History of Drugs and War. New York: Oxford
University Press.
Kappenmann, E., Bikson, M., and Giordano, J. (Eds.) (2016, March). Mechanisms and Effects of
Transcranial Direct Current Stimulation. US Air Force Office of Scientific Research Report.
Kosal, M.E. and Huang, J.Y. (2015). Security implications and governance of cognitive neuroscience.
Politics and the Life Sciences, 34(1), 93–​108.
 51

References 551

Lanzilao, E., Shook, J., Benedikter, R., and Giordano, J. (2013). Advancing neuroscience on the
21st century world stage: the need for—​and proposed structure of—​an internationally relevant
neuroethics. Ethics in Biology, Engineering and Medicine, 4(3), 211–​229.
Lasswell, H.D. (1941). The Garrison State. American Journal of Sociology, 46(4), 455–​468.
Lebedev, M.A. and Nicolelis, M.A.L. (2006). Brain-​machine interfaces: past, present and future. Trends
in Neurosciences, 29(9), 536–​546.
Lewin, L. (1998). Phantastica: A Classic Survey on the Use and Abuse of Mind-​Altering Plants.
New York: Inner Traditions/​Bear & Co.
McCreight, R. (2014). Brain brinksmanship: devising neuroweapons looking at battlespace, doctrine
and strategy. In: Giordano, J. (Ed.) Neurotechnology in National Security and Defense: Practical
Considerations, Neuroethical Concerns, pp.115–​132. Boca Raton, FL: CRC Press.
Miller, R.J. (2013). Drugged: The Science and Culture Behind Psychotropic Drugs. New York: Oxford
University Press.
Moreno, J.D. (2012). Mind Wars. New York: Bellevue Literary Press.
National Research Council. (2008). Emerging Cognitive Neuroscience and Related Technologies.
Washington, DC: The National Academies Press.
National Research Council (US) Committee on Opportunities in Neuroscience for Future Army
Applications (2009). Opportunities in Neuroscience for Future Army Applications. Washington,
DC: National Academies Press. Available from: http://​www.ncbi.nlm.nih.gov/​books/​NBK207975/​.
Nitsche, M.A. and Paulus, W. (2000). Excitability changes induced in the human motor cortex by weak
transcranial direct current stimulation. Journal of Physiology, 527(3), 633–​639.
Nitze, P. (1950). NSC 68: United States Objectives and Programs for National Security. In: May, E. (Ed.)
American Cold War Strategy: Interpreting NSC 68, pp.31–​32. Boston, MA: Bedford/​St. Martins (1993).
Office of Naval Research: Science & Technology (n.d. a). Code 34: Warfighter Performance Department.
Available from: http://​www.onr.navy.mil/​Science-​Technology/​Departments/​Code-​34.aspx [accessed
April 15, 2016].
Office of Naval Research: Science & Technology (n.d. b). Computational Neuroscience Program.
Available from: http://​www.onr.navy.mil/​Science-​Technology/​Departments/​Code-​34/​All-​
Programs/​human-​bioengineered-​systems-​341/​Computational-​Neuroscience.aspx [accessed
April 15, 2016].
Parent, A. (2004). Giovanni Aldini: from animal electricity to human brain stimulation. Canadian
Journal of Neurological Sciences, 31, 576–​584.
Priori, A., Berardelli, A., Rona, S., Accornero, N., and Manfredi, M. (2008). Polarization of the human
motor cortex through the scalp. Neuroreport, 9(10), 2257–​2260.
Quigley, M. (2007). Non-​human primates: the appropriate subjects of biomedical research? Journal of
Medical Ethics, 33(11), 655–​658.
Robins, L.N., Helzer, J.E., and Davis, D.H. (1975). Narcotic use in Southeast Asia and afterward.
Archives of General Psychiatry, 32(8), 955–​961.
Roosevelt, F.D. (1944, November 17). Letter to Vannevar Bush. Available from: https://​www.nsf.gov/​
about/​history/​vbush1945.htm#letter [accessed April 15, 2016.
Sato, H., Vo Doan, T.T., Kolev, S., et al. (2015). Deciphering the role of a coleopteran steering muscle
via free flight stimulation. Current Biology, 25(6), 798–​803.
Shanker, T. and Duenwald, D. (2003, January 19). Bombing error puts a spotlight on pilots’
pills. The New York Times. Available from: http://​www.nytimes.com/​2003/​01/​19/​us/​threats-​
and-​responses-​military-​bombing-​error-​puts-​a-​spotlight-​on-​pilots-​pills.html [accessed April
15, 2016].
Shook, J.R. and Giordano, J. (2014). A principled, cosmopolitan neuroethics: considerations for
international relevance. Philosophy, Ethics, and Humanities in Medicine, 9, 1.
52

552 Security threat versus aggregated truths

Shook, J.R. and Giordano, J. (In press). Assessing performance enhancement before neuroethical
evaluations. Frontiers in Human Neuroscience.
Shook, J.R., Galvagni, L., and Giordano, J. (2014). Cognitive enhancement kept within
contexts: neuroethics and informed public policy. Frontiers in Systems Neuroscience, 8, 1–​8.
Simeral, J.D., Kim, S.P., Black, M.J., Donoghue, J.P., and Hochberg, L.R. (2011). Neural control of
cursor trajectory and click by a human with tetraplegia 1000 days after implant of an intracortical
microelectrode array. Journal of Neural Engineering, 8(2), 1–​24.
Strategic Multilayer Assessment Group, Joint Staff/​J-​3. (2010). Neurobiology of Political Violence: New
Tools, New Insights. Washington, DC: The Pentagon.
Strategic Multilayer Assessment Group, Joint Staff/​J-​3. (2012a). Neurobiological & Cognitive Science
Insights on Radicalization and Mobilization to Violence: A Review. Washington, DC: The Pentagon.
Strategic Multilayer Assessment Group, Joint Staff/​J-​3. (2012b). Cyber on the Brain: The Effects of
CyberNeurobiology & CyberPsychology on Political Extremism. Washington, DC: The Pentagon.
Strategic Multilayer Assessment Group, Joint Staff/​J-​3. (2012c). National Security Challenges: Insights
from Social, Neurobiological, and Complexity Science. Washington, DC: The Pentagon.
Strategic Multilayer Assessment Group, Joint Staff/​J-​3. (2013). Topics in Operational Considerations on
Insights from Neurobiology on Influence and Extremism. Washington, DC: The Pentagon.
Strategic Multilayer Assessment Group, Joint Staff/​J-​3. (2014). Leveraging Neuroscientific and
Neurotechnological Developments with Focus on Influence and Deterrence in a Networked World
(Revised). Washington, DC: The Pentagon.
Strategic Multilayer Assessment Group, Joint Staff/​J-​3. (2015). Social and Cognitive Neuroscience
Underpinnings of ISIL Behavior and Implications to Strategic Communication, Messaging, and
Influence. Washington, DC: The Pentagon.
Szondy, D. (2012, September 20). DARPA’s CT2WS Technology Uses “Mind Reading” to Identify Threats.
Available from: http://​www.gizmag.com/​tag-​team-​threat-​recognition-​technology/​24208 [accessed
April 15, 2016].
Tabery, J. (2014). Can (and should) we regulate neurosecurity? Lessons from history. In: Giordano,
J. (Ed.) Neurotechnology in National Security and Defense: Practical Considerations, Neuroethical
Concerns, pp.249–​258. Boca Raton, FL: CRC Press.
Talwar, S. K., Xu, S., Hawley, E.S., Weiss, S.A., Moxon, K.A., and Chapin, J.K. (2002). Rat navigation
guided by remote control. Nature, 417, 37–​38.
The President’s Council on Bioethics (US) and Kass, L. (2003). Beyond Therapy: Biotechnology and the
Pursuit of Happiness. New York: Harper Perennial.
Tractenberg, R.E., FitzGerald, K.T., and Giordano, J. (2014). Engaging neuroethical issues generated
by the use of neurotechnology in national security and defense: toward process, methods and
paradigm. In: Giordano, J. (Ed.) Neurotechnology in National Security and Defense: Practical
Considerations, Neuroethical Concerns, pp.259–​278. Boca Raton, FL: CRC Press.
Tyler, W.J. (2010, September). Remote control of brain activity using ultrasound. Armed with Science.
Available from: http://​science.dodlive.mil/​2010/​09/​01/​remote-​control-​of-​brain-​activity-​using-​
ultrasound/​[accessed April 15, 2016].
UK ECT Review Group. (2003). Efficacy and safety of electroconvulsive therapy in depressive
disorders: a systematic review and meta-​analysis. The Lancet, 361(9360), 799–​808.
Ukueberuwa, D. and Wassermann, E.M. (2010). Direct current brain polarization: a simple,
noninvasive technique for human neuromodulation. Neuromodulation, 13(3), 168–​173.
 53

References 553

White House (2014). Fact Sheet: Over $300 Million in Support of the President’s BRAIN Initiative.
Available from: https://​obamawhitehouse.archives.gov/​sites/​default/​files/​microsites/​ostp/​brain_​fact_​
sheet_​9_​30_​2014_​final.pdf [accessed February 14, 2017].
White, S.E. (2008). Brave new world: neurowarfare and the limits of international humanitarian law.
Cornell International Law Journal, 41, 177–​210.
Wurzman, R. and Giordano, J. (2014). NEURINT and neuroweapons: neurotechnologies in
national intelligence and defense. In: Giordano, J. (Ed.) Neurotechnology in National Security and
Defense: Practical Considerations, Neuroethical Concerns, pp.79–​114. Boca Raton, FL: CRC Press.
54

Chapter 28

Communicating about the brain

in the digital era
Julie M. Robillard and Emily Wight

Neuroscience communication: A priority for neuroethics

Brain science and public discourse, one of the four original pillars of neuroethics (Marcus
2002), explores the discourse that takes place around neuroscience research and sup-
ports the broader discussion about ethical, legal, and social issues arising from related
advances. In recent years, progress in the development of methods for brain research
and of treatment for conditions of the nervous system has generated much discussion
at the intersection of ethics and neuroscience. For example, optogenetics, an emerging
technique aimed at controlling genetically modified subsets of brain cells with light, has
exploded in popularity in both academic research and on social media platforms such as
Twitter. More closely related to human health, the regenerative properties of stem cells
have been hailed as a miraculous stroke treatment by celebrities in traditional and new
media (Rachul and Caulfield 2015). In parallel with advances in science, the development
of Internet-​and mobile-​based communication channels have expanded and diversified
how conversations about science and health take place. Interactive platforms now play an
important role in shaping public perceptions of scientific and healthcare discoveries and
provide new avenues for the public to interact with research on their terms, and to engage
in multidirectional conversations about innovations in neuroscience.
In this chapter, we explore the history and evolving landscape of neuroscience com-
munication, present work from our team in Canada, and look to the future to understand
the ways that the evolution of technology have improved and challenged our ability to
translate and communicate brain health research and discovery.

The evolution of science communication

The neuroscience communication aspect of neuroethics builds on the broader field of
science communication. Well before the advent of dedicated empirical and theoretical
research in the field of science communication, science discoveries were published in
the mainstream press and were featured at fairs, exhibits, and in popular books (Jacques
and Raichvarg 1991). By the 1700s, books such as Francesco Algarotti’s Il newtonian-
ismo per le dame (“Newtonism for ladies”) were meant to translate science and increase
 5

The evolution of science communication 555

its accessibility for the average person (Bucchi 2008). Over time, the process of science
communication broadened and came to include multiple types of stakeholders. In his
famous 1881 public experiment, French chemist Louis Pasteur demonstrated the concept
of vaccination by injecting a group of livestock with an anthrax vaccine, while another
group remained unvaccinated. Farmers, doctors, veterinarians, physiologists, politicians,
and reporters all witnessed the inoculations. The science experiment was successful: all
unvaccinated animals died and all inoculated animals survived. The public experiment
was successful as well:  the engagement powerfully demonstrated the value of research
and discovery.
In more recent years, the dissemination of scientific knowledge has grown increas-
ingly complex as once-​broad fields of research have become specialized and academic
journals have become the standard for publication of new research findings. In 1985, a
report on the public’s knowledge of science commissioned by the Royal Society urged
scientists to “Learn to communicate with the public, be willing to do so, and consider
it your duty to do so” (Royal Society 1985). However, many years later, scientist com-
municators are seen by their peers as less serious than their less-​communicative coun-
terparts: researchers understand the need to communicate broadly, but there is a stigma
attached to those who actively pursue public engagement. A 2006 survey by the Royal
Society on “factors affecting science communication by scientists and engineers” found
that while 74% of Royal Society members surveyed had participated in “at least one
science communication or public engagement activity in the past 12 months,” in inter-
views researchers revealed that “public engagement activity was seen by peers as bad
for their career,” and that “public engagement was done by those who were ‘not good
enough’ for an academic career.” This view that public engagement is detrimental to a
person’s scientific career was especially damaging for junior and women researchers. In
the same survey, 20% of respondents agreed that scientists who engage with the public
are less well regarded by other scientists (Royal Society 2006); 64% of scientists sur-
veyed that the need to spend more time on research was a barrier to engaging in public
engagement activities. Known as “The Sagan Effect” for Dr. Carl Sagan who popularized
science on television for lay audiences in the 1970s and 1980s, this belief that scien-
tists who pursue media and public engagement opportunities are less serious and less
focused on research persists in modern academia, despite being directly at odds with
society’s need to have an educated and informed populace who trusts and sees the value
in scientific research.
Despite these real and perceived barriers in science communication, a 2014 Public
Attitudes to Science Ipsos Mori poll found that 72% of citizens in the United Kingdom
agree with the statement “it is important to know about science in my daily life”; 90% of
those same people stated that they believe that scientists make an important contribu-
tion to society (Ipsos MORI 2014). The public desire for scientific knowledge is very
high, even as overall science literacy appears to be threatened by the inscrutable, top-​
down nature of academic publishing. There is a clear disconnect between the goals of
science communication and science literacy in the general population. According to the
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556 Communicating about the brain in the digital era

same poll, nearly 30% of respondents believe that science is speculative, and that “sci-
entific research is never or only occasionally checked by other scientists before being
published,” illustrating the important gap in knowledge about the process of scientific
discovery.
To increase public trust in science, and to improve science literacy, researchers and lay
communicators alike have put forward models of knowledge translation. Earlier mod-
els, such as the deficit model, emphasized the transfer of knowledge in one-​way and
one-​time processes, such as popularization of science through books. In recent decades,
there has been much discussion and criticism of this top-​down dissemination model
(Gregory & Miller 2000; Wilsdon & Willis 2004). As the multidirectional nature of sci-
ence communication emerged, the dialogue model was put forward, proposing a two-​
way, iterative process focused on consultation and the recognition and discussion of the
implications of scientific discoveries (Bucchi 2008). In a shift driven by the urgency of
fully engaging lay audiences in research, emerging models of science communication
emphasize engagement between disciplines as well as with the general public. In the
participation model, knowledge is co-​produced; multidirectional communication takes
place between all stakeholder groups with the goal of having all parties participate in
shaping the agenda.
As these models evolve, so does the environment in which science communication
takes place. The last century has seen an exponential increase in the specialization of
science. Neuroscience, for example, now comprises dozens of specialties, each with their
own methods, experimental designs, and terminologies. In addition to this specialization,
neuroscience is also becoming increasingly multidisciplinary, with contributions from
engineering, computer science, social sciences, psychology, and ethics, to mention just a
few. As science broadly and neuroscience specifically become increasingly both special-
ized and multidisciplinary, new challenges arise, such as the lack of training in translating
difficult concepts to lay audience (Illes et al. 2009) and the need to effectively translate
across disciplines at the expert level.

The brain is uniquely challenging

Diseases of the brain are complex, and while the pace of discovery has accelerated in
recent years with improved imaging and genomics technology, the origins of many neu-
rological diseases are still poorly understood. Degenerative diseases of and injuries to the
brain and nervous system—​taken together—​represent an urgent social and medical chal-
lenge and are an important cause of mortality, with the World Health Organization esti-
mating that neurological disorders account for 12% of deaths globally every year (World
Health Organization n.d.). The pace of brain health research challenges scientists and
the public alike, and so engagement on public health issues, and clear communication
of discoveries, challenges, timelines, and research needs are important priorities for the
neuroscience community.
Beyond health and illness, the brain also represents our minds and hosts our sense
of self. Unlike for other organs, understanding the brain and surrounding concepts
 57

The evolution of science communication 557

such as emotions, states of consciousness, and behaviors has important implications

for individuals and interpersonal and societal relationships (Illes 2006). Neuroscience
communication thus presents challenges, distinct from other areas of science com-
munication, in that many mysteries of the brain remain unsolved. Because so little is
known about how the brain functions in health and illness, and because people are
living longer and the population is aging, timely, accurate, and relevant communica-
tion about how to maximize the benefits of advances in neuroscience and neurology is
an urgent global issue. While traditional media remains the primary source of science
news for most people, online searches for and discussion of neuroscience topics are
increasing.
In parallel with the shifting context of neuroscience communication, there has been sig-
nificant growth and democratization of mass media in recent years, enabled by the devel-
opment of dynamic platforms such as Internet and mobile applications. More than ever,
the interactive web and mobile environments and the social media platforms they support
are providing new opportunities to communicate and discuss neuroscience advances. The
increase in the use of Internet-​enabled applications has many potential and proven ben-
efits over past approaches to reaching consumers of science and health information: the
Internet  allows for the rapid dissemination of information, promotes multidirectional
engagement among different types of stakeholders, and reduces barriers to access infor-
mation. For content with implications for health, online and mobile platforms may also
promote autonomy and empowerment in health decision-​making (Kim E.-​H. et al. 2011),
and may lead to increased social support for users interacting with others in discussion
groups and forums (Idriss et al. 2009; van Uden-​Kraan et al. 2009). However, the online
environment as a venue for neuroscience communication is not without risks: many stud-
ies raise concerns over the quality of the information available online and in social media
(Eysenbach et al. 2002; Scullard et al. 2010; Robillard et al. 2013), and the legitimacy of
the information can be difficult to evaluate. Online discussion of discoveries tends to be
trend based, following science news coverage in traditional media (Ipsos MORI 2014).
Conflicts of interest are also frequent, such as when commercially driven websites pro-
mote content meant to educate web users and imply an association between specific prod-
ucts and healthy lifestyles (Illes et al. 2004). As the proportion of Internet users who seek
health information grows, various industries hope to capitalize on this behavior, and the
line between providing health information and direct-​to-​consumer advertising (DTCA)
is increasingly blurred (Racine et al. 2007). This phenomenon predates the digital era: in
2004, investigators uncovered important concerns with print materials promoting self-​
referred imaging, such as a lack of balanced information necessary for the preserva-
tion of autonomy in health decision-​making (Illes et  al. 2004). Similar concerns were
raised for web-​based materials promoting DTCA for genetic services (Risk and Petersen
2002; Gollust et al. 2003) and for complementary and alternative medicine for dementia
(Palmour et al. 2014), among other examples.
This changing media environment gives rise to new challenges and ethical consider-
ations: how can the potential of new media platforms to enhance the delivery of engaging,
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558 Communicating about the brain in the digital era

high-​quality, and multidirectional science communication be harnessed? Here we use

dementia as a case study to answer this question.

Aging advice in a digital world

Recent survey data shows that older adults are increasingly online: over half of Canadians
65 years or older are Internet users, and of those, a majority use the Internet to search
for health information and medical diagnoses (Cline and Haynes 2001; Song et al. 2002;
Vance et al. 2009; Zulman et al. 2011). Online information and tools are reshaping health-
care by offering powerful new ways for stakeholders to gather and share information
(Hawn 2009). Online sources of information and platforms for exchange can potentially
enhance the health of their users, if used in consultation with a physician who can provide
context for how to apply this new information to their existing health or care regimen.
Internet users can increase their social support and feelings of connectedness (Wangberg
et al. 2008; Idriss et al. 2009) as well as feel empowered in managing their health (van
Uden-​Kraan et  al. 2009). Interactive Internet applications can also increase the demo-
cratic aspect of information-​sharing, which in turn leads to a patient-​centered experi-
ence (Hawn 2009). Efforts to promote health through online platforms have a broader
reach than traditional media and have been shown to have a significant impact for certain
conditions that are tightly linked to healthy aging, such as smoking cessation and dietary
interventions (Block et  al. 2008; Norman et  al. 2008; Thackeray et  al. 2008). However,
online health resources are not free of risk. Broad-​reaching, easily accessible platforms
can lead to the wide dissemination of misinformation (Kortum et al. 2008) and informa-
tion of uneven quality. Confusion may arise when unregulated and commercially driven
website content is represented as educational, as users may assume the information is free
of bias (Wolfe 2002). Further, users have reported that they have difficulties in identifying
and using appropriate information, and—​without clarifying their findings with their fam-
ily doctor—​may experience anxiety as a result of consulting online resources (Eysenbach
et al. 2002; Benigeri & Pluye 2003). These risks are particularly acute when the consumers
of the information may suffer from possible cognitive impairment.
Unregulated online information introduces a new variable in health and quality of life
and the patient–​physician relationship. As dementia ranks among the most feared con-
ditions by older adults (Corner & Bond 2004), online resources have emerged to meet
their specific information demands. In this context, we explore the quality of three types
of these resources about dementia: (1) social media posts, (2) websites containing health
information about the prevention of dementia, and (3) self-​assessments.

Social media
Social media platforms allow for content to be created and modified on an ongoing basis,
and as such have transformed information-​sharing from the passive consumption of top-​
down dissemination to active engagement with multidirectional, peer-​based exchange.
Extensive conversations about dementia are taking place on social media platforms.
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Aging advice in a digital world 559

From one 24-​hour period in February 2012, for example, we captured 9200 unique tweets
(Robillard et al. 2013). We used a customized content analysis methodology (Robillard
et al. 2013) to characterize the following features of Twitter posts: (1) users contributing
to this volume of activity on Twitter, (2)  websites that are linked to in the tweets, and
(3) thematic content of the tweets.
In answer to the first question, we collected and analyzed publically available data fields
for freely contributed user information. We found that health professionals were the larg-
est group contributing to the conversation. Of the sample, 17% were from this cohort of
individuals operating in all realms of healthcare such as medicine, pharmacy, and nurs-
ing. News groups and commercial organizations also contributed important proportions
of tweets (news: 10%; commercial: 10%). Care services facilities, journalists, patients and
their families, and researchers represented the remaining groups of sources of tweets.
We answered the second question by analyzing the links to third-​party websites con-
tained within the text of tweets and found that 50% of the links redirected to an article
hosted on a news site, such as BBC News or CBC News. This finding suggests that while
new media provides unprecedented opportunity for engagement with information, at the
present time popular platforms such as Twitter still rely heavily on traditional media to
create and host content, at least for topics related to dementia.
To answer the third research question, we conducted a content analysis of the text of
tweets. Although researchers themselves were relatively low contributors in the sample
studied, their findings certainly made their way into the tweets: 48% referred to a specific
research study, and of these, 76% were about peer-​reviewed, original research. Especially
intriguing was the way that different tweets from different users described the same
research study: for example, an abstract from the 2012 American Academy of Neurology
Annual Meeting entitled “Walking Speed, Handgrip Strength and Risk of Dementia
and Stroke:  The Framingham Offspring Study” was featured in a tweet that read “Fast
walking speed and a strong grip in middle age may help predict dementia risk.” Another
tweet based on the same abstract read “Slow walking ‘predicts dementia.’ ” Similarly,
the research described in an article published in the Journal of the American Medical
Association Neurology in 2012 entitled “Sleep Quality and Preclinical Alzheimer Disease”
was tweeted both as “Disturbed sleep is associated with preclinical signs of Alzheimer’s
disease, researchers found” and as “Study shows sleep prevents Alzheimer’s.” In the case
of both these examples about walking speed and sleep, the first tweet harnessed the 140
available characters to provide an accurate representation of the research and used cau-
tious vocabulary designed to mitigate false hopes; the second tweet leans closer toward
misleading and sensationalized oversimplifications.
Science discoveries and advances in biotechnologies that relate to the brain are often
hyped in the media: their benefits exaggerated and their risks minimally discussed. These
overly positive representations of neuroscience and neurology findings can lead to ethical
conflict when they are responsible for the generation of false hopes in potentially vul-
nerable readers. Many different factors contribute to this problem along the entire pro-
cess from scientific discovery to publication: on the one hand, scientists face pressures
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560 Communicating about the brain in the digital era

to appeal to funders, the industry, and to the public; on the other, journalists and media
institutions must put forward newsworthy content to drive profit (Bubela et  al. 2009).
With the rise of Internet marketing, headline writers at traditional media outlets have
been put into a position where they must compete with new media aggregators and digi-
tal sales channels for a limited share of Internet users’ attention in an increasingly satu-
rated online space. This has led to headlines tailored specifically to generate an emotional
response in readers in order to entice them to click through to read more. In a 2016
study on science news headlines, researchers found that “although tentativeness is part
and parcel of communicating science, popular science journalism employs epistemic
modality strategically to mix reporting with predicting, recounting with speculating and
evidentiality with possibility (Molek-​Kozakowska 2016)”. While the phenomenon of hype
in neuroscience communication has been observed in traditional media (Caulfield and
Rachul 2011; Caulfield and McGuire 2012), it can be further fueled by the format of social
media platforms, for example, those that require very short descriptions of shared con-
tent, such as Twitter. For example, a recent analysis of the discussion about stem cells
and Parkinson’s disease or spinal cord injury on Twitter showed that research was at the
forefront of the discussion but that the majority of tweets were either positive or neutral in
tone and that there was very little discussion of risks (Robillard et al. 2015a). One concern
with sensationalized neuroscience findings is that this would facilitate the early adoption,
use, and promotion of unproven interventions (Ryan et al. 2010). Another consequence
of overly simplified headline-​driven science communication is that expertise is diluted
to the point where researchers’ authority over their subject matter appears questionable,
reducing public trust in scientists and institutions (Fischoff 2013), or fueling the increase
of trust in trends like homeopathy or natural health alternatives with no scientific validity
or clinical endorsement.

Websites
Over half of the 65-​years-​and-​older demographic uses the web specifically to seek health
information. To examine the quality of the available information, we applied a quality
evaluation tool to a sample of articles about the prevention of Alzheimer’s disease. We
retrieved 290 articles through a location-​independent keyword search on Google, the
most used search engine in North America. The evaluation tool is an original adaptation
of previous work by Chumber and colleagues (Chumber et al. 2015), Sandvik (Sandvik
1999), and the JAMA benchmarks developed by Silberg and colleagues (Silberg et  al.
1997). It consists of six weighted criteria for a maximum score of 28:  (1)  authorship,
(2) attribution, (3) conflict of interest, (4) currency, (5) complementarity, and (6) tone.
The articles scored across the full range of quality, but we distinguished two clear tails
of the distribution:  articles that rated poorly (score:  4–​11) and those that rated highly
(score:  24–​27). Three main characteristics separated the low-​and high-​quality arti-
cles: conflict of interest, attribution of claims, and tone. The presence of an endorsement
or commercial advertisement of a product or service within an otherwise informational
article about the prevention of Alzheimer’s disease signaled conflict of interest. This
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Aging advice in a digital world 561

important ethical concern was identified in 20% of the sample. None of the highest scor-
ing articles contained this feature. We found that scientific claims were attributed to gen-
eral research (broad, unverifiable claims using research words, such as “research studies
show that … ,” 60% of the articles), specific studies (58%), and quotes from doctors (30%);
many articles contained more than one type of attribution. High-​quality articles were
more likely to cite a specific study that could be traced back by the researcher. Finally, the
tone of recommendations differed across the sample. We found strong recommendations,
unequivocal language, and little discussion of alternatives or limitations to the featured
prevention strategies in 22% of the articles. Only 13% presented both balanced advice
with cautious vocabulary, and discussed the limitations of the research supporting the
claims.
As online behaviors have been shown to influence offline behaviors, poor commu-
nication about dementia but also about advances in neuroscience and neurology more
broadly may lead to decision-​making toward negative health outcomes. For example, a
study by Walji and colleagues showed that one-​quarter of websites about three popular
herbal supplements contained recommendations that, if followed, would lead directly to
physical harms (Walji et  al. 2004). Of particular concern is the industry around com-
plementary and alternative medicines for brain conditions ranging from depression to
Alzheimer’s disease. Dietary supplements and homeopathic remedies for a number of
conditions are readily available for purchase on the Internet and promoted through social
media. Palmour and colleagues examined websites about dietary supplements specifically
for Alzheimer’s disease and found that only 16% of these sites contained peer-​reviewed
evidence to support the claims about the benefits of the products (Palmour et al. 2014).
While the notion of autonomy in health decision-​making favors empowerment and
accessibility to varied sources of information, an ethical conflict arises when the available
resources are so greatly varied in quality.

Self-​assessments
Online self-​assessments are available for a wide variety of brain-​related conditions
including depression, anxiety, migraines, as well as neurodegenerative conditions such
as Alzheimer’s disease. They are also becoming increasingly popular as measured by the
proportion of Internet users who report going online specifically to establish whether
they or someone they know suffer from a medical condition. Today, that number is more
than 30% (Fox 2013). No doubt, self-​assessments for brain-​related conditions may result
in benefits for the target users: they may feel empowered, they can access information
when traditional health services are difficult to reach, and they may become motivated
to seek medical advice or self-​monitor for preventive purposes (Trustram Eve & de Jager
2014). However, the limited oversight of technology-​assisted self-​assessments may also
adversely lead to inaccurate self-​diagnosis and treatment (Lovett et al. 2012). Users may
misinterpret graphic displays of risk and associated terminology (Johnson & Shaw 2012),
and select inappropriate actions that lead to negative health consequences (Waters et al.
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562 Communicating about the brain in the digital era

2009; Lovett et al. 2012). These risks are exacerbated in the case of Alzheimer’s disease for
which no broadly effective treatments exist.
In 2015, we (Robillard and colleagues) published the results of the first study to our
knowledge to evaluate online self-​assessments for Alzheimer’s disease. We studied 16
tests available on high-​traffic websites (Robillard et al. 2015b) for criteria related to scien-
tific validity such as test–​retest reliability, ethical features such as conflict of interest, and
human–​computer interactions features such as usability. We found that most tests in our
sample were not scientifically valid and failed to deliver meaningful information about
Alzheimer’s disease or other dementias in an ethically sound and user-​friendly way, with
no test scoring excellent across all criteria evaluated. Expert ratings for human–​computer
interaction items were variable, with ratings in the acceptable range for clarity of instruc-
tions and quality of the visuals (e.g., contract, font size) and lower ratings for the detecting
of invalid performances and accommodations for varying levels of computer knowledge.
Expert ratings for ethics-​related factors were the lowest, and ranged from very poor
to poor across most criteria. Despite the fact that the tests resembled legitimate medi-
cal interventions, the informed consent process was either lacking or overly dense. In
response to the wealth of available information online and to concerns with both DTCA
and informed consent in the digital age, Bal and Brenner ask “Has the Internet made
informed consent obsolete?” (Bal & Brenner 2015). Indeed, the digital age has shifted
how patients educate themselves about their conditions, the available conventional but
also alternative treatments, and the risks and benefits associated with each option. While
informed consent was initially designed in the context of a system whereby the physician
is the primary source of health information, a recent survey found that 91% of physicians
surveyed have seen patients who made inquiries about information they found online
(Kim J. & Kim S. 2009). When writing about informed consent in the online environment
more broadly, for example with regard to personalized advertising and behavior tracking,
Friedman and colleagues state: “To date, informed consent is woefully understudied by
the online community and underused as a means of cultivating trust online,” and call for
research into the development of principles to implement consent in the online environ-
ment (Friedman et al. 2000). As the medical community shifts toward new channels of
communication about brain health, it becomes imperative to consider how information
and misinformation acquired through online and mobile platforms will impact the ethi-
cal duty to obtain informed consent for both online interventions and those delivered in
the clinic.
Similarly, for most tests, language around privacy and confidentiality of the data
that were entered as part of the test-​taking process was either absent or incorpo-
rated into lengthy terms of agreement. In Canada, the Freedom of Information and
Protection of Privacy Act was enacted in the 1980s “to govern the collection, use and
disclosure of personal information by organizations in a manner that recognizes both
the right of individuals to protect their personal information and the need of organi-
zations to collect, use or disclose personal information for purposes that a reasonable
person would consider appropriate in the circumstances” (Office of the Information
 563

Looking to the future 563

and Privacy Commissioner 1983). The Act protects the personal information of pri-
vate citizens and limits disclosure of personal information by organizations or pub-
lic bodies; however, this protection extends only to information stored on Canadian
servers. Other jurisdictions may offer different or no protection for personal data.
Without protective legislation in place, personal data may be vulnerable to third-​
party sale, subpoena, or theft.
In the United States, the Genetic Information Nondiscrimination Act (GINA) (United
States 2008)  protects private citizens from discrimination by employers or insurers
based on genetic information, and builds upon the Health Insurance Portability and
Accountability Act (HIPPA) (United States 2004) and related privacy rules. The intention
of these privacy rules was meant to protect individuals’ private health information, but
there is no guideline or legislation in place to ensure privacy of personal health informa-
tion given voluntarily via non-​healthcare commercial entities, such as websites.
Terms of agreement may be vague in detailing how personal data may be used, and
because this is relatively new legal terrain, it is unclear in many jurisdictions whether user
agreements for web services and products are legally binding or if the terms themselves
are ethically sound.
All 16 tests in our sample rated either very poorly or poorly with regard to conflicts of
interest. For example, one of the self-​assessments for dementia in the sample consisted
of a number of questions about daily activities, behaviors, and risk factors. However, all
possible combinations of answers yielded the same result:  a strongly worded warning
about a severe risk of developing Alzheimer’s disease, followed by a recommendation to
purchase three different supplements from the online store of the website. In this case, a
predatory marketing strategy masqueraded as a self-​test aimed at providing meaning-
ful information regarding one’s risk of developing dementia. Though not all conflicts of
interests uncovered in our studies were so deeply problematic, they all had the poten-
tial to compromise the quality of the information offered to a vulnerable segment of the
population, especially as older adults may experience difficulties with the identification
of trustworthy information (Castle et al. 2012). In turn, information that is unbalanced,
biased, or of poor quality may compromise personal autonomy and prevent meaningful
decisions for brain health.

Looking to the future
“In the 16th century,” writes Robert Lucky, “science progressed at the pace of the postal
system. Often it would take six months for one scientist to learn of the ongoing results of
another. It took even more time for scientists to build on one another’s accomplishments”
(Lucky 2000). As the ability of scientists to communicate more efficiently has improved,
so has the ability to uncover the mysteries of the brain and behavior. In parallel, the rate
of discovery has advanced together with technology, with publication rates in scientific
journals increasing by nearly 5% per year (Larsen & von Ins 2010). The benefit of moving
from a top-​down to a participatory model of neuroscience communication in a process
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564 Communicating about the brain in the digital era

enabled by recent advances in technology results in a democratization of science, both for

researchers and for the general population.
There are many advantages to improving scientific literacy, whether through traditional
or novel mechanisms. In the book Neuroethics: Mapping the Field (Marcus 2002), Colin
Blakemore, one of Britain’s most influential science communicators, identifies three: an
informed public is (1) better able to assess risks and benefits of decisions that are rel-
evant for their lives; (2) empowered to participate in discussions and debates about the
scientific and technology agendas; and (3) more likely to support evidence-​based poli-
cies (Blakemore 2002). With these advantages in mind, educating scientists about how to
communicate with the public, and educating the public on how to parse the language of
science can only benefit both parties, both in terms of increased funding for research as
public stakeholders understand the value of that funding, and improved access to essen-
tial information for those who seek it online or elsewhere. By understanding the contexts
each group brings to framing neuroscience news, science communicators can move pub-
lic thinking to a mutually beneficial and productive place.
While calls for more education for both scientists and science communicators have
already been put forward (Illes et al. 2009), these initiatives should now consider incor-
porating lessons about new media. For example, as article and press release titles and
portions of abstracts are often used verbatim in online social media, and particularly on
platforms that limit the quantity of text that can be incorporated into a post, research-
ers should learn to phrase these in a way that, should they become widely accessible to
the public, would not lead to false hopes or misunderstandings. Physicians and other
healthcare providers, whose relationships with patients and their families are increas-
ingly shaped by technology-​enabled health resources, should also be provided with edu-
cational opportunities to better understand the evolving needs of the patient community.
Neurologists and family physicians, for example, would benefit from leadership from the
scientific community about how lay people are being directed in terms of resources and
how these are incorporated into health decision-​making, in order to better serve and treat
highly informed patient populations.
In addition to efforts to educate knowledge producers, knowledge consumers and cli-
nicians, more empirical research will be required to determine the impact of neurosci-
ence communication in the digital age on health decision-​making. The work described
here and that of others has laid down a solid foundation of knowledge with regard to
the quality and the ethics of available online resources for brain health. However, this
is a dynamic and rapidly evolving landscape, and ongoing and collaborative efforts will
be required to continue to monitor the available resources and their potential risks and
benefits. In addition, providing ethical, high-​quality online information is likely not suf-
ficient to ensure that Internet users make decisions that lead to positive health outcomes.
As such, it is imperative to evaluate the role that online information and services play in
health decision-​making and develop responsive and ethical resources that maximize the
benefits to the users in this age of eHealth.
 56

Looking to the future 565

Over 30  years later, the recommendations of the Royal Society’s 1985 report for
scientists to consider science communication a duty are still very relevant. Looking
to the future, all scholars in the life and social sciences must include in these recom-
mendations to keep pace with the rapidly evolving communications landscape and
embrace the conversation about brain, health, and ethics that is taking place on inter-
active platforms (Table 28.1). In the balance of the benefits and risks of new com-
munication channels lies a significant opportunity for scientists to engage with the
public about neuroscience and neuroethics, and to join forces in developing priorities
for the future.

Table 28.1  Comparison between pre-​Internet and digital era modes of neuroscience

communication

Pre-​Internet era Digital era

General

Model of communication Top-​down Peer-​to-​peer

Authoritative Democratic
Direction Unidirectional Multidirectional
Media Paper Paper
Television Television
Radio Radio
Internet
Mobile technology
Culture Siloed Collaborative
Expert-​driven Participatory
Curation News editors News editors
Science writers Science writers
Academic journals Academic journals
Bloggers
Researchers
Public
Vetting Organizations Organizations
Individuals
Reach Targeted Global
Speed of information flow Slow Instant
Number of sources Finite Infinite
Information sharing Original materials Hyperlinks
Paper photocopies, printouts Social sharing buttons
Digital copies
Cost Paid by subscription/​membership Free
Paid by advertising
Paid by subscription/​membership

(continued)
56

566 Communicating about the brain in the digital era

Table 28.1  Continued

Pre-​Internet era Digital era

Ethical considerations
Privacy of personal Secure At risk due to inconsistent regu-
information lations around data storage and
server access, hacking
Commercial conflict of Possible Possible
interest
Risks of self-​diagnosis Low High
Sensationalism/​hype Possible, but limited to life cycle of Possible, long-​lasting as data is
publication archived forever

Acknowledgments
J.M.R would like to acknowledge all co-​authors who contributed to this published work,
research assistant Tanya Feng at the National Core for Neuroethics, University of British
Columbia, for her work on the analysis of websites about the prevention of Alzheimer’s
disease, and all members of the Robillard lab for their contributions to the development
of the online health information quality evaluation tool.

References
Bal, B.S. and Brenner, L.H. (2015). Medicolegal sidebar: informed consent in the information age.
Clinical Orthopaedics and Related Research, 473, 2757–​2761.
Benigeri, M. and Pluye, P. (2003). Shortcomings of health information on the Internet. Health
Promotion International, 18, 381–​386.
Blakemore, C. (2002). From the “public understanding of science” to scientists' understanding of the
public. In Marcus, S.J. (Ed.) Neuroethics: Mapping the Field, pp.211–​221. New York: Dana Press.
Block, G., Sternfeld, B., Block, C.H., et al. (2008). Development of Alive! (A Lifestyle Intervention
Via Email), and its effect on health-​related quality of life, presenteeism, and other behavioral
outcomes: randomized controlled trial. Journal of Medical Internet Research, 10, e43.
Bubela, T., Nisbet, M.C., Borchelt, R., et al. (2009). Science communication reconsidered. Nature
Biotechnology, 27, 514–​518.
Bucchi, M. (2008). Handbook of Public Communication of Science and Technology. Abingdon: Routledge.
Castle, E., Eisenberger, N.I., Seeman, T.E., et al. (2012). Neural and behavioral bases of age differences
in perceptions of trust. Proceedings of the National Academy of Sciences of the United States of
America, 109, 20848–​20852.
Caulfield, T. and McGuire, A. (2012). Athletes’ use of unproven stem cell therapies: adding to
inappropriate media hype? Molecular Therapy, 20, 1656–​1658.
Caulfield, T. and Rachul, C. (2011). Science spin: iPS cell research in the news. Clinical Pharmacology &
Therapeutics, 89, 644–​646.
Chumber, S., Huber, J., and Ghezzi, P. (2015). A methodology to analyze the quality of health
information on the internet the example of diabetic neuropathy. The Diabetes Educator, 41, 95–​105.
 567

References 567

Cline, R.J.W. and Haynes, K.M. (2001). Consumer health information seeking on the internet: the state
of the art. Health Education Research, 16, 671–​692.
Corner, L. and Bond, J. (2004). Being at risk of dementia: fears and anxieties of older adults. Journal of
Aging Studies, 18, 143–​155.
Eysenbach, G., Powell, J., Kuss, O., and Sa, E.R. (2002). Empirical studies assessing the quality of health
information for consumers on the world wide web: a systematic review. JAMA, 287, 2691–​2700. 1.
Fischhoff, B. and Scheufele, D.A. (2013). The science of science communication. Proceedings of the
National Academy of Sciences of the United States of America, 110(Suppl. 3), 14031–​14032.
Fox, S. (2013). Health Online 2013. Washington, DC: Pew Research Center’s Internet & American Life
Project.
Friedman, B., Khan Jr, P.H., and Howe, D.C. (2000). Trust online. Communications of the ACM,
43, 34–​40.
Gollust, S.E., Wilfond, B.S., and Hull, S.C. (2003). Direct-​to-​consumer sales of genetic services on the
Internet. Genetics in Medicine, 5, 332–​337.
Gregory, J. and Miller, S., 2000. Science in Public: Communication, Culture, and Credibility. Cambridge,
MA: Basic Books.
Hawn, C. (2009). Take two aspirin and tweet me in the morning: how Twitter, Facebook, and other
social media are reshaping health care. Health Affairs (Millwood), 28, 361–​368.
Idriss, S.Z., Kvedar, J.C., and Watson, A.J. (2009). The role of online support communities: benefits of
expanded social networks to patients with psoriasis. Archives of Dermatology, 145, 46–​51.
Illes, J. (Ed.) (2006). Neuroethics: Defining the Issues in Theory, Practice, and Policy. Oxford: Oxford
University Press.
Illes, J., Kann, D., Karetsky, K., et al. (2004). Advertising, patient decision making, and self-​referral
for computed tomographic and magnetic resonance imaging. Archives of Internal Medicine, 164,
2415–​2419.
Illes, J., Moser, M.A., McCormick, J.B., et al. (2009). Neurotalk: improving the communication of
neuroscience research. Nature Reviews Neuroscience, 11, 61–​69.
Ipsos MORI (2014, March). Public Attitudes to Science 2014. Available from: https://​www.ipsos-​mori.
com/​researchpublications/​researcharchive/​3357/​Public-​Attitudes-​to-​Science-​2014.aspx [accessed
April 16, 2016].
Jacques, J. and Raichvarg, D. (1991). Savants et ignorants: Une histoire de la vulgarisation des sciences.
Paris: Seuil.
Johnson, C.M. and Shaw, R.J. (2012). A usability problem: conveying health risks to consumers on the
Internet. AMIA Annual Symposium Proceedings, 2012, 427–​435.
Kim, E.-​H., Coumar, A., Lober, W.B., and Kim, Y. (2011). Addressing mental health epidemic among
university students via web-​based, self-​screening, and referral system: a preliminary study. IEEE
Transactions on Information Technology in Biomedicine, 15, 301–​307.
Kim, J. and Kim, S. (2009). Physicians’ perception of the effects of internet health information on the
doctor–​patient relationship. Informatics for Health and Social Care, 34, 136–​148.
Kortum, P., Edwards, C., and Richards-​Kortum, R. (2008). The impact of inaccurate Internet health
information in a secondary school learning environment. Journal of Medical Internet Research,
10, e17.
Larsen, P.O. and von Ins, M. (2010). The rate of growth in scientific publication and the decline in
coverage provided by Science Citation Index. Scientometrics, 84, 575–​603.
Lovett, K.M., Mackey, T.K., and Liang, B.A. (2012). Evaluating the evidence: direct-​to-​consumer
screening tests advertised online. Journal of Medical Screening, 19, 141–​153. 1.
Lucky, R. (2000) The quickening of science communication. Science, 289(5477), 259–​64.
568

568 Communicating about the brain in the digital era

Marcus, S.J. (Ed.) (2002). Neuroethics: Mapping the Field. New York: Dana Press.

Molek-​Kozakowska, K. (2016). Stylistic analysis of headlines in science journalism: a case study
of New Scientist. Public Understanding of Science. Advance online publication. doi:10.1177/​
0963662516637321
Norman, C.D., McIntosh, S., Selby, P., and Eysenbach, G. (2008). Web-​assisted tobacco
interventions: empowering change in the global fight for the public’s (e)Health. Journal of Medical
Internet Research, 10, e48.
Office of the Information and Privacy Commissioner (1983). Personal Information Protection Act.
Quebec, Canada: Office of the Information and Privacy Commissioner.
Palmour, N., Vanderbyl, B.L., Zimmerman, E., Gauthier, S., and Racine, E. (2014). Alzheimer’s disease
dietary supplements in websites. HEC Forum, 25, 361–​82.
Rachul, C. and Caulfield, T. (2015). Gordie Howe’s stem cell “miracle”: a qualitative analysis of news
coverage and readers’ comments in newspapers and sports websites. Stem Cell Reviews and Reports,
11, 667–​675.
Racine, E., van Der Loos, H.A., and Illes, J. (2007). Internet marketing of neuroproducts: new practices
and healthcare policy challenges. Cambridge Quarterly of Healthcare Ethics, 16, 181–​194.
Risk, A. and Petersen, C. (2002). Health information on the internet: quality issues and international
initiatives. JAMA, 287, 2713–​2715.
Robillard, J.M., Johnson, T.W., Hennessey, C., Beattie, B.L., and Illes, J. (2013). Aging 2.0: health
information about dementia on Twitter. PloS One, 8, e69861.
Robillard, J.M., Cabral, E., Hennessey, C., Kwon, B.K., and Illes, J. (2015a). Fueling hope: stem cells in
social media. Stem Cell Reviews, 11, 540–​546.
Robillard, J.M., Illes, J., Arcand, M., et al. (2015b). Scientific and ethical features of English-​language
online tests for Alzheimer disease. Alzheimer’s & Dementia, 1(3), 281–​288.
Royal Society (1985). The Public Understanding of Science. Available from: https://​royalsociety.org/​~/​
media/​Royal_​Society_​Content/​policy/​publications/​1985/​10700.pdf [accessed February 5, 2017].
Royal Society (2006, June). Science Communication. Available from: https://​royalsociety.org/​topics-​
policy/​publications/​2006/​science-​communication/​ [accessed April 16, 2016].
Ryan, K.A., Sanders, A.N., Wang, D.D., and Levine, A.D. (2010). Tracking the rise of stem cell tourism.
Regenerative Medicine, 5, 27–​33.
Sandvik, H. (1999). Health information and interaction on the internet: a survey of female urinary
incontinence. BMJ, 319, 29–​32.
Scullard, P., Peacock, C., and Davies, P. (2010). Googling children’s health: reliability of medical advice
on the internet. Archives of Disease in Childhood, 95, 580–​582.
Silberg, W.M., Lundberg, G.D., and Musacchio, R.A. (1997). Assessing, controlling, and assuring the
quality of medical information on the internet: caveant lector et viewor –​let the reader and viewer
beware. JAMA, 277, 1244–​1245.
Song, T.M., Park, E.J., and Lim, E.J. (2002). The survey of the demand for health information on the
internet. Journal of Korean Society of Medical Informatics, 8, 17–​24.
Thackeray, R., Neiger, B.L., Hanson, C.L., and McKenzie, J.F. (2008). Enhancing promotional strategies
within social marketing programs: use of Web 2.0 social media. Health Promotion Practice, 9,
338–​343.
Trustram Eve, C. and de Jager, C.A. (2014). Piloting and validation of a novel self-​administered online
cognitive screening tool in normal older persons: the Cognitive Function Test. International Journal
of Geriatric Psychiatry, 29, 198–​206.
United States (2004). The Health Insurance Portability and Accountability Act (HIPAA). Washington,
DC: US Department of Labor, Employee Benefits Security Administration.
 569

References 569

United States (2009). The Genetic Information Nondiscrimination Act of 2008 (GINA). Washington,
DC: US Department of Labor, Employee Benefits Security Administration.
van Uden-​Kraan, C.F., Drossaert, C.H.C., Taal, E., Seydel, E.R., and van de Laar, M.A. (2009).
Participation in online patient support groups endorses patients’ empowerment. Patient Education
and Counseling, 74, 61–​69.
Vance, K., Howe, W., and Dellavalle, R.P. (2009). Social internet sites as a source of public health
information. Dermatologic Clinics, 27, 133–​136, vi.
Walji, M., Sagaram, S., Sagaram, D., et al. (2004). Efficacy of quality criteria to identify potentially
harmful information: a cross-​sectional survey of complementary and alternative medicine web sites.
Journal of Medical Internet Research, 6.
Wangberg, S.C., Andreassen, H.K., Prokosch, H.-​U., Santana, S.M.V., Sørensen, T., and Chronaki,
C.E. (2008). Relations between Internet use, socio-​economic status (SES), social support and
subjective health. Health Promotion International, 23, 70–​77.
Waters, E.A., Sullivan, H.W., Nelson, W., and Hesse, B.W. (2009). What is my cancer risk? How
internet-​based cancer risk assessment tools communicate individualized risk estimates to the
public: content analysis. Journal of Medical Internet Research, 11, e33.
World Health Organization (n.d.). Neurology and Public Health. Available from: http://​www.who.int/​
mental_​health/​neurology/​en/​ [accessed April 16, 2016].
Wilsdon, J. and Willis, R. (2004). See-​Through Science: Why Public Engagement Needs to Move
Upstream. London: Demos.
Wolfe, S.M. (2002). Direct-​to-​consumer advertising—​education or emotion promotion? New England
Journal of Medicine, 346, 524–​526.
Zulman, D.M., Kirch, M., Zheng, K., and An, L.C. (2011). Trust in the internet as a health resource
among older adults: analysis of data from a nationally representative survey. Journal of Medical
Internet Research, 13.
570

Chapter 29

The impact of neuroscience in the law:

How perceptions of control and
responsibility affect the definition
of disability
Jennifer A. Chandler

Introduction
For better and worse, biomedical explanations of human behavior, including genetic and
neuroscientific explanations, seem to affect public perceptions of a person’s moral and
legal responsibility for that behavior. This effect flows from the tendency to regard a per-
son’s biological constitution as given and largely fixed and, crucially, as a causal contribu-
tor to that person’s behavior. In other words, the perception seems to be first that a person
has no control over the origin and little control over the continuation of that essential bio-
logical nature, and second, that this biology determines or at least predisposes a person to
a particular behavior. Because the person has little control over any of this, the person is
perceived to have diminished responsibility for that behavior. As I will discuss, the extent
to which this pattern of thought holds true, and the circumstances in which it does so, are
both still matters of debate.
The purpose of this chapter is to consider the hypothesis that neurobiological
accounts of behavior will affect the law, not just in the criminal context, but also in
how disability is defined in the law. The chapter first presents a very short overview of
some of the ways that neurobiology may affect judgments of criminal responsibility,
in order to explore the importance of control in assessing responsibility as well as the
countervailing impulse to control and supervise those who are judged to be dangerous
and incapable of controlling themselves rather than unwilling to do so. The chapter
then proceeds to explain how control and responsibility for one’s condition affects the
concept of disability and the social willingness to offer support and protection. Finally,
examples drawn from the treatment in human rights law of contested conditions like
addictions to gambling, sex or the Internet, and nicotine are used to illustrate the man-
ner in which medicalization and, where possible, neurobiological explanations, have
been used to try to suggest that the conditions constitute disabilities that ought to be
accommodated rather than punished.
 571

Introduction 571

The positive consequences of this phenomenon lie in the reduction of blame for socially
disfavored behavior and traits and increased willingness to forgive and to help. However,
the negative consequences flow from the corollary of the idea that the person’s behavior
is explained by biological factors beyond his or her control, namely that the person is a
faulty biological mechanism lacking self-​control. In other words, the person is viewed
as falling within a different biological category than other people, and furthermore, the
person must be supervised or controlled if the disfavored behavior poses a threat. The
particular mix of these reactions will likely vary from case to case, and the impulse to
help may be swamped by the more negative reactions for behaviors that are perceived as
particularly dangerous.
These are general reactions documented and discussed in the study of mental
health stigma, biopolitics, and many other fields. In recent years, they have been
increasingly discussed in the law. Since the questions of self-​control, responsibility,
and moral blameworthiness are of central importance in ascribing criminal respon-
sibility and selecting the appropriate social response, a large literature has developed
regarding the effect of behavioral genetics and neuroscience on criminal responsi-
bility. The research has been both empirical, attempting to determine the likely or
actual impact on moral reasoning and judgment, and also normative, arguing about
whether, when, and how this evidence ought to affect moral reasoning and judgment
in the context of criminal justice.
But these questions certainly do not exhaust the potential legal ramifications of genetic
and neuroscientific explanations of human behavior. The questions of responsibility and
self-​control are important not just for affixing legal liability for harmful actions; they also
turn out to be fundamental to social solidarity. People who are perceived to be in control
of, and therefore responsible for their problems are much less likely to be perceived as
having disabilities that are deserving of support in the form of financial assistance and
protection from discrimination. This is particularly the case for psychiatric or behavioral
conditions, as opposed to physical disabilities.
A review of the manner in which the brain disease concept has been used to repel blame
and to support claims to solidarity and protection in relation to a multitude of different
highly stigmatized behavioral conditions (e.g., schizophrenia, depression, addiction, and
obesity) over the years reveals these patterns of thought and their political significance.
Of course, the framing of these conditions as a biomedical disease is itself contested. The
neurodiversity movement, for example, pushes back against the biomedical model of dis-
ability. It accepts biological essentialism and indeed crafts a group identity around the
biological difference, but rejects the pejorative framing of the difference as a disease or
disorder. The broader concept of the social construction of disability, which continues to
battle the biomedical model of disability, locates the negative consequences of a physical
or mental difference in the intolerant and inflexible social environment rather than within
the person him-​or herself. While these movements have succeeded to some extent, much
of the law remains firmly within the biomedical model.
572

572 The impact of neuroscience in the law

To some extent this is an old story. The pressure to medicalize various conditions in
order to fend off blame and judgment and to elicit support is not new, and operates even
where neither genetic nor neurobiological causal factors can be identified. Even a psychi-
atric diagnosis offers something in this ideological battle. However, there is evidence that
the public tends to assign more control and therefore more blame to a person for his or
her behavior when it is explained in psychiatric rather than organic terms. In other words,
the brain-​based account is likely to be a more potent force in reducing blame assigned to
those with stigmatized and disfavored behaviors and conditions.
A final dimension in this exploration of the ideological impact of neurobiological
explanations of behavior is the question of self-​fulfilling prophecies. If people are pushed
to claim a lack of self-​control in order to ward off blame and judgment, or to claim a right
to social support, are we in fact forcing them into that corner? The potentially dispirit-
ing and anti-​therapeutic effects of brain disease models of mental illness and addictions
have been pointed out many times. In the legal context, the analogue to this concern is
that biological deterministic explanations of criminal behavior may be demotivating and
may undermine rehabilitation and reintegration. Similarly, a disability definition built on
establishing a lack of control over the condition may itself be disabling because it under-
mines a person’s motivation and sense of control.

Perceived control and criminal responsibility

The question of capacity is central to legal responsibility. We do not tend to blame people
for their actions when they lack the capacity to act otherwise. We may, however, blame
those who cause harm while in the grip of self-​induced incapacity, according to what has
been called the “tracing theory of moral responsibility” (Fischer and Ravizza 1998).
In Canadian law, the threshold for exoneration due to lack of capacity—​the defense of
mental disorder—​is available only to those whose mental disorder renders them inca-
pable of appreciating the nature and quality of their acts or of knowing they were wrong
(Criminal Code, s.16). This test focuses on cognitive capacity as opposed to the capacity
for self-​control. Criminal responsibility also requires a voluntary act, so a person who
commits an act while in the grip of a seizure or while unconscious will not be criminally
responsible (Roach 2012, pp.117–​119). Unlike some other jurisdictions such as Ireland,
South Africa, and some jurisdictions in Australia and the United States, Canada does not
recognize a defense of “irresistible impulse” although it is clear that people differ in their
impulsiveness (Penney 2012).
Only cases of extreme cognitive incapacity or complete lack of self-​control will deflect
criminal responsibility altogether in Canada. Less severe degrees of impaired capacity for
understanding or self-​control are often considered in assessing the moral blameworthi-
ness of an act at the stage of sentencing a convicted offender. The Canadian Criminal Code
identifies as a fundamental principle that “a sentence must be proportionate to the gravity
of the offence and the degree of responsibility of the offender” (Criminal Code, s.718.1;
Roach 2012, pp.476–​477).
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Perceived control and criminal responsibility 573

At the sentencing hearing, convicted offenders frequently point to factors that suggest
diminished capacity in order to try to reduce their degree of responsibility and thus the
moral blameworthiness of their acts. For example, offenders may point to mental disor-
ders that, while insufficient to render a person non-​criminally responsible, may serve to
reduce the moral blameworthiness of their actions and the severity of the sentence that is
viewed as appropriate (Ruby 2004, para. 5.246; R. v. Belcourt 2010).
At the same time, causal explanations for the criminal behavior that suggest diminished
capacity may increase the perception that an offender is out of control and a risk to the
public. A sentence reflects many objectives, including not just retributive punishment
proportionate to the degree of moral blameworthiness but also a range of consequen-
tialist objectives including the protection of the public. Where prospects for rehabilita-
tion are considered to be poor, a heavy sentence may be viewed as necessary for public
safety even if moral blameworthiness is lowered due to diminished capacity. This double
effect—​the reduction of moral blameworthiness, which would reduce the length of the
sentence, along with an increased perception of dangerousness, which might increase the
length of the sentence—​has been termed the “double-​edged sword” of neurobiological
causal explanations of criminal behavior (Aspinwall et al. 2012). To the extent that neuro-
biological explanations invite the conclusion of a “broken brain” that erodes self-​control
and is unlikely to be amenable to treatment, the outcome on sentence may depend upon
the circumstances (e.g., the perceived riskiness of the offender or the type of offence in
question).
An example of these countervailing impulses is the sentencing decision in the case of
R. v. Obed (2006). Obed was sentenced to 10 years of imprisonment for a violent sexual
assault. At the sentencing hearing, the judge considered evidence regarding Obed’s cha-
otic and abusive childhood, as well as evidence of brain damage associated with prenatal
alcohol exposure. The judge clearly felt that these factors meant that Obed had dimin-
ished responsibility for his crime. Yet, the judge also noted that there was neither a good
treatment for Obed’s brain damage nor good prospects for rehabilitation. The judge con-
cluded that the predominant consideration in selecting the sentence was the protection of
the public (Obed 2006, para. 54). At the conclusion of the sentence, the judge addressed
the offender directly in a way that clearly shows the tension between retribution and con-
sequentialism in a case of diminished capacity due to brain damage:
Mr. Obed before you go. I don’t know what more to say to you. I feel almost helpless in one way by
the inability of the court in being able to do something that would offer you some form of reha-
bilitation. This is the first case I’ve ever had where I felt that rehabilitation was not a realistic factor.
I hope that somehow the Federal or Provincial authorities will take a hard look at this FASD [fetal
alcohol spectrum disorder] phenomenon. I hope, as well, that you become the person that they
rally around and work with and see if somehow, some of this damage … Dr. Rosales says that it’s
irreversible and that the brain no longer develops after a certain point. That’s what we know right
now … Five years, two year from now maybe we’ll know a whole lot of different things. Maybe in
a couple of years from now we can actually go inside the brain and reorganize things. I don’t know.
I just hope in your case, because this is one of those cases that to me falls somewhere between total
responsibility and diminished responsibility and I don’t know really … But I refuse to be without
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574 The impact of neuroscience in the law

hope and in your case I hope that something comes along that can focus on you and help you with
this … You’re not that old that further research can’t have a profound effect on you and I would
hope that you do benefit from such future research. In any event, in the meantime, I have to protect
society from your violent behaviour. I have to protect people from you, even from behaviour that
you don’t know you’re going to commit yet. (R. v. Obed 2006, para. 78)

With the development of behavioral genetics, particularly the identification of gene vari-
ants thought to be associated with an increased risk for impulsive violence, as well as neu-
roimaging that is looking for structural and functional correlates of particular behavioral
abnormalities such as psychopathy, there has been an increase in interest in how such
biological evidence might be used in the criminal justice context. Among the questions
posed are the extent to which this evidence is being used in criminal cases, and the issue
of how it is or should be affecting assessments of criminal responsibility and the selection
of the appropriate responses to offending. Of course, evidence related to mental disor-
der has long been presented to criminal courts. The more novel question posed by these
emerging forms of biologically focused accounts of behavior is whether they are more
likely or not than the more typical psychiatric diagnoses to reduce attributions of control
and blame.
While the research results are inconsistent so far, there are intriguing studies that do
suggest that the effects of neurobiological explanations sometimes differ from those of
psychiatric explanations of criminal behavior.
Aspinwall and colleagues surveyed a group of nearly 200 American state trial judges
and found that evidence supporting a neurobiological cause of an offender’s psychopathy
reduced the sentence imposed as well as the extent to which the psychopathy was viewed
as an aggravating factor (Aspinwall et al. 2012). The judges considered a vignette in which
a psychiatrist provided expert testimony that a man who committed a violent assault was
a psychopath. Half of the participants also received the expert testimony of a neurobiolo-
gist who presented a neurobiological explanation of the psychopathy. The participants
were able to provide explanatory comments on their responses. One judge wrote that
“[t]‌he evidence that psychopaths do not have the necessary neural connections to feel
empathy is significant. It makes possible an argument that psychopaths are, in a sense,
morally ‘disabled’ just as other people are physically disabled” (Aspinwall et  al. 2012,
p.847). The neurobiological explanation of psychopathy appears to have reduced per-
ceived moral blame but at the same time may have increased the perception of increased
dangerousness. Another judge wrote that “[p]sychopathy may make the defendant less
morally culpable, but it increases his future dangerousness to society. In my mind, these
factors balance out” (Aspinwall et al. 2012, p.848).
Fuss and colleagues repeated with a group of German judges a version of the study
conducted by Aspinwall and colleagues (Aspinwall et  al. 2012; Fuss et  al. 2015). They
presented the judges with a vignette in which an expert provided a psychiatric diagnosis
of psychopathy. Half also received expert testimony from a neurobiologist explaining psy-
chopathy as a genetically driven developmental condition and indicating that the offender
had the gene in question. Fuss and colleagues found that the neurobiological explanation
 57

Perceived control and criminal responsibility 575

slightly reduced the judgment of legal responsibility, but it did not significantly affect
the prison sentence imposed (Fuss et al. 2015). The presentation of the neurobiological
evidence by the prosecution did greatly increase the decision to order involuntary com-
mitment in a psychiatric hospital, which could lead to a longer detention time.
There have also been studies of public reactions to biological explanations of behav-
ior. Monterosso and colleagues surveyed the public to see whether scientific explana-
tions of undesirable behavior reduced perceived culpability (Monterosso et al. 2004).
They looked at four types of undesirable behavior: setting fire to a building, killing a
store clerk over a disagreement, overeating, and consistent failure to follow through on
plans. They found that physiological explanations were more likely to lead to reduced
judgments of culpability than socioenvironmental explanations in all four cases. For
example, in the case of the man who killed the store clerk, attributions of culpability
were lower where the explanation given for his behavior was a greatly elevated amount
of a particular brain chemical versus the experience of severe and brutal abuse as a
child. The physiological explanations also elicited lower scores on a composite measure,
showing reduced judgments of voluntariness, greater sympathy, greater mitigation of
blame, more positive treatment, and greater likelihood that the participants themselves
would behave in the undesirable way if the explanatory condition were true of them
(Monterosso et al. 2004, p.150).
Monterosso and colleagues speculated that the Western perception of the person is
dualistic, and the mind (or soul) and body are perceived as two separate forces inde-
pendently capable of bringing about behavior (Monterosso et al. 2004, p.154). Further,
behavior tends to be perceived as voluntary or “owned by the self ” only when it flows
from the mind (or soul), and where one force is operating it is perceived as denying the
causal efficacy of the other. They suggest that this explains “why, in our vignettes, when a
physiological explanation was given, participants tended to view the body as the cause of
the behaviour and motivations as less relevant, with the result that the behaviour was per-
ceived as less voluntary” (Monterosso et al. 2004, p.155). They suggest that this manner of
thought may lead to reduced space for intentional agency as the physiological behavioral
sciences advance.
There is also research questioning whether biological explanations of criminal behav-
ior will affect judgments of responsibility. Scurich and Appelbaum (2015) failed to find
an effect of biological (genetic and neurobiological) explanations of wrongful behavior
on public decisions about punishment. They suggest several possible explanations. First,
ordinary people may regard biological predisposition as only one influence on behavior,
and one that is not necessarily the prime determinant of the behavior in a given con-
text. Second, they suggest that these explanations might activate countervailing concerns
about dangerousness, which negate any mitigating impact on punishment.
In sum, the evidence is presently mixed on the question of whether or when bio-
logical explanations of criminal behavior produce different perceptions of control and
responsibility than psychosocial explanations. Nonetheless, some of the experimen-
tal evidence suggests such an effect in both public and judicial decision-​making. The
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576 The impact of neuroscience in the law

ultimate effect on punishment decisions may be slight for serious offences, however,
given that perceptions of dangerousness may increase at the same time as perceived
culpability decreases.

Perceived control, responsibility, and social solidarity

Perceptions of control and therefore responsibility for a condition also affect the will-
ingness to assist and protect people with disabilities or those in financial need. When a
person is perceived to have the power to avoid or to mitigate a particular condition or
situation, others are less likely to respond with sympathy and the desire to help.
Bernard Weiner has suggested that attributions about cause and control leading to judg-
ments about personal responsibility are ubiquitous in human interactions, and they drive
emotional reactions such as anger or sympathy as well as behavioral reactions like help
or punishment (Weiner 1993). This model has come to be known as “attribution theory”
in social psychology, and has been explored as an explanatory model in a wide range of
contexts including mental health stigma (Weiner et  al. 1988; Corrigan 2000; Corrigan
et al. 2003) and support for social welfare programs (Van Oorschot 2000, p.36; Weiner
et al. 2011).
In the model suggested by attribution theory, controllability refers to the degree of vol-
untary influence a person has over a cause. A further distinction in relation to control-
lability is made between “onset controllability” (control over developing a condition) and
“offset responsibility” (capacity and responsibility for coping with or overcoming a condi-
tion) (Corrigan 2000 pp.52–​53).
People who are perceived to be in control of a negative event are more likely to be held
responsible and to elicit angry or punitive reactions. Those who are perceived to lack con-
trol are more likely to be pitied and helped. A third reaction, independent of attributions
of control and responsibility, is driven by perceptions of dangerousness that produce fear
and elicit efforts to avoid or to control a person (Corrigan et al. 2003).
Another body of research looks at whether causal explanations of behavior based on
biology or physiology (as opposed to mental or psychological explanations) have differ-
ent effects on attributions of control and responsibility for that behavior. This has been a
topic of particular interest in the area of mental health stigma, where it was hoped that
biological explanations of psychiatric illnesses would reduce perceived responsibility for
behavior and symptoms and help to de-​stigmatize these conditions. A meta-​analysis by
Kvaale and colleagues suggests that biological explanations may indeed diminish the ten-
dency to blame people for psychological problems (Kvaale et al. 2013). However, these
explanations increase perceived unpredictability or dangerousness, as well as prognostic
pessimism. The impact of biological explanations may, however, vary according to the
specific psychological problem in question, the type of biological causal explanation given
(e.g., genetic versus neurochemical), and treatability, among other variables (Kvaale et al.
2013; Lee et al. 2014).
Finally, researchers have also explored the willingness of the public to recognize
conditions as disabilities worthy of social assistance and protection. Mueller and
 57

Perceived control, responsibility, and social solidarity 577

colleagues explored public views on which of 57 different health conditions should be

viewed as disabilities worthy of legal protection under the Americans with Disabilities
Act (ADA) (Mueller et  al. 2010). The conditions differed according to whether they
were physical or psychological, visible or not, static or progressive, and whether there
was personal control over onset. They found that respondents did not regard condi-
tions that may result from poor decision-​making or lifestyle choices as disabilities
worthy of ADA protection. These included alcoholism, drug addiction, obesity, HIV/​
AIDS, emphysema, and eating disorders. Ultimately, “[v]‌isible physiological health
conditions were accorded higher rates of protection under the provisions of the ADA
than invisible, psychological, or behavioural/​self-​imposed health conditions” (Mueller
et al. 2010, p.178).
Esses and Beaufoy (1994) explored attitudes to three types of disability:  chronic
depression, AIDS, and amputees. They found that attitudes to amputees were more
favorable than toward people with AIDS or chronic depression. Participants attributed
greater control over the occurrence of their conditions to people with AIDS and chronic
depression and very little control to amputees. Furthermore, high attributions of control
were correlated with particularly unfavorable attitudes to those with AIDS and chronic
depression.
Together, these three lines of inquiry all provide some support for several ideas. First, a
person who is perceived to be in control of their condition or situation is more likely to be
considered responsible for it, increasing blame and reducing the impulse to assist. Second,
a biological explanation of a condition or behavior may be a more powerful inducer of
these reactions than a psychological explanation. This provides the foundation for the
following exploration of how neurobiological explanations of behavioral conditions may
serve to support claims that those conditions should be treated as disabilities entitled to
social assistance and protection from discrimination.

The meaning and scope of disability in the law

The human rights of people with disabilities are now protected through international trea-
ties such as the UN Convention on the Rights of Persons with Disabilities (United Nations
General Assembly 2007)  and, in Canada, through the Charter of Rights and Freedoms
(1982) and provincial human rights codes. The Charter requires federal and provincial
governments in Canada to respect the right to equality and equal benefit of the law with-
out discrimination on the basis of physical or mental disability (s.15(1)).
In addition, provincial human rights legislation, such as Ontario’s Human Rights Code,
prohibits discrimination on the ground of disability by public and private actors in par-
ticular contexts such as access to services, employment, and residential accommodations.
The Code requires only reasonable accommodation of disability, or accommodation up
to the point of undue hardship, and there will be no violation of a person’s rights under
the Code if the obstacles cannot be remedied without undue hardship (s.17(1)). It is also
important to note that the jurisprudence that has developed around the concept of rea-
sonable accommodation also makes it clear that the claimant has a responsibility to make
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578 The impact of neuroscience in the law

reasonable efforts to facilitate the accommodation by, for example, participating in a reha-
bilitation program:
When an alcoholic employee has failed to respond to multiple rehabilitation efforts and there is no
objective evidence that further efforts at accommodation would be likely to succeed, it is generally
concluded that the employee has been accommodated to the point of undue hardship. (Kellogg
Canada Inc v. Bakery, Confectionary, Tobacco Workers & Grain Millers 2006)

Many of these legal instruments do not provide particularly precise definitions of disabil-
ity, meaning that the list of specific impairments that fall within the scope of entitlements
to support or protection from discrimination evolves over time and remains uncertain in
some cases (Law Commission of Ontario 2009, pp.10–​11). It is this area of uncertainty
that may ultimately be influenced by emerging neurobiological explanations of stigma-
tized behavior and conditions. As noted in the section “Perceived control, responsibil-
ity, and social solidarity,” attribution theory predicts that conditions and behaviors that
are seen to fall outside personal control are more likely to generate reactions of social
solidarity—​willingness to provide support and protection from discrimination.
The political and economic significance of the definition of disability is clear. As the
Law Commission of Ontario (2009, p.11) puts it, claimants seek “the label of ‘disability’
in order to access benefits and supports, while institutions [withhold] the label in order
to maintain program standards.” Other institutional actors may also use the definition of
disability strategically, inappropriately finding disabilities where this will generate higher
funding allocations (Law Commission of Ontario 2009, p.12). Others police the bound-
ary of disability to ward off what they perceive as inappropriate attempts to appropriate
resources that should be made available to those whose impairments they consider more
genuinely disabling. For example, Gilbert and Majury cite the argument that a legal claim
lodged by an infertile couple that the exclusion of a form of infertility treatment from
provincially funded health care discriminated on the basis of disability (i.e., infertility)
“appropriated a disability rights discourse [in order] to gain access to resources and ser-
vices forged by earlier efforts at advocating very different disability issues” (Gilbert &
Majury 2006, p.112). Of course the use of models that attract social sympathy and sup-
port will be taken up by others seeking a similar response, a pattern revealed by the use
of the concept of addiction to describe other compulsive behaviors unrelated to drugs or
alcohol, including compulsive behavior related to food, the Internet, and sex.
The medicalization of a condition tends to support its inclusion within the scope of dis-
ability for legal purposes, although this is not invariably the case. The biomedical model
of disability—​the dominant understanding of disability for much of the twentieth cen-
tury, and still the dominant public conception of disability—​is reflected in many laws. For
example, access to disability benefits is largely defined in biomedical terms and eligibil-
ity for benefits is verified by medical professionals (Law Commission of Ontario 2009,
p.17). As a result, the development of a biomedical conception of a condition is often
a key requirement to accessing the protections available by law. It is not strictly neces-
sary that this conception involve a known biological etiology to qualify as a disability for
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Perceived control, responsibility, and social solidarity 579

legal purposes, because the human rights laws cover both physical and mental disabili-
ties. However, the claim to inclusion as a disability and to social solidarity is strength-
ened where there is a lack of control over a disabling condition, which biological causal
explanations of the condition suggest more persuasively than do psychological causal
explanations.
Drug and alcohol dependency and addiction are considered disabilities under human
rights legislation (Canadian Human Rights Act s.25; Ontario Human Rights Commission
2014). Thus, the exclusion of people with drug and alcohol dependency or addiction
from eligibility for disability benefits constituted discrimination on the basis of dis-
ability (Ontario v. Tranchemontagne 2009). The human rights jurisprudence now com-
monly refers to drug and alcohol dependency and addiction as a disease of the brain (e.g.,
Milazzo v. Autocar Connaisseur Inc. 2003), a framing that has been in the ascendant since
the early 1970s (Vrecko 2010, p.58).
The path forged by drug and alcohol addictions toward a neurobiological disease model
is now being emulated in relation to a range of other compulsive behaviors. As Vrecko
(2010, p.54) puts it, “[p]‌ersonal, social and legal issues associated not only with drugs, but
with a range of compulsive and problematic behaviours—​including criminal offending,
spending and debt, gambling and obesity—​are coming to be represented as, at least in
part, problems of the molecular body and brain.” Canadian legal cases reveal the manner
in which neurobiology is being adopted in the legal context to reduce perceptions of con-
trol and moral blameworthiness for this broader range of stigmatized behavior.
Disability claims involving addictions to gambling, nicotine, sex, and the Internet are pre-
sented in the following sections. While nicotine addiction has been medicalized for some
time, warranting its own section—​“Nicotine-​related disorders”—​within the Diagnostic and
Statistical Manual of Mental Disorders, fourth edition (DSM-​IV) section on “Substance-​
related disorders” (American Psychiatric Association 2000, p.264), gambling addiction has
recently been reclassified because of neurobiological evidence. Pathological gambling was
formerly classified in the DSM-​IV as an “impulse control disorder” (American Psychiatric
Association 2000  p.312.31) and was reclassified in the DSM-​5 within the section on
“Substance-​related and addictive disorders” (American Psychiatric Association 2013). The
notes on the section indicate that gambling disorder has been added because of “evidence
that gambling behaviors activate reward systems similar to those activated by drugs of
abuse and produce some behavioral symptoms that appear comparable to those produced
by the substance use disorders” (American Psychiatric Association 2013).
As for addictions to sex and the Internet, official psychiatric diagnoses are not yet
recognized. As the notes on gambling disorder in the DSM-​5 (American Psychiatric
Association 2013) state:

Other excessive behavioral patterns, such as Internet gaming, have also been described, but the
research on these and other behavioral syndromes is less clear. Thus, groups of repetitive behav-
iors, which some term behavioral addictions, with such subcategories as “sex addiction,” “exercise
addiction,” or “shopping addiction,” are not included because at this time there is insufficient
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580 The impact of neuroscience in the law

peer-​reviewed evidence to establish the diagnostic criteria and course descriptions needed to iden-
tify these behaviors as mental disorders.

Gambling addiction
Gambling addictions typically arise in legal cases in one of two contexts. First, they are
raised as explanations for criminal behavior (e.g., stealing from an employer to finance
gambling). The judicial reactions to this type of argument are mixed, perhaps reflecting
the degree of perceived lack of self-​control in specific cases. Second, they are raised to
try to challenge dismissal from employment. In these employment grievances, the argu-
ment made is that the gambling addiction is a disability and so the wrongful behavior like
stealing from the employer merits less severe disciplinary measures and in fact may even
require an employer to accommodate the employee’s disability by, for example, reassign-
ing the employee to a position in which theft will not be possible. Courts and arbitrators
have not been very receptive to these arguments. Despite attempts to frame gambling
addiction as a brain disorder, they remain suspicious that the condition necessarily entails
a sufficient lack of self-​control to relieve a person from responsibility. Furthermore, the
accommodations requested may be perceived as unreasonable.
The case of R. v. Smith (2015) involved a woman who pleaded guilty to stealing from
her employer to finance her gambling. At the sentencing, the defense tendered evidence
that pathological gambling was now classified as an addiction in the DSM-​5 because of
“[b]‌rain imaging studies and neurochemical tests [that] have provided compelling evi-
dence that gambling activates reward systems in the brain much the same way that drugs
and alcohols do,” and that it generates “physiological cravings and the experience of being
‘high’ or in an altered state of consciousness similar to the experience of substance depen-
dence” (Smith 2015, para. 48).
The defense expert also indicated that, as with substance addiction, gambling addicts
also experienced craving and loss of control, and that although “[t]‌he neurobiology asso-
ciated with behavioural and substance addictions overlap but are not identical … there is
also convincing research indicating common genetic factors including heritable pheno-
types that underlie substance abuse and gambling disorders” (Smith 2015, para. 49).
The judge considered precedents in which gambling addictions were cited as mitigat-
ing factors at sentence, one of which was R. v. Horvath (1997), in which a distinction was
drawn between pathological and compulsive gambling (R.  v.  Horvath 1997, para. 81).
The court in Horvath had accepted the medical model of pathological gambling and con-
cluded that it reduced moral blame:
The offences were the products of a distorted mind—​a mind seriously diseased by a disorder now
recognized by the medical community as a mental disorder. The acts committed at the command
of that mind were not acts of free choice in the same sense as are the acts of free choice of a normal
mind. A pathological gambler does not have the same power of control over his or her acts as one
who does not suffer from that complex disease. Accordingly, where those acts constitute criminal
offences, the moral culpability—​moral blameworthiness—​and responsibility are not of the same
order as they would be in those cases where the mind is not so affected.
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Perceived control, responsibility, and social solidarity 581

However, the judge in Smith was not ultimately persuaded that Smith had a condition that
undermined her self-​control, and so rejected the argument that her gambling problem
should mitigate personal responsibility:
People with serious mental disorders cannot, through sheer willpower and resolve, rid themselves
of their afflictions. In notable contrast, once Ms. Smith’s crime was discovered and she resolved to
stop gambling, she was able to do so without apparent difficulty and with lasting results. If only it
were so easy for the mentally disordered. (R. v. Smith 2015, para. 92)

In the employment context, employees dismissed for theft sometimes bring grievances
on the basis that the disciplinary measure was unfair because the behavior was caused by
a disability—​pathological gambling—​that had subsequently been addressed. The role of
demonstrable biological etiology in buttressing such a claim is revealed in an older case,
in which the arbitrator considered the claim for reinstatement and drew a distinction
between so-​called easy cases in which there was a clear physical reason for the wrongful
conduct, and the more common cases where there are no physical reasons for it (Canada
Safeway Ltd. 1999):
In the former category would fall cases where there is an identifiable physical reason for aberrant
conduct. An easy example is where an employee had a brain tumor [that] caused improper conduct
such as violence or theft. If it can be shown that the brain tumor was a direct contributor to the
aberrant conduct and that it has now been cured, most employers and arbitrators would reinstate
the employee. The most common cases that seem to arise do not deal with clearly identifiable physi-
cal problems such as a brain tumor, rather they most often deal with alcohol addiction, drug addic-
tion and, more recently, gambling addiction. Even in these cases there is a tendency to characterize
the "condition" as an illness. Often much of the evidence will be led for that purpose. (para. 62)

The arbitrator then went on to say it wasn’t absolutely necessary to establish a “recogniz-
able condition” or “true illness,” but there must be a condition that leads to the improper
behavior and it must be one that essentially removes self-​control from the employee:
Again using the brain tumor example, it may be concluded that the employee was acting as an
automaton and was not responsible whatever for his or her conduct. On the other hand, even
if a gambling or alcohol addiction is established, and it is established that but for the condition
the aberrant conduct, such as theft, would not have occurred, it still may be concluded that the
grievor possesses sufficient responsibility for his or her actions so that a substitution of penalty
is not appropriate. This is precisely what occurred in the SaskTel case where it was accepted that
the grievor had a pathological or compulsive gambling addiction and that it contributed to his
acts of theft but it was concluded that he was still responsible because he had been fully aware of
his problem and he was fully aware of the avenues open to him to have his problem dealt with. In
other words, the mere existence of an addiction does not in itself explain or justify serious aberrant
conduct. There are many people with alcohol, narcotic and gambling addictions but a very small
number of those people steal money. (para. 66)

Similar reasoning has been subsequently followed in a range of other labor arbitrations
involving pathological gambling. For example, in Manitoba v. Manitoba Government and
General Employees’ Union (2005), the arbitration panel doubted that gambling addiction
made the decision to steal involuntary, despite evidence that gambling addictions “hijack
the brain” (paras. 48, 59, 85).
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582 The impact of neuroscience in the law

In the US context, Tovino (2015) writes about another way in which the neurobiologi-
cal conceptions of pathological gambling may affect benefits entitlements and protection
from discrimination. While her example does not have to do directly with how biological
causal explanations affect judgments of control and responsibility, it does suggest another
way in which the legal treatment of disabilities may be affected by neurobiological con-
ceptions of disability. Tovino (2015) observes that the neurobiologically driven reclas-
sification of pathological gambling as a form of addictive behavior in the DSM-​5 may
support the argument that it should no longer fall within the category of “impulse control
disorders” for the purposes of health insurance in Nevada, which excludes that category
from coverage but includes coverage for substance-​related conditions (drug and alcohol
use disorders). She also predicts that neurobiological advances may lead to challenges
to certain exclusions from the scope of anti-​discrimination laws. For example, Title I of
the ADA excludes people engaging in the use of illegal drugs from protection against
discrimination in employment (Tovino 2015, p.723). However, those who have engaged
in drug rehabilitation programs and are not currently using illegal drugs are protected.
Title I of the ADA also specifically excludes from employment discrimination protection
“compulsive gambling,” and several other impulse control disorders, but does not include
a similar proviso protecting those who have been successfully treated. Tovino (2015) sug-
gests that the evolving understanding of compulsive gambling may permit a stakeholder
to argue that gambling disorder should be treated more like alcohol or drug use disorders
under antidiscrimination laws.
The example of gambling addictions sheds some light on the effect of neurobiological
explanations of behavior on the concept of disability. Although brain-​based evidence may
help to support the idea that someone may become addicted to the act of gambling, this
may not be sufficient where the disfavored behavior is the upstream activity of stealing in
order to finance the compulsive behavior. Unlike the following examples of nicotine and
Internet sex addiction where the disfavored behavior that is being punished is the com-
pulsive behavior itself, in pathological gambling it is not the gambling but the stealing that
is being punished. In these cases, decision-​makers appear to doubt that the compulsion to
gamble necessarily made the theft sufficiently involuntary to reduce blame. Nevertheless,
the invocation of neurobiological evidence supports the idea that it is being used in an
attempt to suggest lack of self-​control and responsibility, and may also have other effects
on disability rights protections through the shifting classification of various conditions.

Nicotine addiction
Although nicotine addiction is a medicalized condition, the case law on whether it is a
disability is mixed. The focus of the dispute is the degree of loss of voluntary self-​control.
In McNeill v. Ontario Ministry of the Solicitor General and Correctional Services (1998),
an inmate challenged a smoking ban in a detention center on the basis that it discrimi-
nated against him on the basis of disability. He argued that addiction to drugs and alco-
hol were recognized as disabilities for the purposes of human rights protections and that
addiction to tobacco should similarly be recognized as a disability. The Ontario Court
 583

Perceived control, responsibility, and social solidarity 583

of Justice ruled that smokers do not have a “mental or physical disability.” The Court
held that “[a]‌ddiction to nicotine is a temporary condition that many people voluntarily
overcome, albeit with varying levels of difficulty related to the strength of their will to dis-
continue smoking,” and that “smoking and the addiction that often accompanies it does
not interfere with a person’s effective physical, social and psychological functioning, the
results that often characterize addiction to alcohol” (para. 29). The court also observed
sarcastically that the claimant “was in a position to do something about the discrimina-
tion of which he complained. He could forego his frequent attendances at the Wellington
Detention Centre” (para. 31).
Other courts have rejected the idea that nicotine addiction is a disability for the
purposes of the antidiscrimination provisions of the Charter of Rights and Freedoms
(R.  v.  Ample Annie’s Itty Bitty Roadhouse 2001; Yellowknife (City) v.  Denny 2004). The
judge in Yellowknife wrote that an addiction to smoking:
may be a mental or physical disability by somebody else’s definition, but not pursuant to section 15
[of the Charter]… Smokers can successfully overcome their addiction. Help is close at hand. There
is nothing discriminatory in the [non-​smoking] by-​law. If it has a purpose or effect that addresses
the issue of addiction, it is a positive, rehabilitative by-​law that should be welcomed by the public at
large, including those so addicted. (paras. 56–​60)

In a different context dealing with a union’s challenge to a company’s nonsmoking policy,

an arbitration panel later found that nicotine addiction was a disability protected from
discrimination for the purposes of human rights legislation (Cominco Ltd. 2000). The
union claimed that the policy discriminated on the basis of disability, namely nicotine
addiction, because addicted smokers cannot control their addiction (Cominco Ltd. 2000,
para. 14). The company argued that addiction to nicotine or smoking was not a disability
because it is a temporary condition that many people overcome voluntarily and it does
not interfere with a person’s physical, social, or psychological functioning (Cominco Ltd.
2000, para. 174).
The panel in Cominco Ltd. declined to follow the McNeill decision on the basis that the
judge in that case had not considered the kind of scientific evidence made available to the
panel (Cominco Ltd. 2000, para. 179). It cited evidence that that nicotine was as or more
addictive than cocaine or heroin, that a puff of cigarette smoke was a more direct method
of delivery to the brain than injecting into a vein in the arm (Cominco Ltd. 2000, para.
180), and that those who are heavily addicted are disabled as they are “unable to control
their addiction” (Cominco Ltd. 2000, para. 203). Thus, the nonsmoking policy was dis-
criminatory at least for heavily addicted smokers as it is essentially “tantamount to telling
them that they will not continue to be employed at Cominco because the inevitable result
is that they will be terminated” (para. 204).
This being said, another labor arbitrator rejected a union grievance on behalf of an
employee terminated for smoking contrary to a clear nonsmoking policy in a workplace
with flammable chemicals. The union argued that the employee’s misconduct was not
willful because he was addicted to nicotine. The arbitrator said no medical evidence had
been provided, and even if he was addicted, he could have used nicotine-​containing
584

584 The impact of neuroscience in the law

alternatives as a substitute to smoking (Invista (Canada) Co. 2013). The question of

whether nicotine addiction will be accepted as a disability under human rights legisla-
tion continues to evolve, and a human rights complaint arguing that nicotine addiction
constitutes a disability that must be reasonably accommodated is apparently scheduled
to be heard in the summer of 2016 in a challenge to a condominium’s nonsmoking bylaw
(Strata Plan NW 1815 2016).
The issue of self-​control and nicotine addiction is also raised outside human rights liti-
gation. In a recent product liability class action lawsuit against tobacco companies in the
province of Quebec, the experts engaged in a battle over whether nicotine dependence
should be characterized as a “brain disease.” The importance of this point had to do with
whether the smokers ought to be viewed as solely or partly responsible for the health con-
sequences if they persisted in smoking despite knowing it was harmful. As the companies
put it, smokers “are entitled to take risks and … they knew or could have known about the
health risks associated with smoking” (Letourneau 2015, para. 34.) As a result, the ques-
tions of whether smokers retain control and, if so, how much, were important issues in
dispute, and the experts on both sides cited neurobiological evidence.
One of the companies’ experts rejected the medical model of drug use in favor of a
socioenvironmental approach, but was strongly criticized by the judge for a perceived lack
of objectivity (Letourneau 2015, para. 163):

[H]‌is almost total dismissal of the pharmacological effects of nicotine on the brain is not sup-
ported by the experts in the field. He implicitly recognized this when, after much painful cross-​
examination, he admitted that nicotine does, in fact, have a pharmacological effect on the brain. He
stated that nicotine binds to receptors in the brain, thus causing “brain changes.” … Such changes
do not mean that the brain is damaged, in his view, because they are not permanent. He cited a
study … showing that the brains of people who quit smoking “return to normal” after twelve weeks.
That this indicates that the smoker’s brain was, therefore, not “normal” while he was smoking seems
not to have been considered by him. (Letourneau 2015, paras. 161–​162)

The plaintiffs’ expert, on the other hand, described nicotine dependence as a brain dis-
ease, and characterized the user as a “slave” who had lost “freedom of action” (Letourneau
2015, paras. 172–​173). The companies’ experts energetically disputed this, arguing that
nicotine use does not remove freedom of action, as is clearly demonstrated by the many
people who have quit smoking (Letourneau 2015, para. 173).
The Court ultimately found that “nicotine affects the brain in a way that makes contin-
ued exposure to it strongly preferable to ceasing that exposure. In other words, although
it can vary from individual to individual, nicotine creates dependence. That is the point”
(Letourneau 2015, para. 179). The judge also noted that tobacco dependence was listed as
a psychiatric disorder in the DSM-​5, and the marketing of a dependence-​inducing prod-
uct could be the basis of a product liability claim (Letourneau 2015, paras. 183–​184). As a
result, those who started smoking at a time when the addictive and harmful properties of
tobacco were known were held partly responsible, but the others who were already depen-
dent when the harms became known were not at fault (Letourneau 2015, paras. 829–​830).
 58

Perceived control, responsibility, and social solidarity 585

Although the sample size does not permit firm conclusions about the role of neurobiol-
ogy on the concept of disability, these cases suggest a number of points. First, medicaliza-
tion is not in itself sufficient to guarantee that a condition will be recognized as a disability
for legal purposes. In some of these cases, the effort to deflect blame and to claim accom-
modation of a disability was unsuccessful because the claimant was perceived to retain
some control over the condition. The invocation of neurobiological explanations of nico-
tine addiction seems to help to produce a more sympathetic response to the difficulties of
smokers, as the cases of Cominco and Letourneau reveal. Finally, the legal context appears
to matter. There seems to be a greater willingness to support the claimant where the other
side is profiting in some way from the claimant’s alleged addiction (as in the product
liability case in Letourneau), than there is in cases where a party is being asked to accom-
modate the claimant’s alleged addiction.

Internet sex addiction

The claim of Internet sex addiction is now being raised occasionally in cases concerning
criminal activities involving child pornography or child luring, (e.g., R. v. H.T. 2010) as
well as in labor arbitration cases where employees dispute disciplinary actions taken by
employers arising out of the same behavior. In addition, the claim is also being raised in
other cases that involve non-​criminal behavior that is nonetheless contrary to workplace
policies, such as compulsive viewing of pornography at work.
As with the examples of gambling and nicotine addictions, the focus remains on
whether the person concerned has lost self-​control. At present, the Canadian cases do
not seem to refer to any neurobiological evidence to support the claim of loss of control
in Internet sex addiction, which is surprising given that such evidence is available in the
literature (e.g., Love et al. 2015). Although a diagnosis of “hypersexual disorder” (includ-
ing compulsive use of pornography) was proposed for the DSM-​5, it was not accepted
(Love et al. 2015). On the other hand, “Internet gaming disorder” has been proposed as a
condition warranting further study within the DSM-​5 (American Psychiatric Association
2013, Section III). The current lack of a recognized medical diagnosis may explain the
fact that legal arguments remain tentative and underdeveloped, for now. Several examples
illustrate the current shape of the arguments about the compulsive use of the Internet for
sexual purposes.
In Manitoba Government and General Employees’ Union v. Manitoba (M.W. Grievance)
(2013), the labor union filed a grievance challenging the termination of an employee who
sent and received a large volume of pornography on his work computer. The arbitrator
rejected the argument that sex addiction was a mitigating factor that made the termina-
tion excessive because “sex addiction” was not a medically recognized diagnosis (paras.
94–​96). Interestingly, the employer attempted to turn this argument against the employee,
suggesting that “the grievor’s continued reliance on a sex addiction as an explanation
demonstrated that he was continuing to blame factors out of his control for his behaviour”
(para. 102). The grievance was ultimately successful nonetheless for other reasons.
586

586 The impact of neuroscience in the law

Another case involving an employee fired for pornography use at work contrary to
acceptable use policies was Interior Health Authority (South Similkameen Health Centre)
v. Hospital Employee’s Union (RP Grievance) (2013). The employee argued that he had the
condition of “sexually compulsive behaviour regarding viewing pornography,” and that
the employer was obligated to make reasonable accommodation of his disability. There
was supporting evidence provided in this case by a clinical social worker, accepted as
an expert for the purpose of making diagnoses under the DSM-​IV. The expert acknowl-
edged that sexual compulsivity was not a diagnosis under the DSM-​IV and so no claim
about a diagnosis was advanced, but he did proceed to provide evidence that RP ranked
in the moderate to severe range of compulsive pornography use on a Sexual Addiction
Screening Test and an Internet Sex Screening Test. The arbitrator rejected the claim say-
ing that, in the absence of expert medical or psychiatric evidence supporting the existence
of such a condition, she was “unable to conclude that there exists a disability of ‘sexually
compulsive behavior regarding viewing pornography’ ” (paras. 57–​59). She went on fur-
ther to note that the employee’s behavior did not resemble an addiction since he did not
appear to have “an irresistible drive to view pornography, or any loss of control” (para.
60). Instead, he timed his pornography consumption to times when work was slow.
In Seneca College v.  Ontario Public Service Employees Union (Discharge Grievance)
(2002), a college professor pleaded guilty to child pornography offences after he was caught
using the student computer lab to download child pornography. When his employer fired
him for this behavior, he argued that his pathological Internet use was the result of a men-
tal disorder, and that there was an obligation under the Ontario Human Rights Code to
accommodate this disability. He further argued that he had paid a penalty in the criminal
courts, and that termination of his employment was too harsh a response by the employer
in the circumstances. The arbitration panel rejected his suggestion that he had “a type of
impulse control disorder that took the form of pathological attraction to internet pornog-
raphy,” because the evidence showed he did have control:

The grievor through his own testimony indicated that his activity in searching out and viewing
Internet pornography was both selective and controlled, suggesting that he could exercise self
restraint if he chose to do so. (para. 16)

There was an intriguing dissent by the panel member nominated by the union. The mem-
ber said that even though his condition did not fit the “accepted medical model of psy-
chiatric disorders” in the DSM-​IV, the medical community does recognize compulsive
behavior. The member noted that this was a person who turned to the Internet to escape
from reality due to difficult life circumstances, and asked “[h]‌ow is that different from
those who turn to alcohol, drugs, gambling and other forms of escapism? The difference,
this member submits, is our own personal view on the morality of the issue and of course,
legality of the issue” (para. 26). Because other employees are given time off to “fight their
own personal demons” the grievor also should have been given this opportunity and been
awarded severance even if reinstatement was not possible due to the breach of the funda-
mental responsibilities of his teaching position (paras. 26–​30).
 587

Conclusion 587

The Internet sex addiction cases demonstrate the importance of an accepted medical
diagnosis. Even where expert medical evidence is provided, its weight may be discounted
by the lack of a generally accepted condition, as occurred in Interior Health Authority
(2003) case. The cases also hint at the possibility of a backlash against those who are per-
ceived to be in control of a condition yet are attempting to deny control and responsibility
by invoking a disability. Where this claim is not believed, blame may be aggravated by the
perception of failure to properly take responsibility and the lack of remorse.

Conclusion
A common theme in discussions of law and neuroscience is that behavioral, genetic,
and neuroscientific explanations of behavior will affect judgments of causal control and
responsibility. The suggestion is that people tend to interpret these explanations deter-
ministically to a greater extent than other types of causal explanations of behavior, such
as environmental or psychological factors. Of course, all behavior involves the brain, and
pointing out this fact does not settle the question of whether society should hold someone
legally responsible for it. Legal practice and social psychology seem to show that people
are sensitive to a person’s perceived control over disfavored behaviors or symptoms, and
assign blame and punishment to those who are perceived to have the capacity to control
them and are therefore responsible for them.
This effect has been most often explored in the criminal context, where the impact
of behavioral genetics and neuroscience on retribution are being actively researched.
However, this does not exhaust the possible legal effects of the manner in which people
link brain explanations to a lack of control and to diminished responsibility. The willing-
ness to recognize a behavioral condition as a disability, entitling a person to social assis-
tance and protection from discrimination, also is sensitive to perceived control.
A review of cases in which emerging forms of behavioral addictions are claimed as dis-
abilities reveals a complex picture. Brain-​based explanations are sometimes used in an
attempt to emulate the successful reframing of drug and alcohol addiction as a disease of
the brain. However, this in itself does not seem to be enough to succeed in legal claims.
Decision-​makers often question whether self-​control is sufficiently diminished to excuse
the behavior in question. Furthermore, claimants may be punished for failing to take
responsibility and to show remorse when they ascribe behavior to a condition over which
they are perceived to retain at least some control.
As research continues to elucidate the underlying biological mechanisms involved in
behavioral control, it seems likely that human rights lawyers and complainants will adopt
this evidence in relation to stigmatized conditions not yet firmly accepted as disabilities.
An additional way that neuroscience research may alter the legal response to disabilities
is by developing novel treatments based on greater understanding of the biology of behav-
ior. Since claimants are expected to participate in attempts to make reasonable accommo-
dation of their disabilities under human rights law, claimants may find themselves under
pressure to adopt these new treatments.
58

588 The impact of neuroscience in the law

There are potential negative consequences, familiar from the literature on human rights
theory and the sociological literature on medicalization, to the framing of behavioral
problems as matters of biology or physiology. They deflect attention from other social or
environmental conditions that are also causal contributors, and so may weaken attempts
to make broader responses to behavioral conditions. Furthermore, while it is understand-
able why people may seek to attribute causal control for socially disfavored behavior to
biological mechanisms beyond their control, might this not also undermine their actual
self-​control in a self-​fulfilling way? Future research looking specifically at the law and
legal institutions could fruitfully explore these and other themes to help societies incor-
porate neuroscientific explanations of human behavior.

Acknowledgments
The author gratefully acknowledges the research assistance of Tijana Potkonjak and
Hilary Bond, as well as the financial support of the Bertram Loeb Research Chair and the
Social Sciences and Humanities Research Council of Canada.

References
American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders (4th
edn., text rev.). Washington, DC: American Psychiatric Association.
American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (5th
edn.). Washington, DC: American Psychiatric Association.
Aspinwall, L.G., Brown, T.R., and Tabery, J. (2012). Science, 337, 846–​849.
Canada Safeway Ltd. and RWDSU (MacNeill) Re [1999] S.L.A.A. No. 1 (Sask. Labour Arbitration).
Charter of Rights and Freedoms, Part I of the Constitution Act, 1982, being Schedule B to the Canada
Act 1982 (UK), 1982, c 11.
Cominco Ltd. v. United Steelworkers of America, Local 9705, [2000] B.C.C.A.A.A. No. 62 (QL) Para. 179.
Corrigan, P.W. (2000). Mental health stigma as social attribution: implications for research methods
and attitude change. Clinical Psychology: Science and Practice, 7(1), 48–​67.
Corrigan, P., Markowitz, F.E., Watson, A., Rowan, D., and Kubiak, M.A. (2003). An attribution model
of public discrimination toward persons with mental illness. Journal of Health and Social Behavior,
44(2), 162–​179.
Criminal Code. R.S.C. 1985 c. C-​46.
Esses, V.M. and Beaufoy, S.L. (1994). Determinants of attitudes toward people with disabilities. Journal
of Social Behavior and Personality, 9(5), 43–​64.
Fischer, J.M. and Ravizza, M. (1998). Responsibility and Control: A Theory of Moral Responsibility.
Cambridge: Cambridge University Press.
Fuss, J., Dressing, H., and Briken, P. (2015). Neurogenetic evidence in the courtroom: a randomized
controlled trial with German judges. Journal of Medical Genetics, 42, 730–​737.
Gilbert, D. and Majury, D. (2006). Infertility and the parameters of discrimination discourse. In: Pothier,
D. and Devlin, R. (Eds.) Critical Disability Theory: Essays in Philosophy, Politics, Policy, and Law,
pp.285–​304. Vancouver, BC: UBC Press.
Human Rights Code, R.S.O. 1990, c. H.19.
Interior Health Authority (South Similkameen Health Centre) v. Hospital Employee’s Union (RP
Grievance) [2013] B.C.C.A.A.A. No. 44.
 589

References 589

Invista (Canada) Co., Kingston Site v. Kingston Independent Nylon Workers Union (Asselstine
Grievance) [2013] O.L.A.A. NO. 38.
Kellogg Canada Inc. v. Bakery, Confectionary, Tobacco Workers & Grain Millers, Local 154-​G (Fickling
Grievance), [2006] O.L.A.A. No. 375 at 60.
Kvaale, E.P., Haslam, N., and Gottdiener, W.H. (2013). The ‘side effects’ of medicalization: a meta-​analytic
review of how biogenetic explanations affect stigma. Clinical Psychology Review, 33, 782–​794.
Law Commission of Ontario (2009). The Law as it Affects Persons with Disabilities: Preliminary
Consultation Paper, Approaches to Defining Disability. Available from: http://​www.lco-​cdo.org/​en/​
disabilities-​threshold-​paper [accessed February 11, 2017].
Lee, A.A., Laurent, S.M., Wykes, T.L., Kitchen Andre, K.A., Bourassa, K.A., and McKibbin, C.L.
(2014). Genetic attributions and mental illness diagnosis: effects on perceptions of danger, social
distance, and real helping decisions. Social Psychiatry and Psychiatric Epidemiology, 49, 781–​789.
Letourneau v. JTI-​MacDonald Corp. 2015 QCCS 2382.
Love, T., Laier, C., Brand, M., Hatch, L., and Hajela, R. (2015). Neuroscience of internet pornography
addiction: a review and update. Behavioral Sciences, 5(3), 388–​433.
Manitoba Government and General Employees’ Union v. Manitoba (M.W. Grievance) [2013] M.G.A.D.
No. 10 at para. 81.
Manitoba v. Manitoba Government and General Employees’ Union 2005 MGAD No. 14.
McNeill v. Ontario Ministry of the Solicitor General and Correctional Services [1998] O.J. No. 2288
(Ont. Ct. J.—​Gen Div.).
Monterosso, J., Royzman, E.B., and Schwartz, B. (2004). Explaining away responsibility: effects of
scientific explanation on perceived culpability. Ethics & Behavior, 15(2), 139–​158.
Milazzo v. Autocar Connaisseur Inc. 2003 CHRT 37.
Mueller, P.K., Houser, J.A., and Riddle, M.K. (2010). Regarding disability: perceptions of protection
under the Americans with Disabilities Act. Research in Social Science and Disability, 5, 159–​180.
Ontario (Director, Disability Support Program) v. Tranchemontagne (2009) O.R. (3d) 327, aff ’d 2010
ONCA 593.
Ontario Human Rights Commission (2014). Policy on Preventing Discrimination Based on Mental
Health Disabilities and Addictions. Available from: http://​www.ohrc.on.ca/​en/​policy-​preventing-​
discrimination-​based-​mental-​health-​disabilities-​and-​addictions [accessed February 11, 2017].
Penney, S. (2012). Impulse control and criminal responsibility: lessons from neuroscience. International
Journal of Clinical and Health Psychology, 35, 99–​103.
R. v. Ample Annie’s Itty Bitty Roadhouse (2001) O.J. No. 5968 (Ont. C.J.).
R. v. Belcourt 2010 ABCA 319.
R. v. H.T. 2010 MBPC 8.
R. v. Obed 2006 NLTD 155.
R. v. Smith 2015 BCSC 1267.
R. v. Horvath [1997] S.J. No. 385 (Sask. C.A.).
Roach, K. (2012). Criminal Law (5th edn.). Toronto, ON: Irwin Law Inc.
Ruby, C.C. (2004). Sentencing (6th edn.). Markham, ON: Butterworths.
Seneca College v. Ontario Public Service Employees Union (Discharge Grievance [2002] O.L.A.A.
No. 415.
Tovino, S.A. (2015). Will neuroscience redefine mental injury? Disability benefit law, mental health
parity law, and disability discrimination law. Indiana Health Law Review, 12(2), 695–​728.
United Nations General Assembly (2007). Convention on the Rights of Persons with
Disabilities: Resolution/​Adopted by the General Assembly, 24 January 2007. [UN Document A/​RES/​
61/​106.] New York: United Nations.
590

590 The impact of neuroscience in the law

Van Oorschot, W. (2000). Who should get what, and why? On deservingness criteria and the
conditionality of solidarity among the public. Policy and Politics, 28(1), 33–​49.
Vrecko, S. (2010). Birth of a brain disease: science, the state and addiction neuropolitics. History of the
Human Sciences, 23(4), 52–​67.
Weiner, B. (1993). On sin versus sickness: a theory of perceived responsibility and social motivation.
American Psychologist, 48(9), 957–​965.
Weiner, B., Perry, R.P., and Magnusson, J. (1988). An attributional analysis of reactions to stigmas.
Journal of Personality and Social Psychology, 55(5), 738–​748.
Weiner, B., Osborne, D., and Rudolph, U. (2011). An attributional analysis of reactions to poverty: the
political ideology of the giver and the perceived morality of the receiver. Personality and Social
Psychology Review, 15(2), 199–​213.
Yellowknife (City) v. Denny 2004 NWTTC 2.
 591

Chapter 30

Neuroethics and global mental health:

Establishing a dialogue
Dan J. Stein and James Giordano

Introduction
Neuroethics, alongside the other neuro-​disciplines, has largely been developed within
high-​income Western countries. This is not surprising, given that neuroscience is an
expensive research endeavor that has mostly been undertaken in academic institutions
based in these locations, and given that the conceptual framework of neuroethics is
related to work in areas such as bioethics and neurophilosophy, which have also most
often been pursued in this high-​income Western context. Conversely, an electronic search
of the research literature at the intersection of “neuroethics” and “low-​income or middle-​
income countries” reveals vanishingly few publications, although there is certainly clear
recognition of the importance of issues surrounding neuroethics and globalization
(Lombera & Illes 2009; Giordano 2013).
Global mental health is another recently defined field of intellectual and practical
endeavor, which has emphasized that although the majority of research on mental dis-
orders takes place in high-​income Western countries, the vast bulk of the world’s people
with mental disorders live in low-​and middle-​income countries (LMICs) (the so-​called
10:90 research gap) (Becker & Kleinman 2012; Patel 2012). Researchers in global mental
health have not only emphasized the research gap, but they have also brought attention
to the treatment gap; in LMICs, there are significant barriers to accessing and scaling up
effective treatments (Wang et  al. 2007; Andrade et  al. 2013). Conversely, an electronic
search of “global mental health” and “neuroscience” yields relatively few publications at
this intersection, although there is a growing emphasis on the need for both implementa-
tion and discovery science in LMIC contexts (Collins et al. 2011; Stein et al. 2015).
This chapter makes the argument that despite their different histories and trajectories,
neuroethics and global mental health have a good deal in common, and there is much
to be gained from an ongoing dialogue and interaction between these fields. There are
a number of important areas of overlap between neuroethics and global mental health,
including (1) a naturalist and empirical approach, (2) a concern with both disease and
with well-​being, (3)  a concern with human rights and with patient empowerment—​
intersections which have previously been reviewed (Stein & Giordano 2015). Each
of these areas of overlap is considered in more detail throughout this chapter, and an
592

592 Neuroethics and global mental health

additional area, namely, (4) an appreciation of human diversity, including neurodiversity,

is also addressed.

Naturalist and empirical approach

A central set of concerns for neuroethics includes work on the neuroscience of ethics and
morality (Buniak et al. 2014; Darragh et al. 2015). Methodological advances in fields such
as neuroimaging and electroencephalography have provided insights into the neurocir-
cuitry of ethical and moral judgments and decision-​making. Neuroethics is concerned
with the implications of such new findings for age-​old questions about the nature of the
self and of agency, free will and weakness of will, moral culpability and responsibility, and
so forth. Its approach is a naturalist and empirical one insofar as it emphasizes the value
of both neuroscience and empirical neuroethics in providing more accurate and more
comprehensive answers to such questions (Illes 2007; Racine 2008; Levy 2012).
Analogously, global mental health has advocated an evidence-​based approach and
has advanced in part by developing rigorous study designs and methods for address-
ing long-​standing questions in psychiatry and clinical psychology (Patel & Thornicroft
2009). Rather than simply speculating about the relevance of psychotherapies developed
in Western contexts for LMICs, for example, researchers have done careful research on
how best to adapt such work to new contexts, and how best to build capacity in the deliv-
ery of such adapted interventions (Patel & Prince 2010; Murray et al. 2011; Remien et al.
2013). Such work has in turn arguably contributed to our understanding of the nature and
mechanisms of psychotherapy (Murray et al. 2014).
Important concerns can certainly be raised about the sort of approach that both neuro-
ethics and global mental health have undertaken. From a metaphilosophical perspective,
for example, it might be strongly argued that no amount of science can simply reduce core
conceptual questions in philosophy and ethics to empirical ones (Overgaard et al. 2013).
And critics of global mental health have argued that the field has been overly accepting of
Western diagnostic constructs and therapeutic approaches, failing to see how psychiatry
is embedded in one particular conceptual mold, how it reflects the values of its own social
origins and context, and how it imposes its theories and values in a neocolonialist way
on the rest of the world (Summerfield 2013). Certainly, an absence of evidence does not
imply evidence of absent efficacy (Altman & Bland 1995), simplistic extrapolation of the
evidence based from one setting to another is not always appropriate (Stein et al. 2002),
and there may well be a need to supplement an evidence-​based approach with values-​
based medicine (Fulford 2011).
We would submit that a conversation and collaboration between neuroethics and global
mental health may be useful in addressing some of these concerns. Empirical study of a
broad range of ethical and moral issues, drawn from contexts around the world, is impor-
tant in raising an awareness of—​and appropriately addressing—​the complexity of ethical
and moral decision-​making (Lanzilao et al. 2013). Conversely, a rigorous analysis of the
theories and values underlying and underpinning global mental health is important to
 593

Concern with both disease and wellness 593

ensure that these are made fully explicit, that these are rigorously discussed and debated,
and that adaptation of different constructs and approaches across different contexts is
done in a sensitive and appropriate way.

Concern with both disease and wellness

While much work in neuroethics had been concerned with a range of neuropsychiatric dis-
orders, the field has also had a particular concern with issues about human enhancement
(Savulescu 2006; Sahakian & Morein-​Zamir 2011; Stein 2012b; Shook & Giordano 2016).
Neuroethics has raised questions about the nature of well-​being, the importance of soci-
etal happiness, and issues of optimal neurodevelopment and aging, and has emphasized
that countries need to capitalize on the cognitive resources of their citizens (Beddington
et al. 2008). Again, these concerns emerge from advances in neuroscience and from new
methodologies, which allow a more detailed understanding of both risk and resilience fac-
tors, which provide a range of tools for monitoring and measuring disease and wellness,
and which have led to a range of novel interventions that may maximize the potential of
individuals and of societies (Stein 1998; Farah et al. 2004; Greely et al. 2008).
Global mental health has emphasizing the spectrum of mental disease and health, rang-
ing from mental disease, through to suffering and distress, and on to different forms of
well-​being (Jacob & Patel 2014). It has focused not only on understanding disease mecha-
nisms and the treatment of disorders, but also on understanding the mechanisms underly-
ing resilience and the prevention of disorders. It has argued that we should be careful not
to pathologize different idioms of distress, that we also address the structural determinants
of mental health, and that we aim not only for symptom reduction but also for recovery
(Davidson & Strauss 1995; Kirmayer & Pedersen 2014). Whereas clinical neuroscience has
focused on the endophenotypes, or intermediate phenotypes that underlie the spectrum
of states and traits, a public health perspective has also focused on exophenotypes, or the
range of social and cultural factors that impact such phenotypes (Stein et al. 2013).
An emphasis on both disease and well-​being is not without controversy. A reasonable
argument can be made for the need to focus mental health resources on the small pro-
portion of the community with serious mental disorders, where appropriate human and
health infrastructure can make an enormous difference. In contrast, it may be argued that
a focus on the “worried well,” where long-​term outcomes are good without intervention,
is an investment that has a relatively poor return. Certainly there is a relative paucity of
data on the efficacy and effectiveness of interventions to improve well-​being (Stein 2012a).
Furthermore, while it may be relatively easy to obtain consensus about what constitutes
severe mental disorders and to agree on universal interventions to address such condi-
tions, there may be considerable disagreement about the nature of human well-​being
and on the best ways of attempting to achieve such well-​being (Stein 2012a). In addition,
many have written persuasively about the problems inherent in relying on technological
approaches to resolving social ills (Parens 1998; Sandel 2004).
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594 Neuroethics and global mental health

Both neuroscience and global mental health can usefully contribute to the debate about
the nature and boundaries of mental disorder and mental well-​being. Community survey
data have emphasized, for example, that respondents who do not meet threshold criteria
for presence of disorder, but who have subclinical symptoms, nevertheless suffer from a
great deal of impairment (Kessler et al. 2003). While absenteeism is a major cost, the bur-
den due to presenteeism also requires recognition (Beddington et al. 2008). Delineation
of the boundaries between illness and disease partly reflects the availability and costs
for treatment; thus the introduction of generic statins led to a lowering of definitions
of hypercholesterolaemia (Kessler et al. 2003). Similarly, in the area of mental disorders
and mental health, both conceptual and empirical work is needed to address optimally
the delineation of disorders, and to answer fully the questions of when and how best to
intervene in a global context (Stein 2008; Stein et  al. 2013). We can expect that novel
opportunities to improve individual and societal flourishing will become an increasingly
prominent topic for debate and practice (Shook & Giordano 2014).

Concern with human rights and patient empowerment

Important aspects of neuroethics include work on the ethics of neuroscientific studies, as
well as the intersection of neuroscience and social policy (Buniak et al. 2014). Advances in
fields such as neurogenetics, neuroimaging, and neuropsychopharmacology have raised
a new set of ethical issues for contemporary society. Neurogeneticists are asked about
the implications of polygenic risk scores, neuroimaging scientists encounter inciden-
talomas, and neuropsychopharmacologists have introduced new chemical entities which
raise the possibility of cognitive and emotional enhancement (Illes 2004; Sahakian et al.
2015). Neuroethicists are concerned that we address such questions in a way that maxi-
mizes beneficence, non-​maleficence, autonomy, justice, and other key values, and that
neurotechnologies are not used to fortify asymmetric relationships between individuals
or communities (Giordano 2014; Shook & Giordano 2014). Some have put particular
emphasis on the importance and value of autonomy in decisions about issues such as
enhancement (Schaefer et al. 2014).
Analogously, global mental health is crucially driven by a concern for human rights
and well-​being (Patel et al. 2006; Becker & Kleinman 2013). The field has framed stig-
matization of mental illness, and lack of parity for mental disorder treatments, as human
rights issues (Silove 1999; Yamin & Rosenthal 2005). It has argued that mental health is
central to the developmental agenda, and that there is “no health without mental health”
(Prince et al. 2007). Moreover, authors writing from a global mental health perspective
have emphasized that mental disorders represent only one end of a spectrum of human
suffering, so efforts must be directed not only at reducing symptoms of disorders, but
also at improving resilience and well-​being. Global mental health has emphasized the
importance of patient voices, consumer advocacy, destigmatization, and social inclusion,
as depicted in the slogan “nothing for us, without us.” Some have put particular emphasis
 59

Appreciation of human diversity and neurodiversity 595

on the importance of equitable relationships between researchers from the global North
and South (Fricchione et al. 2012).
Important concerns can be raised about these foci of neuroethics and of global mental
health. There is an argument which emphasizes that human rights should not be thought
of as a natural kind but rather that such constructs are bound to specific times and places
(Donnelly 2013); there is a view that to understand and evaluate an ethical issue, concepts
of human rights need to be augmented with additional constructs such as “duty” and
“virtue” (Benatar 2006); and there is a position that the right to mental healthcare may not
always be the most appropriate approach to ensuring optimization of mental health ser-
vices (Glover-​Thomas & Chima 2015). Some critics have emphasized the risk of including
patient perspectives merely for the sake of political correctness (Spitzer 2004), and there
are certainly limits to the effectiveness of social inclusion as a sole treatment for those suf-
fering from mental disorders. There is a need for careful conceptual and empirical work
on issues such as the stigmatization of mental disorder, in order to ensure that responses
to mental illness fully recognize its reality and its consequences, but at the same time, do
not unfairly discriminate against those who suffer from these conditions.
Indeed, in response to such concerns, there is much room for neuroethics and global
mental health to contribute in a collaborative way. Although they come from quite dif-
ferent perspectives, each emphasizes the growing role of the patient in mental healthcare,
and each strongly values the autonomy of the individual in deciding on what health-
care to access and how. Each is also, however, aware of important limits to autonomy;
sometimes those with serious mental illness are hospitalized against their will, and some-
times consumers use neurotechnologies, including psychotropic agents, in harmful ways.
Rigorous theoretical and empirical work is needed in order to ensure the optimization
and maximization of human rights and consumer empowerment in the area of clinical
neuroscience. As the agenda of global mental health research, including work on discov-
ery and implementation science, gives increasing impetus to studies of mental health and
mental disorders in LMICs, so there will be a need to increase attention to neuroethical
issues arising in these settings, and to the promotion of responsible policies (Shook and
Giordano 2014).

Appreciation of human diversity and neurodiversity

Neuroethics is acutely aware that there is not simply one sort of human brain, but that
each brain is unique. The more we learn about genetics and about the interaction of genes
and environment, the more we are aware of the complexity and diversity of brain–​mind
development and of human phenotypes. New neurotechnologies, including neuroimag-
ing, neurogenetics, neurotranscriptomics, and neurometabolomics, have become ever
more reliant on, and engaged by, the incentives of “big data,” which is challenging our
fastest super-​computers and most sophisticated data-​processing algorithms (Monteith
et al. 2015; DiEuliis & Giordano 2016).
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596 Neuroethics and global mental health

Analogously, global mental health is very much aware that most psychology research
is undertaken on Westernized, educated, industrialized, rich, and democratic (WEIRD)
populations (Henrich et al. 2010). It is also crucially aware of how mental disorders pres-
ent differently in different contexts, of how there are multiple different explanatory mod-
els of mental disorder, and of how these can impact the course of treatment (Kleinman
1991; Stein 1993; Kirmayer 2006). Whereas clinical neuroscience has focused on biologi-
cal diversity, global mental health has emphasized the importance of cultural and social
diversity.
Once again, some concerns can perhaps be raised in this area. Science, including the
field of genetics, does not always have a good track record of celebrating diversity, and it is
crucial to bear in mind those times when neuroscience and psychiatry have had an igno-
minious and deplorable past (Weiss & Lambert 2011; Zeidman 2012). At the same time,
there are perhaps potential risks in not providing neuroscientific and psychiatric treat-
ments when these can relieve suffering. In the current era, recognition of past excesses has
led to a strong focus on the avoidance of over-​medicalization. At the same time, in certain
contexts, medicalization is entirely appropriate (Stein & Gureje 2004).
Neuroethics and global mental health can again perhaps develop a mutually enrich-
ing research agenda in this area. It is important, for example, to understand fully our
genetic diversity by employing global populations in the study of normal and abnormal
behavior. There is a strong argument that the inclusion of African populations is needed
to delineate fully the genetic risk factors for mental disorders, and that the exclusion of
African populations from such studies may potentially lead to exclusion from the positive
benefits of certain kinds of research (e.g., not fully understanding pharmacogenetics of a
particular psychotropic drug) (Dalvie et al. 2015). Indeed, the study of global populations
may yield crucially important lessons for neuroscience and for psychiatry (Patel 2010;
Patel & Saxena 2014).

Conclusion
Neuroethics and global mental health have strikingly different origins and trajectories.
The former has focused mainly on new and specialized technologies being introduced
into high-​income countries, while the latter has focused on primary care interventions
and their scale-​up in LMICs. At the same time, these fields also share a number of impor-
tant concerns and approaches. There has been relatively little conversation between neu-
roethics and global mental health to date; this chapter argues that collaboration between
these fields may be useful in advancing a number of key areas of work and of debate. Our
hope is that lessons from global neuroscience may impact positively on the development
and articulation of an internationally sensitive, relevant, and valuable neuroethics.
Such a conversation and collaboration between neuroethics and global mental health
may be important in ensuring ongoing progress in advancing a naturalist and empiri-
cal approach to mental disorders, in addressing both disease and wellness in the mental
health context, in maintaining an ongoing focus on the importance of human rights and
 597

References 597

patient empowerment, and in appreciating human diversity, including neurodiversity.

Such work will need to address a range of issues that are important for both fields, includ-
ing neuroethical aspects of global mental health research, as well as the expansion of
neuroethical discourse and research to address the introduction of neuroscientific devel-
opments and novel neurotechnologies into the low-​and middle-​income world (Stein &
Giordano 2015).

References
Altman, D.G. and Bland, J.M. (1995). Absence of evidence is not evidence of absence. BMJ, 311, 485.
Andrade, L.H., Alonso, J., Mneimneh, Z., et al. (2013). Barriers to mental health treatment: results
from the WHO World Mental Health surveys. Psychological Medicine, 1–​15.
Becker, A.E. and Kleinman, A. (2012). An agenda for closing resource gaps in global mental
health: innovation, capacity building, and partnerships. Harvard Review of Psychiatry, 20, 3–​5.
Becker, A.E. and Kleinman, A. (2013). Mental health and the global agenda. New England Journal of
Medicine, 369, 1380–​1381.
Beddington, J., Cooper, C.L., Field, J., et al. (2008). The mental wealth of nations. Nature, 455,
1057–​1060.
Benatar, D. (2006). Bioethics and health and human rights: a critical view. Journal of Medical Ethics,
32, 17–​20.
Buniak, L., Darragh, M., and Giordano, J. (2014). A four-​part working bibliography of
neuroethics: part 1: overview and reviews –​defining and describing the field and its practices.
Philosophy, Ethics, and Humanities in Medicine, 9, 9.
Collins, P.Y., Patel, V., Joestl, S.S., et al. (2011). Grand challenges in global mental health. Nature,
475, 27–​30.
Dalvie, S., Koen, N., Duncan, L., et al. (2015). Large scale genetic research on neuropsychiatric
disorders in African populations is needed. EBioMedicine, 2, 1259–​1261.
Darragh, M., Buniak, L., and Giordano, J. (2015). A four part working bibliography of
neuroethics: part 2: neuroscientific studies of morality and ethics. Philosophy, Ethics, and Humanities
in Medicine, 10, 1.
Davidson, L. and Strauss, J.S. (1995). Beyond the biopsychosocial model: integrating disorder, health,
and recovery. Psychiatry, 58, 44–​55.
DiEuliis, D. and Giordano, J. (2016). Neurotechnological convergence and big data: a “force multiplier”
toward advancing neuroscience. In: Collmann, J. and Matei, S. (Eds.) Ethical Reasoning in Big Data:
An Exploratory Analysis, pp.71–​80. New York: Springer.
Donnelly, J. (2013). Universal Human Rights in Theory and Practice (3rd edn). Ithaca, NY: Cornell
University Press.
Farah, M.J., Illes, J., Cook-​Deegan, R., et al. (2004). Neurocognitive enhancement: what can we do and
what should we do? Nature Reviews Neuroscience, 5, 421–​425.
Fricchione, G.L., Borba, C.P., Alem, A., Shibre, T., Carney, J.R., and Henderson, D.C. (2012). Capacity
building in global mental health: professional training. Harvard Review of Psychiatry, 20, 47–​57.
Fulford, K.W. (2011). The value of evidence and evidence of values: bringing together values-​based and
evidence-​based practice in policy and service development in mental health. Journal of Evaluation in
Clinical Practice, 17, 976–​987.
Giordano, J. (2013). Ethical considerations in the globalization of medicine –​an interview with James
Giordano. BMC Medicine, 11, 69.
598

598 Neuroethics and global mental health

Giordano, J. (2014). The human prospect(s) of neuroscience and neurotechnology: domains of

influence and the necessity—​and questions—​of neuroethics. Human Prospect, 4(1), 1–​18.
Glover-​Thomas, N. and Chima, S.C. (2015). A legal “right” to mental health care? Impediments
to a global vision of mental health care access. Nigerian Journal of Clinical Practice, 18(Suppl),
S8–​S14.
Greely, H., Sahakian, B., Harris, J., et al. (2008). Towards responsible use of cognitive-​enhancing drugs
by the healthy. Nature, 456, 702–​705.
Henrich, J., Heine, S.J., and Norenzayan, A. (2010). Most people are not WEIRD. Nature, 466, 29.
Illes, J. (2004). Medical imaging: a hub for the new field of neuroethics. Academic Radiology, 11,
721–​723.
Illes, J. (2007). Empirical neuroethics. Can brain imaging visualize human thought? Why is neuroethics
interested in such a possibility? EMBO Reports, 8(Spec No), S57–​60.
Jacob, K.S. and Patel, V. (2014). Classification of mental disorders: a global mental health perspective.
Lancet, 383, 1433–​1435.
Kessler, R.C., Merikangas, K.R., Berglund, P., Eaton, W.W., Koretz, D.S., and Walters, E.E. (2003).
Mild disorders should not be eliminated from the DSM-​V. Archives of General Psychiatry, 60,
1117–​1122.
Kirmayer, L.J. (2006). Beyond the ‘new cross-​cultural psychiatry’: cultural biology, discursive
psychology and the ironies of globalization. Transcultural Psychiatry, 43, 126–​144.
Kirmayer, L.J. and Pedersen, D. (2014). Toward a new architecture for global mental health.
Transcultural Psychiatry, 51, 759–​776.
Kleinman, A. (1991). Rethinking Psychiatry: From Cultural Category to Personal Experience.
New York: Free Press.
Lanzilao, E., Shook, J., Benedikter, R., and Giordano, J. (2013). Advancing neuroscience on the
21st century world stage: the need for—​and proposed structure of—​an internationally relevant
neuroethics. Ethics in Biology, Engineering and Medicine, 4(3), 211–​229.
Levy, N. (2012). Neuroethics. Wiley Interdisciplinary Reviews: Cognitive Science, 3, 143–​151.
Lombera, S. and Illes, J. (2009). The international dimensions of neuroethics. Developing World
Bioethics, 9, 57–​64.
Monteith, S., Glenn, T., Geddes, J., and Bauer, M. (2015). Big data are coming to psychiatry: a general
introduction. International Journal of Bipolar Disorders, 3, 21.
Murray, L.K., Dorsey, S., Bolton, P., et al. (2011). Building capacity in mental health interventions in
low resource countries: an apprenticeship model for training local providers. International Journal of
Mental Health Systems, 5, 30.
Murray, L.K., Dorsey, S., Haroz, E., et al. (2014). A common elements treatment approach for adult
mental health problems in low-​and middle-​income countries. Cognitive and Behavioral Practice, 21,
111–​123.
Overgaard, S., Gilbert, P., and Burwood, S. (2013). An Introduction to Metaphilosophy.
New York: Cambridge University Press.
Parens, E. (1998). Is better always good? The Enhancement Project. Hastings Centre Reports, 28, S1–​S17.
Patel, V. (2010). Research priorities for Indian psychiatry. Indian Journal of Psychiatry, 52, S26–​29.
Patel, V. (2012). Global mental health: from science to action. Harvard Review of Psychiatry, 20, 6–​12.
Patel, V. and Prince, M. (2010). Global mental health: a new global health field comes of age. JAMA,
303, 1976–​1977.
Patel, V. and Saxena, S. (2014). Transforming lives, enhancing communities—​innovations in global
mental health. New England Journal of Medicine, 370, 498–​501.
 59

References 599

Patel, V. and Thornicroft, G. (2009). Packages of care for mental, neurological, and substance use
disorders in low-​and middle-​income countries: PLoS Medicine Series. PLoS Medicine, 6, e1000160.
Patel, V., Saraceno, B., and Kleinman, A. (2006). Beyond evidence: the moral case for international
mental health. American Journal of Psychiatry, 163, 1312–​1315.
Prince, M., Patel, V., Saxena, S., et al. (2007). No health without mental health. Lancet, 370, 859–​877.
Racine, E. (2008). Which naturalism for bioethics? A defense of moderate (pragmatic) naturalism.
Bioethics, 22, 92–​100.
Remien, R.H., Mellins, C.A., Robbins, R.N., et al. (2013). Masivukeni: development of a multimedia
based antiretroviral therapy adherence intervention for counselors and patients in South Africa.
AIDS and Behavior, 17, 1979–​1991.
Sahakian, B.J. and Morein-​Zamir, S. (2011). Neuroethical issues in cognitive enhancement. Journal of
Psychopharmacology, 25, 197–​204.
Sahakian, B.J., Bruhl, A.B., Cook, J., et al. (2015). The impact of neuroscience on society: cognitive
enhancement in neuropsychiatric disorders and in healthy people. Philosophical Transactions of the
Royal Society B: Biological Sciences, 370, 20140214.
Sandel, M.J. (2004). The case against perfection: what’s wrong with designer children, bionic athletes,
and genetic engineering. Atlantic Monthly, 292, 50–​54, 56–​60, 62.
Savulescu, J. (2006). Justice, fairness, and enhancement. Annals of the New York Academy of Sciences,
1093, 321–​338.
Schaefer, G.O., Kahane, G., and Savulescu, J. (2014). Autonomy and enhancement. Neuroethics, 7,
123–​136.
Shook, J.R. and Giordano, J. (2014). A principled and cosmopolitan neuroethics: considerations for
international relevance. Philosophy, Ethics, and Humanities in Medicine, 9, 1.
Shook, J.R. and Giordano, J. (2016). Neuroethics beyond normal: performance enablement and self-​
transformative technologies. Cambridge Quarterly of Healthcare Ethics, 25, 121–​140.
Silove, D. (1999). The psychosocial effects of torture, mass human rights violations, and refugee
trauma: toward an integrated conceptual framework. Journal of Nervous and Mental Disease, 187,
200–​207.
Spitzer, R.L. (2004). Good idea or politically correct nonsense? Psychiatric Services, 55, 113.
Stein, D.J. (1993). Cross-​cultural psychiatry and the DSM-​IV. Comprehensive Psychiatry, 34, 322–​329.
Stein, D.J. (1998). Philosophy of psychopharmacology. Perspectives in Biology and Medicine, 41,
200–​211.
Stein, D.J. (2008). Philosophy of Psychopharmacology. Cambridge: Cambridge University Press.
Stein, D.J. (2012a). Positive mental health: a note of caution. World Psychiatry, 11, 107–​109.
Stein, D.J. (2012b). Psychopharmacological enhancement: a conceptual framework. Philosophy, Ethics,
and Humanities in Medicine, 7, 5.
Stein, D.J. and Giordano, J. (2015). Global mental health and neuroethics. BMC Medicine, 13, 274.
Stein, D.J. and Gureje, O. (2004). Depression and anxiety in the developing world: is it time to
medicalise the suffering? Lancet, 364, 233–​234.
Stein, D.J., Xin, Y., Osser, D., Li, X., and Jobson, K. (2002). Clinical psychopharmacology
guidelines: different strokes for different folks. World Journal of Biological Psychiatry, 3, 64–​67.
Stein, D.J., Lund, C., and Nesse, R.M. (2013). Classification systems in psychiatry: diagnosis and global
mental health in the era of DSM-​5 and ICD-​11. Current Opinion in Psychiatry, 26, 493–​497.
Stein, D.J., He, Y., Phillips, A., Sahakian, B.J., Williams, J., and Patel., V. (2015). Global mental health
and neuroscience: potential synergies. Lancet Psychiatry, 2, 178–​185.
Summerfield, D. (2013). “Global mental health” is an oxymoron and medical imperialism. BMJ,
346, f3509.
60

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Wang, P.S., Angermeyer, M., Borges, G., et al. (2007). Delay and failure in treatment seeking after first
onset of mental disorders in the World Health Organization’s World Mental Health Survey Initiative.
World Psychiatry, 6, 177–​185.
Weiss, K.M. and Lambert, B.W. (2011). When the time seems ripe: eugenics, the annals, and the subtle
persistence of typological thinking. Annals of Human Genetics, 75, 334–​343.
Yamin, A.E. and Rosenthal, E. (2005). Out of the shadows: using human rights approaches to secure
dignity and well-​being for people with mental disabilities. PLoS Medicine, 2, e71.
Zeidman, L.A. (2012). Re: neuroscience in Nazi Europe part I: eugenics, human experimentation,
and mass murder. Can J Neurol Sci. 2011; 38:696–​703. Canadian Journal of Neurological Sciences,
39, 400.
 601

Part IV

Epilogue
602
 603

Chapter 31

Neuroethics and neurotechnology:

Instrumentality and human rights
Joseph J. Fins

Neuroethics as an ethics of technology

Five years ago, in writing an epilogue for the Oxford Handbook of Neuroethics (Illes &
Sahakian 2011), I questioned if neuroethics was distinct from mainstream medical eth-
ics (Fins 2011). I was not sure, but asserted that if neuroethics could be differentiated it
would be as an ethics heavily predicated upon a confluence of technological advances
that opened up a heretofore unchartered problem space. So if we were to differentiate
neuroethics, it would be fundamentally as an ethics of technology. I want to return to this
question here for Neuroethics: Anticipating the Future.
Neuroethics and technology is a perennial theme, with its own eternal recurrence.
Think of what one emerging technology, neuroimaging, has done for our rather naïve
understanding of disorders of consciousness. Our faith in the classic bedside exam has
been shaken. Behavioral manifestations of self, of consciousness used to assess brain
states from coma to the vegetative and minimally conscious states have been augmented
by a new reality made possible by brain scans, colorful flares on functional magnetic reso-
nance imaging, which sometimes suggest that individuals once thought irretrievably lost,
might still be there, albeit only in their head. Technological advance made apparent what
once went unnoticed and thus unreflected upon for its normative significance. What was
once beyond our gaze now looked us straight in the eye asking us to reconsider our moral
obligations to others.
Neuroimaging has revealed a degree of complexity akin to what Mendel discerned from
the colorful pea plants in his monastery’s garden (Fins 2007). Some patients revealed cog-
nitive motor dissociation, a discordance between overt action and implicit thought, much
like the distinction between phenotype and genotype (Schiff et al. 2005; Owen et al. 2006;
Monti et al. 2010; Bardin et al. 2011). What was seemingly obvious at the bedside was no
longer so simple. As the technology of neuroimaging expanded our empirical reality, the
normative universe in which people exist needed to expand (Fins 2008a). Indeed, it had
to become more inclusive about who might retain covert consciousness.
Technology was a powerful normative force. Not only did neuroimaging alter the
scientific status quo, it fundamentally disrupted the moral landscape (Fins 2005). Even
though neuroimaging is actually less sensitive in detecting covert consciousness than the
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604 Neuroethics and neurotechnology

gold standard Coma Recovery Scale-​Revised (Giacino et  al. 2004), the colorful visuals
of neuroimaging captured media attention and generated academic discourse. Although
neuroimaging was inferior as a diagnostic tool, it was far more spectacular because only
a nonbehavioral metric could reveal a dissociation between overt and covert signs of
consciousness. This discordance, born of technological advance, prompted neuroethi-
cal reflection about what should be done for those who might have a life of the mind
(Naccache 2006).

Halfway technologies
As neuroscience began to unravel what the great Canadian neurosurgeon Wilder Penfield
(1976; Fins 2008b) called the “mystery of the mind”, the revelations were accompanied
by both angst and hope. People thought forever gone might literally be trapped in their
heads, deprived of community and communication (Fins 2015), isolated and alone. And
it also suggested the seemingly impossible. Might those stranded somehow be rescued?
Once again neuroethics becomes concerned with its recurring theme of technology. If
technology reveals a problem, might it not also resolve it? That is, could neurotechnology
help address the isolation of those recently identified as suffering from cognitive motor
dissociation and reintegrate them into community through the restoration of functional
communication? And of course, this effort has begun with the use of neuroprosthetics like
deep brain stimulation (DBS) (Schiff et al. 2007), drugs (Giacino et al. 2012), and neuro-
imaging paradigms to communicate with the severely injured brain (Giacino et al. 2014).
It would seem to be a neat resolution to our problem with technology. One technology
creates an ethical challenge only for another to solve it. But if it were that simple, it would
be impoverishing. We would risk falling prey to Leon Kass’s (2003) critique of modern
bioethics with its penchant for a technological quick fix of complex problems, reducing
human experience to engineering solutions that truncate the lived experiences of affected
communities. He warns that:
To a society armed with biotechnology, the activities of human life may come to be seen in purely
technical terms, and more amenable to improvement than they really are. Or we may imagine
ourselves wiser than we really are. Or we may get more easily what we asked for only to realize it is
vastly less than what we really wanted. (Kass 2003)

While the use of neuroprosthetics is a brilliant scientific response to cognitive motor

dissociation, it is hardly enough. Neuroscience’s current therapeutic forays are primitive
and cumbersome and what the American physician and essayist Lewis Thomas (1974)
might have considered halfway technologies, medical innovations which improve but
do not eliminate a condition. But it is more than merely a question of feasibility and
utility:  if our technologies are still halfway there, so too is an analysis which views
the problem space too exclusively as a technological one. By doing so we discount our
motivations for intervening and neglect the broader import of any effort to manipulate,
heal, or restore the function of the human brain and mind. To view the challenge of
 605

A self-critique 605

brain science solely through the prism of technology is both clinically incomplete and
normatively thin.

A self-​critique
While neuroscience is nurtured by the scientist’s curiosity, neuroethics should help
ensure that the quest discovery is more than a science project. The stakes are higher
than that and the work has to be understood in a broader humanistic context in which
the purpose and telos of technological advance is well articulated. Short of that, neuro-
ethics will be a hollow, self-​justifying framework, one prone to misdirection, distrac-
tion, and even abuse.
This is not a trivial statement. To be more than just the handmaiden of technological
advance, neuroethics needs to examine the uses of instrumentality. But asking such ques-
tions can be a challenge. It is all too easy to be seduced by an emergent ability to manipu-
late the chemistry of a synapse or alter current flow through a circuit. The explanatory
power of these maneuvers can be overwhelming, especially when they achieve an elusive
(and often dramatic) therapeutic need. Such success can be blinding, especially when
ancient nihilism about brain-​based disorders is replaced by a fledgling optimism. When
this happens, the technological can easily become triumphant, obscuring important ethi-
cal considerations too easily pushed into the shadows caused by a glaring success, making
it all the more difficult to question success.
Indeed, a thoughtful commentator can be thought a Philistine when even broach-
ing concerns about the purpose and limits of emerging technologies in the wake of an
important discovery. But question we must, lest we fall prey to what the bioethicist Daniel
Callahan (1996) has termed “scientism” by which he suggests a “non-​falsifiable faith in the
capacity of science not simply to provide reliable knowledge but also to solve all or most
human problems, social, political, and economic.”
Callahan critiques science as a member of what he describes the “loyal opposition”
(1996) committed to, but still questioning its goals. His skepticism about the sweep of sci-
ence is wise and prudent, especially in an age of discovery that we live today. But I would
add a friendly amendment to his critique. Such skepticism is essential to, and not counter
to, good science itself.
This was known to Isadore I. Rabi, who was awarded the Nobel Prize for physics for
his work on nuclear magnetic resonance, essential to modern neuroimaging. When
asked why he became a scientist, he reportedly responded that he became a scien-
tist because of his mother’s influence upon him, even though that was not her intent.
Instead of asking him, as all the other Jewish mothers in Brooklyn did, whether he had
learned anything in school, Mrs. Rabi would query him about methods. She’d ask him
if he had asked a “good question.” Rabi attributes this focus to his becoming a scientist
(Sheff 1988).
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606 Neuroethics and neurotechnology

Rabi, better than most, understood that it was not certainty about our answers but our
ability to question that leads us forward. So while discovery is cause for celebration, these
moments also call for humility and careful deliberation. When we do this we are not dis-
loyal to the scientific enterprise but rather squarely in its best traditions.

Sustaining success
Humility even in moments of scientific triumph is prudent because success is no guar-
antee of sustained progress. Despite the spectacular advances we have seen in the past
decades, much of which is recounted in this volume, barriers to progress remain (Fins
et  al. 2012). One critical challenge is the proverbial “valley of death,” a phrase used to
describe the premature demise of promising proof-​of-​principle efforts for lack of funding
that bridges the perilous terrain, typically between government funding and that of ven-
ture capital or pharma or device companies (Finkbeiner 2010). When this happens, good
ideas linger on the sidelines.
This challenge is a profound one for two types of what one might call messy innova-
tion. The first is for emerging drugs and devices aimed at conditions that do not con-
stitute a ready market and thus do not attract capitalization. While the Orphan Drug
Act of 1983 (Orphan Drug Act of 1983), has helped to ease some of the US Food and
Drug Administration’s (FDA’s) regulatory barriers for such drugs (and to a lesser extent
devices under the aegis of the “Orphan Products Board,” now the FDA Office of Orphan
Products Development (FDA 2016)  and the more recently constituted Center for
Devices and Radiological Health (FDA 2015)), there is no provision to address the fis-
cal challenges that can doom promising research lingering between basic science fund-
ing streams and underwriting from conventional market sources. Moreover, there are
distinct challenges for device development for orphan conditions versus the promotion
of pharmacological approaches to therapy (Fins et al. 2011a; Mokhtarzadeh et al. 2016).
The challenge of ongoing support is even more complicated when basic neurosci-
ence research is predicated upon having access to devices and to devices of greater and
greater sophistication needed for experimental work. This has been an ongoing chal-
lenge in the realm of neuromodulation where DBS may not always be readily available
to investigators by their manufacturers. Device makers may withhold access to devices,
or their rights of reference required for regulatory approval, because of concerns about
liability when they are used in experimental trials, cost, or in order to maintain a
competitive advantage of one sort or another (Mokhtarzadeh et al. 2016). This can be
highly problematic because devices like DBS are not only therapeutic agents but pro-
bative agents (Fins 2012) that can help map circuits essential to the understanding of
systems neurobiology, and ultimately the creation of a three-​dimensional brain map
or connectome (Fins and Shapiro 2013). When these devices are unavailable, tools of
discovery are taken out of the hands of the scientist, disadvantaging all and imperiling
access to the fruits of neuroscience.
 607

The instrumentality of the humanities 607

In sum, while the future is bright for neuroscience, success is not assured. Economic
forces, the commodification of new ideas through patenting (Fins 2010a; Fins and Schiff
2010a; Fins et al. 2011b), and the all too human quest for notoriety can distort the central
ethos of scientific discovery.

The instrumentality of the humanities

The constraints I have just discussed suggest that whatever ethos governs emerging neu-
rotechnologies, it needs to be grounded in something more robust than the technologi-
cal imperative or unbridled faith in market forces as neither is sustainable nor reliable.
Instead, neuroethics, as a field, needs to place this work into a broader context worthy of
those who might depend upon its success.
In this we need to seek the wisdom of the humanities (Fins et al. 2013). In turning
to the humanities for deeper insights into the sciences, and the biomedical sciences
in particular, William Osler (1919) said it best. In an address, “The Old Humanities
and the New Sciences,” given to Oxford’s Classical Association just before his death,
Osler told those assembled, “Now, the men of your guild secrete materials which do
for society at large what the thyroid gland does for the individual. The humanities
are the hormones.” He was forceful in his admonition asserting a divide between
the sciences and the humanities, observing that “… the so-​called Humanists have
not enough Science, and Science sadly lacks the Humanities” suggesting as a remedy
“liberal education” that would provide guidance on how to “… give the science school
the leaven of an old philosophy, how to leaven the old philosophical school with the
thoughts of science” (Osler 1919). Osler’s admonition is as current today as it was
nearly a century ago.
So how do we bring the “leaven of an old philosophy”—​as Osler put it—​to bear on the
future of this still growing field? (Osler 1919). If neuroethics is indeed an ethics of tech-
nology, what then should be the guiding ethos of its use? To what goals and objectives
should these tools be directed? How do we broaden out the conversation so as not to fall
prey to scientism or its neuroethics neologism, neuroscientism? And how do we engage
the humanities and social sciences in this critical discussion?
As a physician, I am naturally drawn to the therapeutic possibilities posed by neuro-
technology. I think that the amelioration and relief of human suffering caused by neu-
ropsychiatric disorders should be the primary goal of our efforts. While some might
criticize this focus as overly medicalizing these efforts, and a perspective expected from
a doctor, I  would maintain that such goals can generate a broad consensus and avoid
the controversy that comes with more contentious efforts like enhancement or the uses
of neurotechnology for law enforcement or national security purposes. These prohibi-
tions were articulated by the National Commission for the Protection of Human Subjects
of Biomedical and Behavioral Research in its 1977 report, “Use of Psychosurgery in
Practice and Research” which proscribed nonclinical uses of that technology (National
Commission 1977; Fins 2003).
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608 Neuroethics and neurotechnology

While the line can be blurred between restoration and enhancement, and nonclinical
applications are inevitable, I  believe that it is normatively appropriate and politically
useful to cast neurotechnology in the service of those who are sick, injured, or suffering
from a neuropsychiatric condition. This will maintain the broad societal consensus and
provide a platform for translational discovery that will be good for basic and clinical
neuroscience. In short, by prioritizing the clinical instrumentality of emerging neuro-
technologies, neuroethics can minimize contention, provide comfort to those afflicted
with neuropsychiatric conditions, and foster scientific advance both at the bench and
the bedside.
But mine is not solely a clinical appeal. It is a broader one grounded under the broad
banner of human rights, specifically the civil and disability rights of individuals with neu-
ropsychiatric conditions (Fins 2010b, 2015). As a physician, and as a humanist, I believe
that such a prioritization is just and fair. Directing emerging neuro-​instrumentality to
the remediation of conditions that cause physical or mental distress, constrain liberty,
or compromise a person’s ability to participate in human community helps to equalize
opportunity for those who suffer from life’s most malignant conditions.
And beyond the effects of these therapies on the well-​being of individuals, as a class,
people with neuropsychiatric conditions have a long history of marginalization and dis-
crimination. We only need turn to the history of medicine and consider the legacy of the
asylum for those with psychiatric conditions (Rothman 1971) or the more modern neu-
ronal segregation of those with severe brain injury that I have described in my work (Fins
and Hersh 2011; Fins 2013, 2015), to appreciate that these populations have been under-
served by medicine and society at large. Emerging neurotechnologies have the potential
to even that score and restore functional status and equanimity to those burdened by
these conditions, though of course technology can only be part of any solution to such
complex social problems.

Toward a rights agenda
Viewing neuroethics through this prism of rights both distances it from Callahan’s “sci-
entism” (1996) and brings it closer to a sad, but important, truth about neuropsychiatric
conditions and their treatment in society. Historically, those with neuropsychiatric condi-
tions have been marginalized by society. Whether it is paralysis or a movement disorder
that makes mobility a challenge or cognitive or psychiatric conditions that require insti-
tutional care, diseases of the brain and mind can lead to the segregation of affected indi-
viduals and their sequestration from others in society, much as racism of the Jim Crow,
American South segregated individuals because of race.
Legal scholar Timothy Cook (1991) has written of the historic confluence between atti-
tudes toward the disabled and racism. He observed that, “The Jim Crow system estab-
lished after Plessy and the government-​supported, systematic segregation of persons with
disabilities during precisely the same time were no mere coincidence of historical events.
The historical record abounds with evidence that disability discrimination emanated
 609

Toward a rights agenda 609

from the same attitudes and prejudices fomenting at the turn of the century regarding
race.” (Cook 1991).
Although the Americans with Disability Act (Americans with Disability Act 1990) and
the United Nations Convention on the Rights of Persons with Disabilities (United Nations
General Assembly 2007) both call for the maximal integration of individuals with dis-
ability into civil society, this legacy of segregation and marginalization has been difficult
to overcome, much less acknowledge or recognize as a problem. Bias toward these popu-
lations remains, and individuals with neuropsychiatric conditions continue to suffer, as
former US Surgeon General David Satcher (2000) noted, from profound health dispari-
ties and substandard care. More recently, Jaffe and Jimenez (2015) have written of health
disparities in rehabilitation medicine.
My own research examining the treatment of individuals with disorders of conscious-
ness reveals a class, of mostly young people, segregated in chronic care facilities designed
for the aged with degenerative conditions. There they struggle for services, a credible
diagnosis, and are denied needed rehabilitation (Fins 2013, 2015). Collectively these
omissions can deprive these individuals of the possibility of returning to their homes and
families, often robbing them of fundamental rights, such as the right to remain part of
their communities.
Of course sometimes, the burden of injury or illness makes institutional care neces-
sary. But increasingly, and expectantly, neurotechnology might make this less necessary,
providing opportunities for people with disabilities to be more routinely integrated into
society with the help of neuroprostheses. This is more than wishful thinking. If society
takes stock of what neurotechnology has done and promises to achieve in the next decade,
this aspiration can be viewed as more than a promissory note.
Neurotechnology is beginning to lift the burden of neuropsychiatric maladies and ame-
liorate many conditions. To name but a few notable examples . . . The work of engineers like
P. Hunter Peckam (Moss et al. 2011), Miguel Nicolelis (2012), and others have provided
mobility to those with paralysis. John Donoghue and Leigh Hochberg (Hochberg et  al.
2012), and Andrew Schwartz (Collinger et al. 2013) have even begun to broach the locked-​
in-​state giving individuals mobility with brain–​computer interfaces. Our team’s efforts
with thalamic DBS helped an individual in the minimally conscious state speak for the first
time in 6 years and eat food by mouth (Schiff et al. 2007). Bart Nuttin’s (1999) pioneering
use of DBS for obsessive–​compulsive disorder and Helen Mayberg’s for depression (2005)
have begun to bring relief to those whose conditions were refractory to pharmacologic
and conventional therapy. And beyond invasive technologies, neuroimaging—​as exempli-
fied by Monti et al. (2006)—​has the potential to serve as a communication channel in the
setting of what appeared to be the vegetative state but was in fact, a patient with apparent
cognitive motor dissociation in the minimally conscious state (Fins and Schiff 2010b).
What all these technologies have in common is the possibility of reintegration, bring-
ing people with motor, cognitive, or psychiatric disabilities back into the room, back into
civil society by ending the sequestration caused by both their illness and society’s treat-
ment of their disability. When I consider how the active neuroimaging paradigm used by
610

610 Neuroethics and neurotechnology

Monti et al. (2006) liberated a conscious individual from cognitive motor dissociation,
I  am reminded of that famous image of Nelson Mandela (1994) when he returned to
Robben Island and the place of his decades-​long imprisonment and peered out of the bars
that had kept him captive.
In the context of our efforts using thalamic DBS in the minimally conscious state, neu-
roprosthetics have helped to restore voice, and with the restoration of functional com-
munication a person severed from his family was able to rejoin his community. Note the
resonant cognates: communication makes the return to community possible (Schiff et al.
2007; Fins 2015).
Each of these efforts is a story of liberation and reintegration into civil society. While
work with thalamic DBS in the minimally conscious state is not an established therapy
and remains in the realm of proof of principle (Schiff et al. 2009), I believe that it, and the
aforementioned examples of technological innovation, are emblematic of the construc-
tive role that neurotechnology might come to play in securing rights for those left too
long on the margins by neuropsychiatric conditions. It also suggests how neuroprosthetic
technology might become the centerpiece of an emerging rights agenda for patients with
neuropsychiatric disabilities (Schiff et al. 2007).
Beyond providing direct assistance to patients in need, this confluence of neuroethics
and the law will also help expand neuro-​law scholarship beyond its current purview with
its focus on criminal law, culpability, and the credibility of evidentiary information (The
MacArthur Foundation n.d.), to broader considerations of how a human rights perspec-
tive can help inform the future of neuroscience and neuroethics (Fins 2016; Wright & Fins
2016), and become an important tool for civil rights advocacy to advance health in the
twenty-​first century (McGowan et al. 2016).

Neurotechnology as heuristic
A refrain … returning to my original argument that if neuroethics was a distinct ethics, it
would be as an ethics of technology, we have seen here that not only has neurotechnology
like neuroimaging pointed us to a technical solution, but that it also pointed to arguments
beyond itself, making us appreciate that society was willfully disregarding the needs of
members of its citizenry and ignoring their right to be more fully integrated into civil
society. This is surely a question that transcends technology, and it would be a mistake
to resort to technology for its solution. But we would also be mistaken not to be grateful
to technology as a heuristic that allows society to better apprehend dimensions of our
reality that heretofore had been obscure and unrecognized. While neuroscience does not
provide an easy answer to our questions, it does help us pose new and sometimes deeply
disturbing questions. For that, we should be grateful.

Acknowledgments
The author is grateful to Amy B. Ehrlich and Cathleen A. Acres for their comments, and
Jennifer Hersh for editorial assistance, and acknowledges the Jerold B. Katz Foundation
 61

References 611

for its support of the Consortium for the Advanced Study of Brain Injury (CASBI) at Weill
Cornell Medical College and Rockefeller University and an NIH Clinical & Translational
Science Center Award (UL1-​RR024966) to Weill Cornell Medical College.

References
Americans with Disability Act of 1990. Public Law 101-​336. 104 stat. 328 (1990).
Bardin, J.C., Fins, J.J., Katz, D.I., et al. (2011). Dissociations between behavioural and functional
magnetic resonance imaging-​based evaluations of cognitive function. Brain, 134(3), 769–​782.
Callahan, D. (1996). Calling scientific ideology to account. Society, 33(4), 14–​19.
Collinger, J.L., Wodlinger, B., Downey, J.E., et al. (2013). High-​performance neuroprosthetic control by
an individual with tetraplegia. The Lancet, 381(9866), 557–​564.
Cook, T.M. (1991). The Americans with Disability Act: the move to integration. Temple Law Review, 64,
393–​470.
FDA Center for Devices and Radiological Health (2015). 2014–​2015 Strategic Priorities. Available
from: http://​www.fda.gov/​downloads/​AboutFDA/​CentersOffices/​OfficeofMedicalProductsandTobacco/​
CDRH/​CDRHVisionandMission/​UCM431016.pdf [accessed July 11, 2016].
FDA Office of Orphan Products Development (2016). Developing Products for Rare Diseases
& Conditions. (Updated March 30, 2016.) Available from: http://​www.fda.gov/​ForIndustry/​
DevelopingProductsforRareDiseasesConditions/​ucm2005525.htm [accessed July 11, 2016].
Finkbeiner, S. (2010). Bridging the Valley of Death of therapeutics for neurodegeneration. Nature
Medicine, 16(11), 1227–​1232.
Fins, J.J. (2003). From psychosurgery to neuromodulation and palliation: history’s lessons for the ethical
conduct and regulation of neuropsychiatric research. Neurosurgery Clinics of North America, 14(2),
303–​319.
Fins, J.J. (2005). Rethinking disorders of consciousness: new research and its implications. The Hastings
Center Report, 35(2), 22–​24.
Fins, J.J. (2007). Border zones of consciousness: another immigration debate? American Journal of
Bioethics-​Neuroethics, 7(1), 51–​54.
Fins, J.J. (2008a). Neuroethics & neuroimaging: moving towards transparency. American Journal of
Bioethics, 8(9), 46–​52.
Fins, J.J. (2008b). A leg to stand on: Sir William Osler and Wilder Penfield’s “Neuroethics.” American
Journal of Bioethics, 8(1), 37–​46.
Fins, J.J. (2010a). Deep brain stimulation, free markets and the scientific commons: is it time to revisit
the Bayh-​Dole Act of 1980? Neuromodulation, 13, 153–​159.
Fins, J.J. (2010b). Minds apart: severe brain injury. In: Freeman, M. (Ed.) Law and Neuroscience, Current
Legal Issues (Vol. 13), pp.367–​384. New York: Oxford University Press.
Fins, J.J. (2011). Neuroethics and the lure of technology. In: Illes, J. and Sahakian, B.J. (Eds.) Handbook
of Neuroethics, pp.895–​908. New York: Oxford University Press.
Fins, J.J. (2012). Deep brain stimulation as a probative biology: scientific inquiry & the mosaic device.
AJOB Neuroscience, 3(1), 4–​8.
Fins, J.J. (2013). Disorders of consciousness and disordered care: families, caregivers and narratives of
necessity. Archives of Physical Medicine and Rehabilitation, 94(10), 1934–​1939.
Fins, J.J. (2015). Rights Come to Mind: Brain Injury, Ethics and the Struggle for Consciousness.
New York: Cambridge University Press.
Fins, J.J. (2016, May 10) Bring them back. AEON. Available from: https://​aeon.co/​essays/​thousands-​of-​
patients-​diagnosed-​as-​vegetative-​are-​actually-​aware [accessed 12 July 2016].
612

612 Neuroethics and neurotechnology

Fins, J.J. and Hersh, J. (2011). Solitary advocates: the severely brain injured and their surrogates.
In: Hoffman, B., Tomes, N., Schlessinger, M., and Grob, R. (Eds.) Transforming Health Care
from Below: Patients as Actors in U.S. Health Policy, pp.21–​42. New Brunswick, NJ: Rutgers
University Press.
Fins, J.J. and Schiff, N.D. (2010a). Conflicts of interest in deep brain stimulation research and the ethics
of transparency. Journal of Clinical Ethics, 21(2), 125–​132.
Fins, J.J. and Schiff, N.D. (2010b). In the blink of the mind’s eye. The Hastings Center Report,
40(3), 21–​23.
Fins, J.J. and Shapiro, Z.E. (2013). Deep brain stimulation, brain maps & personalized medicine: lessons
from the human genome project. Brain Topography, 27(1), 55–​62.
Fins, J.J., Schlaepfer, T.E., Nuttin, B., et al. (2011a). Ethical guidance for the management of conflicts
of interest for researchers, engineers and clinicians engaged in the development of therapeutic deep
brain stimulation. Journal of Neural Engineering, 8(3), 033001.
Fins, J.J., Mayberg, H.S., Nuttin, B., et al. (2011b). Neuropsychiatric deep brain stimulation research
and the misuse of the humanitarian device exemption. Health Affairs (Millwood), 30(2), 302–​311.
Fins, J.J., Dorfman, G.S., and Pancrazio, J.J. (2012). Challenges to deep brain stimulation: a pragmatic
response to ethical, fiscal and regulatory concerns. Annals of the New York Academy of Sciences,
1265, 80–​90.
Fins, J.J., Pohl, B., and Doukas, D. (2013). In praise of the humanities in academic medicine: values,
metrics and ethics in uncertain times. Cambridge Quarterly of Health Care Ethics, 22, 355–​364.
Giacino, J.T., Kalmar, K., and Whyte, J. (2004). The JFK Coma Recovery Scale-​Revised: measurement
characteristics and diagnostic utility. Archives of Physical Medicine and Rehabilitation, 85(22),
2020–​2029.
Giacino, J.T., Whyte, J., Bagiella, E., et al. (2012). Placebo-​controlled trial of amantadine for severe
traumatic brain injury. New England Journal of Medicine, 366(9), 819–​826.
Giacino, J.T., Fins, J.J., Laureys, S., and Schiff, N.D. (2014). Disorders of consciousness after acquired
brain injury: the state of the science. Nature Reviews Neurology, 10, 99–​114.
Hochberg, L.R., Bacher, D., Jarosiewicz, B., et al. (2012). Reach and grasp by people with tetraplegia
using a neurally controlled robotic arm. Nature, 485(7398), 372–​375.
Illes, J. and Sahakian, B.J. (Eds.) (2011). Handbook of Neuroethics. Oxford: Oxford University Press.
Jaffe, K.M. and Jimenez, N. (2015). Disparity in rehabilitation: another inconvenient truth. Archives of
Physical Medicine and Rehabilitation, 96: 1371–​1374.
Kass, L.R. (2003). Foreword. In: President’s Council on Bioethics, Beyond Therapy: Biotechnology and
the Pursuit of Happiness, p.xvii. New York: Harper Perennial.
The MacArthur Foundation Research Network on Law and Neuroscience (n.d.). Available at: http://​
www.lawneuro.org [accessed July 11, 2016].
Mandela, N. (1994). Long Walk to Freedom. New York: Little, Brown and Company.
Mayberg, H.S., Lozano, A.M., Voon, V., et al. (2005). Deep brain stimulation for treatment-​resistant
depression. Neuron, 45(5), 651–​660.
McGowan, A.K., Lee, M.M., Meneses, C.M., Perkins, J., and Youdelman, M. (2016). Civil rights laws as
tools to advance health in the 21st century. Annual Review of Public Health, 37, 185–​204.
Mokhtarzadeh, M., Eydelman, M. and Chen, E. (2016). Challenges and opportunities when developing
devices for rare disease populations. Expert Opinion on Orphan Drugs, 4(5), 457–​459.
Monti, M.M., Vanhaudenhuyse, A., Coleman, M.R., et al. (2010). Willful modulation of brain activity
in disorders of consciousness. New England Journal of Medicine, 362(7), 579–​589.
 613

References 613

Moss, C.W., Kilgore, K.L., Peckham, P.H. (2011). Training to improve volitional muscle activity in
clinically paralyzed muscles for neuroprosthesis control. Conference Proceedings of the Annual
International Conference of the IEEE Engineering in Medicine and Biology Society, 2011, 5794–​5797.
Naccache, L. (2006). Is she conscious? Science, 313(5792), 1395–​1396.
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research
(1977). Use of psychosurgery in practice and research: report and recommendations of National
Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. Federal
Register, 42(99), 26318–​26332.
Nicolelis, M.A. (2012). Mind in motion. Scientific American, 307(3), 58–​63.
Nuttin, B., Cosyns, P., Demeulemeester, H., Gybels, J., and Meyerson, B. (1999). Electrical stimulation
in anterior limbs of internal capsules in patients with obsessive-​compulsive disorder. The Lancet,
354(9189), 1526.
Orphan Drug Act of 1983. Public Law 97–​414. 96 Stat. 2049 (1983).
Osler, W. (1919). The Old Humanities and the New Science: An Address before the Classical Association,
Oxford. London: John Murray.
Owen, A.M., Coleman, M.R., Boly, M., et al. (2006). Willful modulation of brain activity in disorders of
consciousness. Detecting awareness in the vegetative state. Science, 313(5792), 1402.
Penfield, W. (1976). Mystery of the Mind: A Critical Study of Consciousness and the Human Brain.
Princeton, NJ: Princeton University Press.
Rothman, D. (1971). The Discovery of the Asylum: Social Order and Disorder in the New Republic.
New York: Little Brown.
Satcher, D. (2000). Executive summary: a report of the surgeon general on mental health. Public Health
Reports, 115(1), 89–​101.
Schiff, N.D., Rodriguez-​Moreno, D., Kamal, A., et al. (2005). fMRI reveals large scale network
activation in minimally conscious patients. Neurology, 64, 514–​523.
Schiff, N.D., Giacino, J.T., Kalmar, K., et al. (2007). Behavioral improvements with thalamic stimulation
after severe traumatic brain injury. Nature, 448(7153), 600–​603.
Schiff, N.D., Giacino, J.T., and Fins, J.J. (2009). Deep brain stimulation, neuroethics and the minimally
conscious state: moving beyond proof of principle. Archives of Neurology, 66(6), 697–​702.
Sheff, D. (1988, January 19). Izzy, did you ask a good question today? The New York Times. Available
from: http://​www.nytimes.com/​1988/​01/​19/​opinion/​l-​izzy-​did-​you-​ask-​a-​good-​question-​today-​
712388.html [accessed July 12, 2016].
Thomas, L. (1974). The Lives of a Cell: Notes of a Biology Watcher. New York: The Viking Press.
UN General Assembly (2007). Convention on the Rights of Persons with Disabilities. Available
from: http://​www.un.org/​disabilities/​convention/​conventionfull.shtml [accessed July 12, 2016].
Wright, M.S. and Fins, J.J. (2016). Rehabilitation, education, and the integration of individuals with
severe brain injury into civil society: towards an expanded rights agenda in response to new insights
from translational neuroethics and neuroscience. Yale Journal of Health Policy, Law, and Ethics,
16(2), 233–​288.
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 615

Author Index

7 Cups of Tea  92–​7 APA Task Force  431

9Solutions 84 Apold, V.S. 61
Appelbaum, P.S. 130
Aarts, H. 480, 491 Apple Inc 81
Abend, N.S. 182, 184 Araki, S. 459
Abi-​Rached, J.M. 456, 509 Arbour, L. 463
Abney, K. 547 Arias, J.J. 7
Abraham, C. 462 Ariely, D. 202
Achard, S. 187 Arrighi, H.M. 302
Adam, H. 214 Arrowsmith, J.B. 209
Adams, F. 109 Asch, S.E. 393
Adams, R.D. 109 Ashwal, S. 188
Ader, R. 228 Aspinwall, L.G. 573
Adesman, A. 73 Aston-​Jones, G. 128
Advisory Committee, National Institutes Atlas, L.Y. 199, 204
of Health Director  147 Au, P.K. 204
Agar, N. 415, 416 Aubry, M. 524
Agarwal, N. 56
Ahmed, S.H. 498, 501 Bachman, J.G. 500
Air Force Studies Board  534 Baillet, S. 26, 35
Aita, K. 341 Baker, A.P. 25
Aizawa, K. 109 Baker, L.A. 165
Akcakaya, M. 126 Bal, B.S. 562
Akkad, A. 90 Baler, R. 497, 499
Al-​Deeb, S.M. 341 Baler, R.D. 497
Alavanja, M.C.R. 429 Bandettini, P.A. 17
Alba, D. 83, 87 Banerjee, T. 84, 85, 87
Albert, M.S. 295 Bardin, J.C. 603
Albrecht, G. 432, 461, 470 Bargh, J.A. 389, 402
Alexander, B.K. 501 Barker, R.A. 467
Alexander, E. 349 Barnard, C. 324
Allan, B. 462 Barnhill, A. 226
Alpert, S. 130 Baron, R.S. 393
Alphonso, C. 269 Baroncelli, L. 434
Alphs, H.H. 57 Barron, F.L. 458
Altman, D.G. 592 Barth, M. 15
Alzheimer’s Association  144 Bartlett, E.T. 347
Amanzio, M. 222, 223 Basser, P.J. 20, 38
American Medical Association  206, 216 Bassett, D.S. 19
American Psychiatric Association  94, 488, 585 Bateman, R.J. 297
American Society of Addiction Medicine  508 Battiste, M. 465
Americans with Disability Act  609 Baumeister, R.F. 396, 401, 402, 404, 405
Amodio, D.M. 396 Baumel, A. 93
Anderson, G.C. 456, 463 Baxendale, S. 257
Anderson, J.A. 6 Bayer, T.L. 204
Anderson, K. 123 Baylis, F. 251
Anderson, K.D. 136 Bazarian, J.J. 517
Anderson, L.C. 521 Beaty, R.E. 17
Anderson, R.B. 457 Beauchamp, T.L. 112, 216, 250
Andrade, L.H. 591 Beaufoy, S.L. 577
Andrade, P. 237 Beaulieu, C. 16
Andrews, K. 186 Becker, A.E. 591, 594
Angermeyer, M.C. 504 Becker, K.J. 312
61

616 Author Index

Beckford, C.L. 467 Booth, T.C. 57

Beddington, J. 594 Boothman, N. 205
Bedo, N. 27, 28 Borich, M.R. 16
Beever, J. 398, 403 Bostick, N.A. 216, 217
Belin, D. 481 Bostrom, N. 418
Belkin, G.S. 339 Botticelli, M. 498
Belknap, R. 81, 85 Boudway, I. 98
Bell, C. 532 Bourdette, D. 129
Bell, E. 131, 180, 250 Bourque, F. 461
Bell, S. 504, 505, 506 Boutet, C. 62
Bell, W.O. 235 Bowler, D.E. 433
Benatar, D. 594 Boycott, K. 381
Bender, A. 186 Boyd, S.C. 266
Bendtsen, L. 223 Boyer, B.B. 461
Benedetti, F. 219, 220, 221, 222, 223, 224, 228 Boyer, E.L. 271
Benedikter, R. 546, 547 Braak, E. 283
Benigeri, M. 558 Braak, H. 283
Benjaminy, S. 270 Brackmann, D.E. 31
Bennett, A.S. 535 Brand, C. 119
Bennett, J.D. 209 Brandeis, L. 115
Benson, P. 394 Breakthrough 85, 93
Bentall, R.P. 430 Breden, T.M. 250
Benusic, M. 458 Breiter, H.C. 481
Berendse, H.W. 26 Brems, C. 460
Berger, H. 28 Brenner, L.H. 562
Berger, R.P. 183 Brenninkmeijer, J. 119
Bergfeld, I.O. 241, 242 Bressan, P. 397
Bering, J. 111 Breton, E. 38
Berke, J.D. 483, 486, 491 Brock, D.W. 169, 342
Berkman, E.T. 407 Brody, B. 314, 330, 348
Bernat, J. 306, 308, 309, 312, 315, 319, 336–​65, 343, Brody, H. 135, 215, 218
345, 346, 353, 355 Bromet, E. 128
Berridge, K.C. 481, 483 Bronstein, J.M. 252
Berry, H.L. 432, 460 Brookes, M.J. 24, 37
Bested, A.C. 435 Brookmeyer, R. 377
Betzel, R.F. 20 Brown, C.J. 40
Bieler, D. 520 Brown, M.A. 63
Bilgic, B. 16 Browne, A.J. 467
Bingel, U. 228 Brownstein, M. 395
Birbaumer, N. 125, 126, 131 Bubela, T. 560
Bird, S.J. 3, 150 Bucchi, M. 554, 556
Bishop, F.L. 228 Buccino, G. 18
Bishop, S. 163 Buchanan, A.E. 169
Black, B.S. 380 Buchman, D.Z. 500
Blakemore, C. 564 Buckley, K.M. 31
Bland, J.M. 592 Buckner, R.L. 289
Blankfield, R.P. 198 Bullmore, E.T. 19
Blas, E. 427 Bunge, M. 350
Blease, C. 198, 206, 216, 218 Buniak, L. 592, 594
Bleich, D. 359 Bunnik, E.M. 54
Block, G. 558 Burgstaller, J.M. 199
Block, M.L. 460 Burkle, C.M. 340
Bloom, D.E. 144 Burton, R. 215
Boersma, M. 26 Burwood, S. 119
Bohn, D. 101 Bush, V. 533
Boly, M. 329 Butterworth, R.F. 429
Bond, J. 558 Buzsáki, G. 26
Bond, R. 393 Byrne, P. 359
Bonelli, R.M. 351, 352
Boorse, C. 416 Cabrera, L.Y. 175, 436, 437, 443, 456, 464
Booth, B.G. 37, 38, 39, 40 Cacioppo, J. 17
 617

Author Index 617

Cacioppo, J.T. 205 Cieszanowski, A. 56

Cajete, G. 465 Cipriani, J. 87
Calabro, R.S. 185, 186 Cisek, P. 480, 484, 491
Calderon-​Garcidueñas, L. 430, 460 Citerio, G. 356
Callahan, D. 605 Claassen, J. 191
Callaway, E. 5 Clairmont, D.H. 470
Campbell, A.T. 160 Clark, A. 99, 108
Campbell, C.S. 341 Clark, L. 479, 481
Campbell, K.B. 31 Clausen, J. 123
Campbell, S.B. 160 Clayton, P. 351
Campbell-​Meiklejohn, D.K. 394 Clifford, D.B. 135
Canada Safeway Ltd. 581 Cline, R.J.W. 558
Canadian Environmental Health Atlas  438 Clouser, K.D. 135, 136
Canadian Institutes of Health Research  377 Coffey, R.J. 536
Caplan, A.L. 361, 492, 498 Cohen, E.D. 127
Capron, A.M. 345, 356 Cohen, H. 463
Carlisle, W. 519 Cohen, J. 111, 359, 389, 403
Carpenter, D.O. 460, 462 Cohen, J.D. 486
Carroll, D.C. 289 Cohen, M.J.M. 498
Carter, A. 492, 497, 504, 509 Colborn, T. 431
Casebeer, W.D. 545, 547 Cole, J. 58
Castle, E. 563 Colletti, V. 127
Castro, A.L. 76 Collinger, J.L. 125, 137, 609
Caulfield, T. 554, 560 Collingridge, D. 532
Cavazos, J. 84 Collins, P.Y. 591
Cavuoto, J. 241, 242 Colloca, L. 219, 220, 221, 222, 225
Centers for Disease Control and Prevention  203, 437 Coluccia, D. 17
Centers for Medicare and Medicaid Services  203 Combs, H.L. 130
Chadwick, R. 413 Cominco Ltd. 583, 585
Chafe, R. 269 Commission on Social Determinants of Health  441
Chalmers, D. 99, 108 Committee on Opportunities in Neuroscience for
Chameau, J.L. 9, 533, 547 Future Army Applications, National Research
Chandler, J.A. 570–​613 Council of the National Academies  536
Chapman, S. 505 Conrad, P. 479
Charland, L.C. 498 Conway, E.M. 446
Chartrand, T.L. 389 Cook, D. 463
Chaudhary, U. 126 Cook, M. 235
Chen, F.S. 435 Cook, T.M. 609
Chen, J. 200 Corner, L. 558
Chen, L. 6 Corrigan, P.W. 503, 504, 576
Chepesiuk, R. 460 Corripio, I. 237
Cheung, K. 56 Corvalán, C. 436, 437
Chew, C. 266 Council of Europe  373, 375, 376
Chiappa, K.H. 31 Council for International Organizations of Medical
Childress, J.F. 112, 216, 250 Sciences (CIOMS)  373, 374, 379
Childs, N.L. 186 Covi, L. 226
Chima, S.C. 595 Cox, S.M. 64
Chin, V.N. 7 Coyle, P.K. 135
Chiong, W. 349 Cramer, S.C. 60
Cho, M.K. 7, 62 Cranor, C. 426, 437, 445
Choa, D. 56 Crawford, M.L. 18
Chodakiewitz, Y. 235, 238 Crawley, P. 518
Choi, E.K. 357 Crews, D. 426, 434
Chooi, C.S. 199 Crow, James  8
Choudhury, S. 369 Crowe, K. 458
Christen, M. 238, 250, 257 Cruse, D. 30
Christman, J. 113 Cryan, J.F. 396, 397
Chumber, S. 560 Csonka, Y. 460
Church, G.M. 91 Cumes, D. 433
Churchland, P.M. 405 Cummings, M.L. 537
Cialdini, R.B. 393, 394 Cunningham, J.A. 505
618

618 Author Index

Cunsolo Wilcox, A. 431, 432 Diamond, A. 159, 175

Custers, R. 480, 491 Dibiase, R. 137
Cutter, S.L. 442 Dick, F.D. 429
Cyna, M.A. 198 Diederen, K.M. 481, 482
Diederich, N.J. 224
D’Abbs, P. 463 Diekema, D.S. 162, 369, 421
Dackis, C. 497, 500, 501, 502 Diering, S.L. 235
Dagher, A. 481 Dietz, T. 446
Dakeishi, M. 429 Dieuliis, D. 595
Dalal, S. 36 Dimitriadis, S.J. 26
Dalvie, S. 596 Dinan, T.G. 396, 397
Damasio, A.R. 283 Ding, K. 19
Dando, M. 537, 547 Diringer, M.N. 358
Daneshvar, D.H. 515 Dodds, S. 250
Daniels, N. 439 Doepp, F. 268
Daoust, A. 343 Doesburg, S.M. 27, 28, 41
DARPA  533–​7 Donnelly, J. 594
Darragh, M. 592 Donovan, E. 535
Dasgupta, L. 5 Doran, C.M. 506
Davidson, A. 287 Dougherty, D.D. 128, 241, 242, 253
Davidson, J.S. 593 Downie, J. 61
Davies, J.B. 505 Dresser, R. 275, 276
Dayan, P. 480, 484, 491 Druckhman, D. 533
de Beaufort, I. 467 Dubljevic, V. 389, 390, 400, 405, 406
de Burbure, C. 429 Dubois, B. 295, 298, 299
de Calignon, A. 289 Duenwald, D. 535
de Condorcet  412 Duggan, T.J. 401, 407
de Jager, C.A. 561 Duncan, G.J. 167
De Kluizenaar, Y. 460 Dunham, Y. 480
De La Fuente-​Fernandez, R. 220, 223, 224 Dunkley, B.T. 25, 26
De Salles, A. 235, 241, 242 Dunn, W.R. 521
De Salles, A.A. 239, 253, 254 Dupré, D.D. 237
De Strooper, E. 298 Dutt-​Gupta, J. 206
De Vos, A. 300 Duyn, J.H. 16
De Zwaan, T.E. 256 Dworkin, G. 112
Deary, I.J. 55 Dworkin, R.H. 223, 278, 284
Debes, F. 428 Dyson, F. 145
Debette, S. 58
Decety, J. 17 Eberling, J.L. 23
Deci, E.I. 404 Ecker, J. 315
Deco, G. 27 Ecobee 101
DeGrazia, D. 347 Edelman, G.M. 321
deHaan, W. 26 Edidin, J.P. 76
Deisseroth, K. 236 Editorial (Nature) 508, 532
DeLee, S.T. 204 Edwards, L. 100
DeLong, M.R. 146 El-​Hayek, Y.H. 460
Delorme, A. 27 Elbaz, A. 429
Deng, Z.D. 146 Elder, G.J. 127
Denning, T. 123, 131 Eljamel, S. 243
Department of Health and Prime Minister’s Elkins, G. 204
Office 377 Elliott, K.C. 426, 446
DePasquale, F. 25 Elshahabi, A. 26
DeRidder, D. 251 Emanuel, E.J. 135, 136
Derse, A. 378 Emanuel, L.L. 135, 136, 348
DeVita, M.A. 354 Enck, P. 224
Devries, K.M. 462 Engel, A.K. 25
Dewey, J. 402, 404, 405, 407 Engelhardt, H.T. 416, 417
Di Blasi, Z. 219 Enserink, M. 7
Di, H. 188 Erickson-​Davis, C. 250
Di, H.B. 329 Ersche, K.D. 486, 491, 502
Di Pietro, N.C. 458 Eskandary, H. 56
 619

Author Index 619

Espay, A.J. 223 Fleminger, S. 516

Esses, V.M. 577 Fleurence, R. 227
Etkin, J. 99 Florin, E. 26
European Commission  90 Focquaert, F. 251
European Union  90, 370 Foc.us 536
Evans, N.G. 532 Foddy, B. 228
Everett, J.J. 204 Fogg, B.J. 113
Everitt, B.J. 485, 486, 491 Folkins, C.H. 84
Evers, K. 214 Ford, P.J. 130, 132
Ewald, A. 32 Ford, P.L. 215
Ewin, B.N. 204 Forman, E.N. 163
Executive Board of the American Academy Fornai, F. 267
of Neurology  312 Forsythe, C. 546
Eysenbach, G. 266, 558 Fortnum, H. 31
Foster, J.A. 396, 397
Fabing, H.D. 535 Fox, M.D. 21, 290, 561
Fabsitz, R.R. 5 Fox, N.C. 377
Faden, R. 173 Fox, S. 561
Fagan, A.M. 299 Franca, A. 5
Fann, J.R. 517 Frankfurt, H.G. 112
Farah, M.J. 111, 115, 118, 150, 159, 413, 593 Franssen, E. 283
Farrar, J. 59 Franzini, A. 237
Farwell, J. 547 Frayne, R. 16
Fassler, M. 215, 216 Free, C. 462
Faucher, L. 396 Freedman, R. 228
Faugeras, F. 329 Freeman, J.B. 480
Faunce, T. 467 Fregni, F. 536
Favaro, A.E. 268 French, R. 328
Faymonville, M.E. 204 Freund, H.J. 127
FDA  87, 89, 606 Fricchione, G.L. 594
Feinberg, J. 161 Friedman, B. 562
Feinberg, T.E. 119 Friedman, M. 113
Feldman, R. 463 Friedman, T.L.
Felsen, G. 399, 400, 401 Friehs, G.M. 239, 243
Felt, A.P. 89 Fries, P. 24, 26
Feltenstein, M.W. 498, 499 Frisaldi, E. 224
Fent, R. 216 Friston, K.J. 21, 28
Fenton, A. 130 Fritze, J.G. 432, 460
Fenwick, P. 349 Frumkin, H. 433
Ferenczi, E.A. 481, 482 Fry-​Revere, S. 342
Ferguson, J.R. 547 Fuchs, T. 119
Fernandez, C. 373 Fujiura, G.T. 424
Fernyhough, C. 430 Fukushi, T. 132
Feudtner, C. 186 Fulford, K.W. 592
Field, R.A. 430 Furniss, E. 458
Fink, S. 209 Furton, E.J. 341, 359
Finkbeiner, S. 606 Fuss, J. 574, 575
Finley Caulfield, A. 190
Finniss, D.G. 215 Galeotti, F. 378
Fins, J.J. 133, 150, 186, 187, 240, 250, 256, 257, 312, Gallagher, M. 480, 484
313, 323, 328, 329, 332, 603–​10, 610 Gallagher, S. 119
Fischer, D.B. 317, 318, 327, 328, 329 Garbarino, J. 91
Fischer, J.M. 572 Gardiner, D. 340
Fischoff, B. 560 Gardner, A. 517
Fisher, C.B. 75 Gartner, C. 503
Fisher, C.E. 250 Gartner, C.E. 502
Fiske, S.T. 395 Garvin, T. 456
Fitz, N.S. 108, 118 Gay, J. 431
Fitzgerald, T.H.B. 41 Geddes, J. 85, 87
Fitzgibbon, S.P. 28 Gehring, K. 413
Flamm, A.L. 343 General Assembly of the United Nations  385
620

620 Author Index

Genesen, L.B. 344 Greely, H.T. 115, 118, 593

George, M.S. 128 Green, J.J. 27
George, R.P. 347 Greenberg, B.D. 243
Gergen, K.J. 443 Greene, J. 111, 389, 403
German National Cohort Consortium  54 Greene, J.A. 88
Gerrard, D.F. 521 Greenlaw, J. 343
Gert, B. 349, 401, 407 Greenwood, C.E. 432
Gervais, K.G. 347, 352 Greer, D.M. 183, 357
Geula, C. 282 Gregory, J. 556
Giacino, J. 127, 130, 186, 308, 309, 310, 604 Griffith, D.B. 370
Giacomini, M. 358 Grigg, M.M. 314
Giaschi, D.E. 18 Grill-​Spector, K. 18
Gigerenzer, G. 100 Grisso, T. 130, 163
Gilbert, D. 578 Groopman, J. 270
Gilbert, E. 124, 521 Gross, J. 36
Gilbert, F. 235, 245, 250, 251, 253 Grossman, E. 429, 446
Gilbert, S.F. 320 Guan, X. 16
Gilbertson, M. 460, 462 Gunnoe, J. 137
Gillett, G. 462, 463 Gunther, D.F. 162, 421
Gilligan, C. 394 Guo, J.Y. 220
Giordano, J. 251, 531–​53, 533, 538, 548, 591–​614, Guo, Z. 516
594, 595 Gureje, O. 596
Girotra, S. 181, 183 Guskiewicz, K.M. 515, 516, 517
Giza, C.C. 515, 520
Gladstone, P. 458 Haas, J.M. 359
Glannon, W. 119, 124, 131, 251 Habermas, J. 404
Glass, D.C. 404 Haddad, L. 431
Glimcher, P.W. 480, 491 Hadjistavropoulos, T. 130
Globe Editorial  269 Haga, S.B. 5
Glockner 480, 491 Haggard, P. 389, 395, 480
Glover-​Thomas, N. 595 Haines, A. 459, 460
Goate, A.M. 299 Halevy, A. 314, 330, 348
Gobas, F.A. 460, 462 Hall, K.T. 225, 500, 506
Goebel, M.U. 220 Hall, W. 492, 497, 503, 509, 519
Goering, S. 123, 124 Haluza, D. 433
Goetz, C.G. 223, 224 Hamalainen, M.S. 32
Gold, J.I. 480, 491 Hamarneh, G. 38, 39
Goldberg, D.S. 250 Hamilton, R. 18, 536
Goldberg, S. 76 Hansson, S.O. 137
Goldenberg, A.J. 5 Harada, M. 458
Goldstein, R.D. 445, 488 Harari, R. 429
Gollust, S.E. 557 Hardy, J. 297, 300
Golub, A. 535 Harmon, K.G. 520
Gómez-​Pinilla, F. 432 Harvard Medical School: Ad Hoc Committee
Goodine, C. 458 to Examine the Definition of Brain Death 
Goodman, M. 266 324, 358
Goodyear, B.G. 18 Harwerth, R.S. 18
Google Play  94–​7 Haselager, P. 123, 131, 251
Gorgulho, A. 239, 253, 254 Hashmi, J.A. 199
Gostin, L.O. 344 Haslam, C. 84
Goubert, L. 200 Haslam, N. 119
Goulon, M. 337, 358 Hastings Center  7–​8
Grafton, S.T. 18 Hatfield, E. 205
Gramm, H.-​J. 314 Hatira, P. 204
Grandjean, P. 428, 429, 430, 436, 437, 445, 460 Haubensak, W. 148, 155
Grant, S. 72 Hawn, C. 558
Grashow, R. 428 Hayashi, K. 199
Graves, A.B. 516 Haynes, J.D. 115
Gray, J.R. 163, 164 Haynes, K.M. 558
Gray, M.T. 402 He, J.H. 186
Graybiel, A.M. 484 Heatherton, T.F. 407
 621

Author Index 621

Hebb, A.O. 124 Human Rights Code  577, 586

Heesen, C. 135 Humphrey, N. 225
Hegenscheid, K. 55, 57, 62 Hutmacher, D.W. 6
Heidegger, M. 98 Hyafil, A. 480, 491
Heiervang, K.S. 431 Hyman, S. 483, 486, 487, 491
Heiss, W.D. 187 Hyman, S.E. 491
Held, V. 440
Henderson, J.M. 132 iClarified 101
Henrich, J. 596 Idriss, S.Z. 557, 558
Herdman, A. 36 Ikram, M.A. 55
Herfst, S. 7 Ilieva, L.P. 118
Hermundstad, A.M. 20 Illes, J. 3, 7, 9, 58, 115, 150, 151, 160, 264, 271, 436,
Herron, J. 126 440, 459, 556, 557, 564, 591, 603
Hertzman, C. 429 Ilmoniemi, R.J. 32
Herz, K.T. 428, 460 Iltis, I.S. 356
Hester, D.M. 163, 170 Immordino-​Yang, M.H. 17
Heyman, G.E. 478, 479 Ingold, T. 440
Heyman, G.M. 500 Institute of Medicine and National Research
Hichens, C. 519, 521 Council 7, 354
Hickner, J. 215, 216, 218, 225 Interior Health Authority (South Similkameen
Hicks, J. 460 Health Centre)  586
High, S. 457 Invista (Canada) Co. 589
Hill, K. 117 IOM 164
Hillier, V. 515 Isaak, C.A. 467
Hindle, E.M. 183 iTunes App Store  94
Hinton-​Bayre, A.D. 515 Izuma, K. 394
Hinxton Group  9
Hipp, J.F. 24 Jack, C.R., Jr  297
Hirsch, A.R. 470 Jackson, D.D. 456, 460
Ho, A. 270 Jacob, K.S. 593
Ho, C.S. 18 Jacobson, J.L. 430
Hochberg, L.R. 123, 125, 609 Jacobson, R. 88
Hodge, F.S. 462, 463 Jacobson, S.W. 430
Hodson, H. 89 Jacques, J. 554
Hoggard, N. 59 Jaffe, K.M. 609
Hohagen, F. 253 Jain, S. 341
Holroyd, J. 396 Jang, B. 458
Holsheimer, J. 132 Jaremko, J.L. 56
Holz, E.M. 40 Jaworska, A. 276
Holzer, M. 182 Jeffrey, C. 85
Holzkamp, K. 119 Jennett, B. 309
Hopkin, M. 318 Jerbi, K. 25
Hoppin, J.A. 429 Jian, B. 38
Hornby, K. 354 Jimenez, N. 609
Horstkötter, D. 176 Joffe, A. 336, 342
Horvath, J.C. 536 Johnson, C.M. 561
Houdsen, C.R. 413 Johnson, L.S.M. 521
Houston, S.M. 165 Johnston, J. 115
Hovda, P. 360 Joint Commission in Accreditation of Healthcare
Howick, J. 216 Organizations 203
Høyersten, J.G. 535 Jolly, D. 465
Hradsky, J. 38 Jonas, W.B. 219
Hrobjartsson, A. 216 Jones, D.K. 16
Hser, Y.I. 481, 487, 488 Jones, R. 467
Hu, H.W. 428 Jorm, A.E. 504
Huang, J.Y. 532 Joseph, J.A. 435
Huang, M.X. 25 Jotterand, F. 416
Hubel, D.H. 18 Jox, R.J. 189
Huggins, J.E. 137 Jozaghi, E. 266
Hui, H.B. 36 Juengst, E.T. 412
Hull, S.C. 215, 216, 226 Jurcoane, A. 19
62

622 Author Index

Kable, J.W. 480, 491 Kittelsaa, A.M. 420

Kahn, J. 8 Kitzbichler, M.G. 26
Kaiser, E. 76 Klaming, L. 251
Kaiser, M. 20 Kleiderman, E. 5
Kalant, H. 503, 506 Kleiman, M. 500
Kalaska, J.F. 480, 484, 491 Klein, E. 123, 129, 137
Kamath, S. 56 Kleinman, A. 591, 594, 596
Kam-​Hansen, S. 206, 223 Klotz, O. 459
Kamel, F. 429 Klyuzhin, L.S. 23
Kamienski, L. 535 Knight, H.M. 63
Kang, J. 23 Knoppers, B.M. 7, 369, 377, 384, 385
Kant, E. 402 Koch, C. 187, 348
Kant, I. 467 Koechlin, E. 480, 491
Kaplan, J.T. 17 Kohl, S. 237, 242, 244, 245, 252
Kappenmann, E. 536 Kohlberg, L. 159
Kaptchuk, T.J. 219, 226, 227 Kolata, G. 131
Karch, C.M. 299 Kolibree 101
Karlawish, J. 380 Konrad, P. 127
Karran, E. 298 Konrad, T.R. 229
Kass, L. 360, 416, 538, 608 Koob, G. 500, 502, 508
Kass, L.R. 345 Koob, G.F. 487, 498, 501, 503
Katz, D.J. 185 Koppelmans, V. 56
Katzman, G.L. 57 Korein, J. 352
Kauffman, S.A. 351 Korrick, S.A. 430
Kaye, A.H. 521 Kortum, P. 558
Kaye, K. 90 Kosal, M.E. 532
Keene, S. 395 Kosten, T.R. 503
Kelley, A.E. 481, 483 Kowal, S.P. 266
Kelly, B.D. 430 Kowalski, R.G. 189
Kelly, E.N. 456 Krack, P. 498
Keltner, J.R. 204 Kraemer, F. 251
Kelty, C. 92 Kramer, A.F. 434
Kendell, R.E. 228 Kramer, P. 133, 397
Kendler, K.S. 499, 500, 502 Krames, E.S. 132, 133
Kennedy, I.M. 359 Kringelbach, M.L. 27
Kenny, P.J. 481 Kroger, W.S. 204
Kermen, R. 215, 225 Krupnik, I. 465
Kerti, L. 432 Kübler, A. 131, 137
Kesey, K. 235 Kubu, C.S. 130
Kessler, R.C. 594 Kuehn, B.M. 74
Kessler, S.K. 181 Kuhn, J. 127
Khandanpour, N. 56 Kuhnlein, H.V. 460
Kikuchi, A. 23, 26 Kullo, I.J. 5
Kilmer, B. 500 Kuo, M.H. 74
Kilwein, J.H. 200 Kupers, R. 204
Kim, E.-​H. 557 Kvaale, E.P. 504, 576
Kim, J. 562 Kwong, K.K. 17
Kim, P. 167
Kim, S. 562 La Vaque, T. 228
Kim, S.Y. 302, 369, 380 Laakso, M.P. 282
Kimmelman, J. 270 Lachaux, J.P. 33, 36
Kimura, R. 317, 332 Lacour, A. 299
Kincaid, H. 501 Ladd, R.E. 163
King, C. 125 Lai, J.S. 435
King, M. 467 Lam, D.C.K. 505
King, N.J. 168 Lamas, D. 85
Kinomura, S. 149 Lambert, B.W. 596
Kiorpes, L. 18 Lamkin, P. 81
Kirmayer, L.J. 228, 432, 593, 596 Landrigan, P.J. 429, 436, 437, 460
Kirsch, I. 220, 222 Lane, A. 315
Kirschen, M.P. 64, 182, 184, 186 Lane, S. 519
 623

Author Index 623

Lang, D.J. 16 Lin, X. 19

Lang, E.V. 198, 201, 204, 205, 206 Lindemann, H. 171
Lange, M.M. 383 Lindquist, C. 253, 254
Lanphear, B.P. 428, 438 Lingford-​Hughes, A.R. 503
Lanzilao, E. 547, 592 Liossi, C. 204
Lao, Y. 166 Lipsman, N. 235, 244, 245, 251, 252
Larsen, P.O.M. 563 Lisanby, S.H. 146
Larson-​Prior, L.J. 26 Liu, J.C. 116
Laser, E. 205 Liu, S. 16, 23, 154
Lasswell, H.D. 533 Liu, X. 154
Laule, C. 16 Lizza, J. 347, 360
Laupacis, A. 268 Llinás, R. 40
Laureys, S. 185, 187, 308, 309, 310 Lo, B. 419, 420
Lavigne, K.M. 21, 22 Lobier, M. 28
Law Commission of Ontario  578 Lock, M. 317, 341
Law Reform Commission of Canada  340 Lodygensky, G.A. 16
Leavitt, N. 89 Loeb, J. 350
Lebedev, M.A. 537 Logothetis, N.K. 21
LeBihan, D. 38 Lomax, G.P. 5
Lederbogen, F. 431 Lombera, S. 591
Lee, A.A. 576 Loria, K. 83, 85
Lee, C. 442 Lou, J.S. 221
Lee, I.S. 220, 489, 576 Love, T. 585
Lee, J.D. 489 Lovett, K.M. 561
Lee, K. 175 Lubman, D.I. 56, 64
Lee, P. 347, 456 Luby, J. 167
Lee, S.S.J. 462 Lucchini, R.G. 429
Lee, Y.K. 517 Luckhoo, H. 37
Legon, W. 149 Luckmann, T. 443
Lehman, E.J. 517 Lucky, R. 563
Lehmkuhle, M. 81, 84, 87 Luescher, C. 483, 487
Lehti, V. 456, 460 Lufkin, B. 94
LeMoal, M. 498, 501 Lui, F. 221
Leng, S. 203 Luigjes, J. 235, 498
Lenhart, A. 70 Luna, F. 442
Leon, M. 434 Luparello, T. 220
Leonard, A. 83, 99 Lupton, D. 58
Lerner, Y. 18 Lupton, M.K. 81
Leshner, A. 264 Lutkenhoff, E.S. 189
Leshner, A.I. 497, 508 Luxton, D.D. 83, 85, 88
Lévèque, M. 235, 237, 242, 243, 245 Lye, T.C. 516
Levitt, P. 172 Lynch, M. 117
Levy, N. 111, 118, 437, 592 Lynoe, N. 215, 216, 226
Lewin, L. 535
Lewis, A. 343 Maas, J. 433
Lewis, C.M. 28, 500 MacArthur Foundation Research Network on Law
Lewis, M.H. 5 and Neuroscience  610
Lexchin, J. 525 MacDonald, J.P. 460
Li, T.-​K. 498, 499, 502, 503 MacDonald, M.E. 16
Li, W. 16 MacKay, A. 16
Li, X. 19 Mackenzie, C. 113, 392, 505
Liang, X. 187 Mackenzie, R. 251
Liao, S.M. 162 MacLean, S. 463
Libet, B. 389, 394 Magnus, D.C. 344
Licht, D.J. 184 Magnuson, K. 167
Lichtenberg, P. 228 Maheshawari, M.C. 341
Lidstone, S.C. 220, 221, 222, 223 Mahner, M. 350
Lidz, C.W. 250 Mainsah, B.O. 127
Lilienfeld, S.O. 479, 500, 505, 509 Majury, D. 578
Lim, Y.-​H. 430 Mak, J.N. 123, 125, 127, 131
Lin, L.Y. 72 Makdissi, M. 515
624

624 Author Index

Malenka, R.C. 483, 487 Mercado, R. 223

Malle, B.F. 405 Merikangas, K.R. 481, 506
Malloy, D.C. 130 Merkel, R. 251
Malone, D.A. 128 Meshi, D. 6
Mandela, N. 388, 610 Meslin, E.M. 6
Manogaran, P. 16 Metzak, P.D. 21
Marchant, J. 205 Meurisse, M. 204
Marchessault, G. 467 Meurk, C. 505, 508
Marcin, J.P. 182 Meyers, D. 113
Marcus, S. 3, 264, 443, 554, 564 Mezzacappa, E. 175
Markus, H.S. 58 Mfutso-​Bengo, J. 65
Marmot, M. 427 Micheau, J. 282
Marquis, D. 355 Michiels, E. 184
Martínez-​Álvarez, R. 243, 245 Miles, S. 342
Mason, C.E. 91 Milgram, S. 393
Masuda, J.R. 456 Mill, J. 426
Mathews, D.J.H. 5, 6, 8 Miller, A.C. 341
Matschinger, H. 504 Miller, E.K. 486
Matthews, P.M. 55 Miller, F.G. 129, 218, 219, 220, 222, 225, 315, 325,
Matuszek, S. 434 341, 342, 355
Maxwell, A.W.P. 60 Miller, G. 214
Mayberg, H.S. 128, 146, 224, 609 Miller, P. 506
Mayer, C.A. 268 Miller, R.J. 535
Mazanderani, F. 269, 271 Miller, S. 556
Mazurek, M.O. 74 Miller, W.R. 505
McAlpine, D. 459 Miller-​Ziegler, J.S. 407
McCaffery, K.J. 64 Mills, C.A. 459
McCall, C. 17 Milstein, A.C. 57
McCombs, M.E. 265 Minassian, A. 84
McCreight, R. 538 Miodovnik, A. 429, 430, 445
McCrory, P. 517, 520, 521, 524 Miresco, M.J. 228
McDermott, Q. 519, 521 Mirzadeh, Z. 127, 237
McDermott, V.G.M. 202 Miskovic, V. 25
McEwen, B.S. 435 Mitchell, S.M. 73
McGie, S.C. 129, 131 Mitchell, T.M. 115
McGowan, A.K. 610 Moerman, D.E. 219
McGregor, D. 467 Mogil, J.S. 200
McGuire, A. 560 Mohamed, F.B. 145
McKee, A.C. 515, 517, 519 Mohan, G. 168
McKee, S.P. 18 Moiseev, A. 33, 36
McKergow, F. 463 Mokhtarzadeh, M. 606
McLaren, L. 467 Molek-​Kozakowska, K. 560
McLellan, A.T. 502 Moler, F.W. 182
McLoyd, V.C. 167 Molgaard, C.A. 516
McMahan, J. 347 Molinari, G.F. 358
McMichael, A.J. 459 Mollaret, P. 337, 358
McNamee, M.J. 515 Moller, A.C. 405, 407
McNeal, G.S. 89 Monroe, A.E. 396, 401, 402
McQuigge, M. 458 Montague, P.R. 402, 484, 485, 491
Medical Consultants on the Diagnosis of Death Monteith, S. 595
to the President’s Commission for the Study of Monterosso, J. 575
Ethical Problems in Medicine and Biomedical and Montgomery, G.H. 204, 220
Behavioral Research  308 Monti, M.M. 188, 318, 610
Medical Research Council and Wellcome Mora, F. 434
Trust 54, 59, 61 Morales, M. 501
Medina, L.S. 31 Morar, N. 398, 403
Meissner, K. 216 Morein-​Zamir, S. 413, 593, 594
Mele, A. 394 Moreno, J.D. 531–​53
Melnyk, R.M. 88, 93 Moreno, M. 481
Menary, R. 109 Mori, S.P.C.M. 38
Mendelsohn, D. 235, 252, 339 Morishita, T. 237, 240, 241, 242, 244, 245
 625

Author Index 625

Morison, R.S. 360 Noë, A. 119

Morris, Z. 56, 150 Nolan, J.P. 183
Morse, S. 399, 479, 490 Nolan, T.A. 224
Moss, C.W. 609 Norbash, A. 205, 208
Moyers, T.R. 505 Norman, C.D. 558
Muckli, L. 18 Northern Brain Injury Association  457
Mueller, P.K. 577 Northoff, G. 187, 251
Mullen, T. 27 Norup, M. 216
Müller S. 236, 237, 243, 245, 246, 250, 251, 252, 253, Nussbaum, M.C. 438
255, 256, 257, 258, 401 Nutt, D. 503
Müller, U.J. 237 Nuttin, B. 252, 257, 609
Multiple Sclerosis International Federation  267
Multi-​Society Task Force on PVS  310 O’Brien, C. 497, 500, 501, 502
Munjal, K.G. 354 O’Doherty, K. 266
Munshi, L. 358 Office of the Information and Privacy
Murata, K. 460 Commissioner  562–​3
Muratore, R. 524 Office of Naval Research: Science & Technology  534
Murphy, E. 65 Office of Technology Assessment  8
Murphy, M.D. 123 Ogawa, S. 17
Murphy, N. 111 Olick, R.S. 342
Murray, C.J. 144, 146 Olson, E. 348
Murray, L.K. 592 Omalu, B.I. 515, 517
Murray, T.H. 170 O’Neil, A. 432
Mustanski, B. 75 O’Neill, G.C. 25
Mustanski, R. 75 O’Neill, O. 226
Ontario Human Rights Commission  579
Na, Y.C. 235, 240, 243, 244, 246 Opler, M.G.A. 428
Naccache, L. 604 Orchard, J. 522, 523
Nagarajan, S. 31 Oreskes, N. 446
Nagel, S.K. 108, 110, 119 O’Rourke, S. 431
Nair-​Collins, M. 330, 336 Orphan Drug Act  606
Nakagawa, T.A. 342 Orr, R.D. 344
Nand, K. 38 Osler, W. 607
Nardone, R. 128 Ovadia, D. 250
Naselaris, T. 115 Overby, K.J. 356
Nasrallah, F.A. 16 Overgaard, S. 592
National Commission for the Protection of Owen, A.M. 187, 188, 318, 603
Human Subjects of Biomedical and Behavioral Oz, G. 16
Research 607
National Institute on Drug Abuse  497 Padela, A.I. 341
National Institutes of Health Director, Advisory Padoa-​Schioppa, C. 480, 484
Committee 147 Pallis, C. 314, 352
National Research Council  507, 540, 547 Palmour, N. 557, 561
Nedelsky, J. 113 Palop, J.J. 22
Needleman, H.L. 428 Palva, J.M. 24, 36
Nelson, H.L. 171 Palva, S. 24, 36
Nemetz, P.N. 516 Pannek, K. 26
NEPA 439 Panofsky, A. 92
Nestler, E.J. 481, 485, 487 Pantic, I. 72
Netherland, J. 506 Papanikolaou, V. 56
Neufeld, K.A. 396, 397 Pardo, M.S. 119
Ngandu, T. 377 Parens, E. 115, 118, 593
Nicholas, C.R. 188 Parent, A. 536
Nicolelis, M.A. 609 Parfit, D. 438
Nielsen, N. 182 Park, H.-​J. 56
Nikiforuk, A. 458 Park, L.C. 226
Niso, G. 27 Parker, J. 56
Nissani, M. 393 Parnia, S. 349
Nitsche, M.A. 536 Parsons, R. 458
Nitze, P. 533 Partridge, B. 519, 520, 521
Noble, K.G. 167 Pascoli, V. 481, 482
62

626 Author Index

Pascual-​Leone, A. 536 Pope John Paul II  341, 359

Pasic, M.D. 151 Pope, T.M. 340
Passchier, W.F. 460 Portier, C.J. 441
Passchier-​Vermeer, W. 460 Posner, J.B. 308, 309, 316, 317
Patel, V. 591, 592, 593, 594, 596 Potter, V.R. 440
PatientsLikeMe 91 Potts, J. 470
Patil, P.G. 127 Powell, H.F. 56
Patterson, C.C. 428 Powers, M. 173
Patterson, D. 119 Powner, D.J. 306
Patz, J.A. 459 Prasloski, T. 16
Paulus, M.P. 499 Presidential Commission for the Study of Bioethical
Paulus, W. 536 Issues 151
Pavlov, I.P. 219 President’s Commission for the Study of Ethical
Pazderka, H. 463 Problems in Medicine and Biomedical and
Peace, W.J. 162 Behavioral Research  7, 339
Pedersen, D. 593 President’s Council on Bioethics  320, 343, 413, 538
Peen, J. 430 Prest, G. 458
Peerdeman, K.J. 199 Preston, J.L. 111
Penfield, W. 604 Price, J.L. 520, 521
Pennefather, S.H. 314 Prince, M. 592
Penney, S. 572 Prince, M.R. 61, 594
Pepper, J. 238, 241, 242, 243, 244, 245, 246, 252 Priori, A. 536
Pereira, A.C. 434 Proctor, R.D. 56
Perera, F.P. 167 Pruessmann, K.P. 15
Perkins, D.D. 405 Prüss-​Üstün, A. 436, 437
Perman, S.M. 182, 190 Psaltopoulou, T. 435
Pernick, M.S. 364 Public Health Agency of Canada  427
Perova, Z. 148 Pugh, C. 101
Perrin, M. 429 Pugh, J. 215, 216
Perry, S.L. 431 Pullman, D. 269, 270
Pescosolido, B.A. 504, 505 Purtilo, R.B. 138, 225
Peters, A. 430
Peters, C. 160 Quattrocchi, C. 56, 57
Peters, K.R. 299, 302, 303, 430 Quigley, M. 537
Petersen, A. 270 Quimby, E.G. 76
Petersen, C. 557
Petersen, R.C. 377 Rabinowitz, P.M. 431
Peterson, B.S. 166, 167 Rachels, J. 169
Peterson, C. 404 Rachul, C. 554, 560
Peterson, T.O. 203 Racine, E. 160, 180, 190, 192, 214, 250, 343, 389, 390,
Petrol Link-​up  463 392, 398, 400, 406, 467, 509, 557, 592
Petronis, A. 426 Raeburn, S. 61
Petrovic, P. 220 Raffin, T.F. 160
Pew Research Center  112 Raichle, M.E. 24, 290
Peyron, R. 199 Raichvarg, D. 554
Pfurtscheller, G. 125 Raj, A. 289
Pham, T. 73 Randall, B. 61
Phelan, J.C. 505 Ranney, M.L. 73
Piaget, J. 159 Ransohoff, R.M. 135
Picton, T.W. 31 Rasminsky, M. 269
Pierce, J.P. 506 Raspe, H. 253
Pierce, R. 6 Rauscher, A. 16
Pinker, S. 348, 466 Ravizza, M. 572
Pinkerton, E. 456 Rawls, J. 438
Plum, F. 309, 332 Ray, J.G. 456
Pluye, P. 558 Raz, R. 430
Podd, J. 222 Reavley, N.J. 504
Poldrack, R.A. 17 Redish, A.D. 485, 491
Pollo, A. 220 Reekers, J.A. 268
Polsky, S. 521 Rees, G. 115
Pontifical Academy of Sciences  341 Régis, J. 239
 627

Author Index 627

Reimer, J. 270 Ryan, K.A. 560

Reiner, P.B. 108, 110, 111, 118, 399, 400, 401 Ryan, R.M. 404
Remien, R.H. 592
Repertinger, S. 353 Sabat, S.R. 281
Resch, J.E. 526 Sacks, O. 274, 291
Reske, M. 499 Sadatsafavi, M. 62
Resnik, D.B. 426, 431, 439, 441 Saggar, M. 17
Ribary, U. 40 Sagiv, S.K. 430
Rice, E. 76 Sagoff, M. 426
Richardson, H.S. 62 Sahakian, B.J. 150, 593, 594, 603
Riedel, G. 282 Saigle, V. 389, 394
Rieder, M.J. and Hazardous Substances Salgado-​López, L. 237
Committee 377 Salib, E. 515
Risch, N. 506 Salter, E.K. 170
Risk, A. 557 Samson, J.A. 432
Rissman, J. 115 Samson, K. 83, 84, 269
Rizvi, S.A. 135 Sandberg, A. 413
Roach, K. 572 Sandel, M.J. 593
Robbins, T.W. 479, 481, 485, 486, 491 Sandeman, E.M. 62, 64
Roberts, E.M. 429 Sander, C.Y. 23
Roberts, R.M. 188 Sandler, A.D. 228
Robertson, J.A. 311 Sandroni, C. 183
Robillard, J.M. 6, 557, 559 Sandvik, H. 560
Robins, L.N. 488, 500, 535 Sanghavi, D. 330
Robinson, S. 36, 483 Sanicola, L. 89
Rodin, E. 314 Sankar, T. 128
Rodriguez-​Arias, D. 343 Sarasohn-​Kahn, J. 88, 92
Rodríguez-​Barranco, M. 429 Sarkar, S. 320
Roepke, A.M. 85 Sartorius, N. 504
Rogers, B.P. 19 Satcher, D. 609
Rommelfanger, K.S. 215, 218 Satel, S. 479, 500, 505, 509
Roosevelt, F.D. 533 Sato, H. 537
Rosado, J.L. 429 Sauseng, P. 40
Rose, G. 506 Savill, J. 59
Rose, J.P. 227 Savulescu, J. 593
Rose, N.S. 456, 509 Saxena, S. 596
Rose, S.P.R. 119 Scarlett, A.G. 456
Rosenberg, C.E. 218 Schaefer, G.O. 594
Rosenthal, E. 594 Schaefer, T.W. 459
Rosenzweig, M.R. 167 Schäfer, C.B. 25, 37, 215, 227
Rosin, B. 236 Schafer, S.M. 227
Roskies, A.L. 111, 214 Schechtman, M. 251
Rosner, F. 359 Scheltens, P. 294, 299
Rosner, G. 90 Schermer, M. 133, 250
Ross, B.D. 17 Scheufele, D.A. 265
Ross, L.F. 163, 170 Schiff, N.D. 127, 149, 603, 604, 607, 609, 610
Roth, B.L. 149 Schläpfer, T.E. 240, 242, 250
Rothman, D. 608 Schmidt, C.O. 61
Rothstein, M.A. 91 Schnakers, C. 186
Rousseau, J.J. 388, 406 Schneider, J.W. 479
Roy, C. 162 Schneider, M.J. 123
Royal College of Radiologists, The  60, 62, 63 Schneiderman, L.J. 420
Royal Society  555, 565 Schoenbaum, G. 484, 485
RRT Expert Panel on Health Measurement  424 Schoffelen, J.M. 36
Rubin, E.B. 312 Schonert-​Reichl, K.A. 175
Rubinov, M. 20 Schrader, H. 314
Ruby, C.C. 573 Schreiber, T. 28
Rück, C. 245 Schüll, N.D. 98, 100
Rule, N.O. 392 Schultz, W. 224, 483
Rupert, R.D. 109 Schwab, A. 270
Russell, W.T. 459 Schwartz, B.S. 428
628

628 Author Index

Schweitzer, P. 460 Slote, M. 440
Schweser, F. 16 Small, G. 432
Scialabba, G. 119 Smith, C.F. 99
Sclove, R. 9 Smith, E.E. 55
Scott, D.J. 222 Smith, K. 395
Scullard, P. 557 Smith, K.R. 427, 580
Searle, J.R. 321 Smith, M.E. 413
Secen, J. 19 Smith, P.B. 393
See, R.E. 498, 499 Smith, S. 136
Seel, R.T. 127 Smith, S.M. 38, 153
Seeley, W.W. 289, 290 Smylie, J. 462
Seeman, T.E. 435 Snow, C.P. 8
Sekihara, K. 31 Snyder, J. 269, 270
Selemon, L.D. 165 Snyder, J.V. 354
Seligman, M.E.P. 404 Soekadar, S.R. 123, 124, 125, 126, 127
Selkoe, D.J. 297, 300 Soloveichik, A. 359
Selters, W.A. 31 Song, T.M. 558
Sen, A. 438 Souren, L. 283
Sénécal, K. 5, 6 Sowell, E.R. 165
Shadlen, M.N. 480, 491 Spearman, C. 20
Shafer, J.P. 37 Spellecy, R. 378
Shah, N.J. 17 Spiegel, D.P. 19
Shah, S.K. 325, 342 Spike, J. 343
Shaham, Y. 487 Spiro, H.M. 223
Shanker, T. 535 Spitzer, R.L. 594
Shanks, D.R. 222 Sporns, O. 20, 33
Shanks, T. 127 Sproul, A.A. 6
Shapiro, J.R. 504 Squire, L.R. 282
Shaw, D.L. 265 Stables, J. 84
Shaw, R.J. 561 Stam, C.J. 26, 32
Sheff, D. 605 Stanbury, W.T. 456
Shelton, J.F. 429 Stanford Medicine  91
Shen, F.X. 115, 116 Stanley, S.A. 149
Sherman, R. 215, 216, 218, 225 Stanovich, K.E. 109
Sherwin, E. 397 Starling, R.M. 181
Shewmon, A. 346, 347, 348, 353 Stedman, R.C. 431
Shewmon, D. 315, 353 Steel, D. 446
Shewmon, E. 346, 348 Stein, D.J. 591–​614
Shih, J.J. 123, 428 Stein, L.D. 369
Shirkey, H. 377 Steinsbekk, K.S. 62
Shively, S. 516 Stejskal, E.O. 38
Shonkoff, J.P. 172, 435 Stemmer, B. 463
Shook, J. 538, 594, 595 Stephan, B.C.M. 55
Shores, E.A. 516 Steriade, M. 333
Shrader-​Frechette, K.S. 426, 438, 439, 441, 442, 446 Stevenson, S. 464
Silberg, W.M. 560 Stewart, P.W. 430
Silove, D. 594 Stewart-​Williams, S. 222
Silvers, A. 135 Stilgoe, J. 266
Sime, W.E. 84 Stins, J.F. 328
Simeral, J.D. 537 Stockard, J.J. 31
Siminoff, L.A. 357 Stolier, R.M. 480
Singer, T. 200 Stolyar, N. 392
Singh, I. 384 Stout, R. 460
Singh, V. 17 St Philip, E. 268
Siu, A.L. 93 Strategic Multilayer Assessment Group  534
Sivashanker, K. 72 Strauss, J.S. 593
Sjögren, M.J.C. 127 Strawson, P.F. 402
Skloot, R. 5, 7 Sturm, V.E. 290
Skuban, T. 250 Stutzman, F. 117
Slaughter, L.M. 153 Sudlow, C. 55
Slimak, M.W. 446 Sudo, N. 397
 629

Author Index 629

Sullivan, A. 460 Tuttle, A.H. 223

Sullivan, J.A. 501 Tyler, W.J. 536
Sullivan, P.F. 481
Summerfield, D. 592 Uhlhaas, P.J. 40
Sun, B. 235, 241, 242, 243, 245 UK ECT Review Group  536
Sutner, S. 87 Ukueberuwa, D. 536
Swan, M. 100 United Nations Educational, Scientific and Cultural
Swets, J.A. 533 Organisation (UNESCO)  373, 375, 376, 378
Synofzik, M. 133 United Nations Environment Programme  438
Szondy, D. 537 United Nations General Assembly  577
US Department of Health and Human
Tabery, J. 547 Services 5, 96
Tahmasian, M. 23 US Genetic Information Nondiscrimination
Tairyan, K. 9 Act 156, 563
Takahashi, K. 5 US Health Insurance Portability and Accountability
Takeuchi, T. 459 Act 89, 563
Talbott, E.O. 460 US Preventive Services Task Force  93
Talwar, S.K. 537 US Supreme Court  325
Tamatea, A.J. 462
Tan, T.J. 250 Valaskakis, G.G. 432
Tang, C.Y. 429 Valenstein, E.S. 235, 492
Tanner, J.E. 38 van der Werf, Y.D. 149
Tass, P.A. 236 Van Fleet, D.D. 203
Taylor, H.A. 378 Van Laarhoven, A.I. 220
Taylor, J.P. 127 Van Oorschot, W. 576
Taylor, R.M. 342 Van Oostdam, J. 460
Teicher, M.H. 432 van Os, J. 430, 433
Tendler, M.D. 359 van Praag, H. 434
Tennant, P. 456, 458 van Uden-​Kraan, C.F. 557, 558
Teoh, G.Z. 6 Van Veen, B.D. 31, 36
Thackeray, R. 558 van Zellem, L. 183
Thomas, J. 459 van Zijl, P.C.M. 38
Thompson, A. 65 Vance, K. 558
Thompson, B. 18 Vanhaudenhuyse, A. 329
Thompson, P.M. 163, 164 Varela, F. 28, 40
Thomson, B. 61 Varela, F.J. 119
Thorgeirsson, T.E. 481 Varelmann, D. 206
Thornicroft, G. 592 Varma, G. 16
Tiffany, S.T. 484, 486 Varney, S.M. 505
Tilburt, J.C. 215, 216, 218 Vavasour, I.M. 16
Timoney, K.P. 456 Veatch, R.M. 134, 330, 347, 352
Tipper, C.M. 17, 18 Veith, F.J. 340
Tokmetzis, D. 116 Vemuri, B.C. 38
Tomasi, D. 187 Verbeek, P.-​P. 113
Tononi, G. 187 Vernooij, M.W. 54, 56, 59
Topjian, A.A. 181, 182, 183 Vespa, P. 191
Torres, C.V. 237 Vicente, R. 28
Tost, H. 432, 433, 435 Vierling, L. 163
Tournier, J.D. 38 Villanueva, C.M. 430
Tovino, S.A. 580 Villemagne, V.L. 22, 23, 297
Townsend, A. 64 Vincent, N.A. 251
Traboulsee, A.L. 268 Vinck, M. 36
Tractenberg, R.E. 546, 547 Visser-​Vandewalle, V. 237
Trufyn, J. 56 Vohs, K.D. 405, 407
Truog, R.D. 311, 314, 315, 317, 318, 324, 327, 328, Voida, S. 84
329, 336, 355 Volkmann, J. 133
Trustram Eve, C. 561 Volkow, N.D. 479, 488, 497, 499, 500, 501, 502, 503,
Tsai, S.-​Y. 429 506, 507, 508
Tsuang, M.T. 481 Vollmann, J. 250
Tuch, D.S. 38 von Ins, M. 563
Turner, D.A. 127 Vorgan, G. 432
630

630 Author Index

Vos, S.J. 299, 300 Wicks, P. 267

Vrba, J. 36 Widge, A.S. 128
Vrecko, S. 579 Wiggermann, V. 16
Vukic, A. 432 Wijdicks, E.F. 183, 308, 340, 342, 358
Wildeman, S. 378
Wager, T.D. 199, 204, 221 Wilkinson, D. 160, 184, 189
Wagner, B. 93 Willis, R. 556
Wagner, D.D. 407 Willox, A.C. 164, 461
Wahlster, S. 340, 357 Wilsdon, J. 556
Wahlund, L.O. 56 Wilson, F.C. 186
Walji, M. 561 Wilson, K. 456, 460, 467
Walker, D.M. 487 Wilson, S.J. 253
Walker, J. 88, 89 Wilson, T.D. 100
Walker, M.J. 505 Winblad, B. 294, 297
Walter, H. 236, 251, 401 Windham, G.C. 430
Walter, J.K. 182, 184, 186 Winkfield v. Rosen  359
Wang, F. 188, 591 Winocur, G. 432
Wang, H.E. 20 Winslade, W.J. 330
Wang, P.S. 591 Winston, G.P. 56
Wang, T. 19 Winter, C. 84
Wang, X.J. 40 Wintermark, M. 189
Wang, Y. 16 Wiseman, C.L. 460, 462
Wangberg, S.C. 558 Witt, K. 251
Wangmo, T. 416 Wittes, B. 116
Ward, K.M. 28 Wiwchar, D. 462
Ward, L.M. 40 Wolf, G. 57
Warden, D. 128 Wolf, M.E. 487
Wardlaw, J.M. 62, 64 Wolf, S.M. 5, 6, 98
Warren, S. 115 Wolfe, S.M. 558
Wassermann, E.M. 536 Wollmer, M.A. 205
Waters, E.A. 561 Wolpaw, E.W. 123, 139
Watson, B.O. 26 Wolpaw, J.R. 123, 125, 127, 131, 139
Watson, S. 431 Wolpe, P. 115, 389
Watt-​Watson, J. 201 Wong, A.M. 18
Wearable Technologies  81 Woo, C.C. 434
Wegener, J.R. 404 Woodward, T.S. 19, 21
Wegner, D. 389, 395, 399, 480 Woolford, A. 459
Weijer, C. 189 Woopen, C. 134, 250
Weiner, B. 576 World Health Organization 94, 377, 477, 556
Weinstein, E.J. 204 World Medical Association  371, 373
Weir, R.F. 160 Wright, A.D. 16
Weiss, K.M. 596 Wright, M.S. 610
Weisskopf, M.G. 428 Wright, R. 429
Weithorn, L.A. 160 Wu, H. 250
Weldeselassie, Y. 38 Wu, X. 187
Wellcome Trust  64 Wurzman, R. 548
Wenar, L. 172
Westin, C.F. 38 Xie, J. 480, 484
Wheatley, B. 460 Xu, Z. 501
Wheatley, M.A. 460
Wheeler, M.A. 149 Yagiela, J.A. 209
White, A.M. 435, 547 Yamanaka, S. 5
White House  534 Yamin, A.E. 594
White, P.E. 520 Yang, C.I. 19, 165
White, S.E. 547 Yang, Q. 214
White, V. 506 Yang, Y. 165
Whitman, J.C. 37 Yaqub, B.A. 341
Whittle, A.J. 149 Yarborough, M. 378
Wibral, M. 28 Yazzie, R. 458
Wichmann, T. 146 Ybarra, M.L. 75
 631

Author Index 631

Ye, A.X. 26 Zeidman, L.A. 596

Yoshinaga-​Itano, C. 30 Zhai, J. 19
Young, P.A. 283 Zhang, R.R. 220, 221
Young, P.H. 283 Zhao, J.Q. 5
Young, T.K. 458 Zheng, Y.L. 81
Youngner, S.J. 347, 356 Zhou, J. 290
Ystby, Y. 289 Zimmerman, M.A. 405
Zinko, C. 81
Zalesky, A. 24, 37 Zola-​Morgan, S. 282
Zamboni, P. 267, 268 Zubieta, J.K. 223
Zealley, L.A. 57 Zulman, D.M. 558
632
 63

Subject Index

Note: “b”, “f ” and “t” indicate box, figure, and table

ablative microsurgical procedures see neurosurgery, preclinical Alzheimer’s disease diagnosis  294–​304
ablative microsurgical procedures preventive clinical trials  301–​3
addiction self-​assessments  562
animal models of  483, 498–​9 see also dementia, demented patients
high rates of recovery  501 amblyopia
concept, describing other compulsive event-​related, parametric fMRI  18–​19
behaviors  578–​80 localizing neuropathology  18–​19
drugs Americans with Disabilities Act (ADA)  577
abnormal dopamine signal  485 amphetamines, enhancement therapy  535
advantage over natural rewards  485–​6 amyloid-​related imaging abnormalities
dependency and  578–​9 (ARIAs) 302
individual differences in liability and risk of amyloidosis
drug use  480–​2 antiamyloid drugs  300, 302
gambling, neurobiology claimed/​adopted in legal beta-​amyloid protein  22, 295–​8
context  579, 580–​2 clinical trials, monoclonal antibodies  295
impaired agency  491–​2 analytic framework sharing  8–​11, 10t
medical model see brain disease model of anorexia nervosa
addiction (BDMA) ablative procedures  243
moral model  477, 489, 490, 491, 492, 509 deep brain stimulation (DBS)  242
nicotine  582–​5 anterior limb of the internal capsule (ALIC)  242
persistence of relapse risk  487–​8 antiamyloid drugs  300, 302
public views of addiction, stigma, and antiviral drugs, compassionate access  266
discrimination  503–​4 Apple, Health Kit 81
punishment and  490, 492 arsenic intoxication  428
scientific model  477–​93 arterial spin labeling, estimates of cerebral blood flow
implications for moral responsibility and legal rates 16
culpability  490–​1 attention deficit hyperactivity disorder  167
implications for understanding placebo therapy  226–​7
behavior  488–​90 attribution theory  576, 578
see also brain disease model of addiction (BDMA) auditory brain stem implants, speech
adolescents recognition 127
consent issues  73 auditory brainstem response (ABR)  30–​1
social media, cyberbullying  70–​9 auditory event-​related potentials  30–​2
vulnerability and homelessness  70–​9 auditory steady-​state response (ASSR)  30–​1
advance directives  258 AugCog (augmented cognition)  537
aging, advice in a digital world  558 autism, gut dysfunction  397
air and water pollution  430 autism spectrum disorders and social media  73–​4
Albertan tar sands projects  458, see also First autonomy
Nations Canada constrained parental autonomy  170
alpha-​synuclein, Parkinson’s disease  23 deception of placebo therapy  225–​7
alpha-​theta-​gamma (ATG) switch, thalamocortical definition 407
processing 41 demented patients  284–​9
Alzheimer’s disease ethics of deep brain stimulation (DBS)  250
antiamyloid drugs and amyloid-​related imaging extended mind hypothesis (EMH)  112–​15, 124
abnormalities 300, 302 free moral agency and  392
case study  275 free will  169
competing theoretical perspectives  275–​6 microbiome research and  398
costs of care, US  144 notes  291–​2
genetic risk  302 personality-​changing interventions  251
hippocampal function  289–​91 standard model  399
634

634 Subject Index

beamforming perfusion measurement techniques  16

multiple constrained minimum-​variance  33–​7f signal processing advances  35–​7
source leakage  36 see also magnetic resonance imaging
traditional LCMV (single-​source)  34f, 35f BRAIN Initiative® (US National Institutes of
behavior Health)  144–​56
behavioral addictions  579–​80 ethical issues  150–​4
behavioral genetics  574 history  146–​8
brain-​based research on free moral agency scientific focus  148t
and  388–​410 brain injury in children
compulsive behaviors, concept of addiction to acute phase  182–​3
describe 578 advanced neuroimaging techniques  187–​9
voluntary control of, addiction and  477–​97 ethical issues  189–​90
beta-​amyloid protein  22–​3, 295–​8 neuroprognostication  180–​96
see also amyloidosis European Resuscitation Council algorithm  183
bias future directions  190–​2
explicit/​implicit  395–​6 key questions from parents  183b
government biases  446 resuscitation phase  181–​2
publication bias  240–​1 subacute phase  184–​5
Biological and Toxin and Weapons Convention BRAIN Multi-​Council Working Group
(BTWC) 535 (MCWG) 152
biomarkers brain networks
disclosure 301 connectivity analyses  35
ethical debate  296–​300 localization of specific functions  19
prostate-​specific antigen, test dilemma  301 magnetoencephalography /​
Bits of Freedom, metadata  116 electroencephalography (MEG/​EEG) analyses
brain, computers and see brain–​computer interface of brain signals  24–​37
(BCI) medicine number of neurons  144
Brain Canada  147 organization of brain networks  19
brain death personality and  214
definitions, flawed definition, reversible lesion  237
elimination  314–​15, 358 reward circuitry  482–​4, 487, 498–​9f
definitions and diagnostic criteria  306–​8t, 344–​56 spatial and temporal replication  21–​2
circulatory criterion of death  353–​6 topological network analysis  19–​20
common definitions  350 tractography 16
criterion of death  351–​2 water diffusion  16
paradigm  346–​9 brain-​based research on free moral
factors stimulating acceptance  338–​44 agency  388–​410
future consensus  356–​8 brain–​computer interface (BCI) medicine  123–​43
history  336–​7, 358 adverse effects on cognition  130
religious exemptions for declaring  341–​2 affect and  128
vs coma  311, 313, 314–​17 biocompatibility and durability  129–​30
brain disease model of addiction (BDMA) 497–​514 clinical ethics  124–​30
assessment of evidence  498–​501 communication 126
genetic factors  499–​500 consciousness and cognitive processes  127–​30
effectiveness of public health policies vs individual consent  128–​30
treatments 506 near-​term horizon  124–​6
escaped volitional control  477, 480 neuromodulation  132–​3
ethical implications  498–​9 sensation 127
failure to develop new effective treatments  507 as enabling technology  137–​8
has model of addiction delivered  502–​4 motor impairment  125–​6
impact of brain disease explanations on addicted military research  536
individuals  505–​7 privacy and security  131–​2
more modest version of model  501–​3 progressive cognitive impairment  129–​30
most widely used medical treatments  503–​4 research  123–​4, 128
neural plasticity relevance  508 safety 129
neuroimaging studies  499 unrealistic expectations  131
policy consequences of neuromedicalization of brain–​gut microbiota interactions  396–​8
addiction  506–​7 brain–​machine interface (BMI)  139
reframing neurobiological accounts  507–​9 Braingate system  125
rejection of  501, 509 Brodmann areas  36
brain imaging Criminal Code, criminal responsibility and  572
 635

Subject Index 635

Canadian College of Medical Genetics (CCMG), cognitive motor dissociation  603, 604

Professional and Ethical Guidelines apparent 609
(incompetent adults)  381, 382f prosthetics 604
Canadian Prospective Urban Rural Epidemiological coma  185, 308–​9
(PURE) study  55 vs brain death  311, 313, 314–​17
capacity communication see science communication
interactive capacity  328–​9 community engagement see public participation in
task-​related capacity, children and incompetent science
adults 384 compassionate access, antiviral drugs  266
to value  276–​8 competence see incompetent adults
case registries  256 compulsion  479–​81
cerebral blood flow rates, arterial spin labeling  16 medicalization of deviance and  479
cerebrospinal venous insufficiency see chronic compulsive behaviors, concept of addiction to
cerebrospinal venous insufficiency (CCSVI) describe 578
research concussion in sport  515–​30
chemical shift saturation transfer  16 challenges in diagnosis  516–​18
Charter of Rights and Freedoms, Canada  577 long-​term effects  516–​20
Chemical Weapons Convention (CWC)  535 chronic traumatic encephalopathy
child/​childhood  159–​79, 180–​96 (CTE)  517–​20
adolescents, social media, cyberbullying  70–​9 neuropsychological test devices, conflicts of
bioethics issues  159–​79 interest  524–​5
best interests standard (BIS)  169–​70 prevalence 515
core issues  168–​9 professional sporting bodies  518–​27
neuroimaging in at-​risk populations  164–​6 conflicts of interest  524–​7
rights for self-​determination and ethical obligations and alternative
decision-​making  168–​71 position  518–​20
biomedical research, minors and incompetent conformity, functional and structural imaging and  394
adults  369–​85 conscious awareness  321
consent, assent and dissent  375–​6 consciousness, definitions of, interactive
incidental findings  376–​7 capacity  328–​9
inclusion in research  373, 374t consciousness, disorders of  185b, 305–​35
brain injury  180–​96 civil rights and  312–​13
case study  181, 182, 184 clinical assessment  186
developmental issues in identity and definitions and diagnostic criteria  305–​10
self-​determination  163–​5 using diagnostic criteria as a legal fiction  324–​6
maltreatment, learning disabilities  432–​3 epistemological continuity between  322–​3
neurocognitive potential, altering  164 importance of discrete distinctions  313–​15
neuroprognostication, brain injury  180–​96 incorporating values  331–​3
open future  161–​3 lack, withholding food/​fluid  187
competing models  169 minimally conscious state  310–​11
concept  161–​3 natural history of brain recovery  185
environmental pollutants and toxins  166–​8, 175 ontological continuity between  319–​20
pragmatic interventions  175–​6 problematization of diagnostic boundaries  323–​4
resource allocation  174 significance of diagnostic categories  310–​12
social justice for, capabilities of  172–​4 unresponsive wakefulness syndrome  185
task-​specific capacities  384 consent issues
transparency of communication with  163–​4 adolescents 73
China, psychiatric neurosurgery  250 alternative model for neuromodulation,
chronic cerebrospinal venous insufficiency rehabilitation medicine  138–​9
(CCSVI)  265–​71 brain–​computer interface (BCI)
chronic traumatic encephalopathy (CTE)  517–​20 medicine  128–​30
sport-​linked  517–​20 inclusion of children in research  375–​6
climate change and global warming  431–​2 incompetent adults  380–​3
clinical ethics, and consent, brain–​computer control
interface (BCI) medicine  128–​9 attribution theory  576, 578
clinical neuroimaging, applications and diminished/​removed self-​control  572, 573, 581
challenges  30–​1 onset controllability and offset responsibility  576
closed-​loop medical devices with embedded artificial perceived, responsibility and social
intelligence 124 solidarity  576–​8
cognition, parity principle  109 of substance use  479
cognitive enhancement see enhancement control systems and their limitations  486–​7
63

636 Subject Index

Council of Europe Convention on Human Rights personal identity changes  252

and Biomedicine  373 quick onset of effect  254
Council for International Organizations of Medical reversibility 238
Sciences (CIOMS) reversible lesion  237
consent issues, research, minors  373 sham-​controlled trials  256
Guidelines for Health-​related Research Involving Defense Advanced Research Projects Agency
Humans 379t (DARPA)  533–​4, 537
vulnerable individuals  371t delirium 185
vulnerable individuals  371t, criterion of dementia, demented patients
vulnerability 383 autonomy  284–​9
creatine/​phosphocreatine pool  16 brain–​computer interface (BCI)
criminal offending, neurobiology claimed/​adopted in medicine  127, 127–​8
legal context  579 experiential interests vs critical interests  276–​9
criminal responsibility/​criminality  570 incompetent adults  377–​999
addictions 479, 489 onset age  303
diminished self-​control  572, 573 quality of three types of resources  558–​60
perceived control and  572 self-​assessments and  563
see also moral responsibility understanding values  279–​84
depression
data, privacy and confidentiality  562 ablative procedures  243
data sharing, Global Alliance for Genomics and brain–​computer interface (BCI) medicine  128
Health 385 electroconvulsive therapy  146
death, definitions and diagnostic treatment-​refractory major, deep brain
criteria  306–​8t, 344–​56 stimulation 242
debt and compulsive spending, neurobiology Diagnostic and Statistical Manual of Mental
claimed/​adopted in legal context  579 Disorders (DSM-​5)  477
deception behavioral addictions  579–​80
and placebo therapy  225–​7 definition of drug addiction  478
disclosure 226 dietary factors, brain and mental health  432, 434–​5
patient autonomy  225–​6 diffusion magnetic resonance imaging
physician belief  225–​7 (dMRI)  37–​40
see also placebo therapy diffusion tensor imaging (DTI)  16
decision-​making digital culture, cyberbullying  72–​9
conscious vs unconscious  484 digital literacy  72
contradiction by neurobiology  479–​80 direct-​to-​consumer advertising
control and implications for addiction  479–​80 (DTCA)  557–​8, 562
volitional acts  480 disability
Declaration of Helsinki, rights of the child  370, 375 Americans with Disabilities Act (ADA)  577
deep brain stimulation (DBS) attitudes to  576–​7
advantages  236, 253–​4 concept, used to describe compulsive
adverse effects  244–​5 behaviors 578
applications  237–​8 definition
brain–​computer interface (BCI) meaning and scope in law  570, 577–​9
research  123–​4, 128 political and economic significance  578
claims for  252 social assistance and protection  576–​7
closed-​loop  128 social construction  571
comparison of techniques  247–​8t disease as clinical problem(s)  416–​18
costs 238, 253 concept 416
efficacy, publication bias  240–​1 species-​typical functions and  417
ethical issues  237 see also enhancement
superiority questionable  252 dopamine
experimental use, psychiatric disorders  235–​6 abnormal signals from addictive drugs  485, 486
mapping circuits  606 Parkinson’s disease and  221
methodological and study heterogeneity  241–​4 regulation of plasticity in synapses  487
minimally conscious state  130, 185, 307, release
603, 609–​10 positron emission tomography/​magnetic
moral/​legal responsibility of patient  251 resonance imaging  23
as neuromodulatory technique  236 reward circuitry  482–​4, 487, 498–​9
in Parkinson’s disease  146 smoking 485
personality change and legal responsibility unavailability (conscious introspection)  484
following 251 dopamine agonists, placebo responses  220–​1
 637

Subject Index 637

drowning, long QT syndrome  184 protective/​health-​enabling environmental

drugs see addiction factors  433–​4
social support and  432–​3, 435
ecological affect, environmental change  461 ethical, legal, and social implications (ELSI)
electroconvulsive therapy (ECT)  249, 536 (of neurotechnology)  3
treatment-​resistant depression  128, 146 associated with Human Genome Project  6
electroencephalography (EEG) conflict between clinician and patient  133
brain injury cases  182, 187 debates and future challenges  54–​69
connectivity maps  35f regenerative medicine and  7
continuous EEG monitoring  84 European Clinical Trials Directive  370
diagnosis of epilepsy foci  27 event-​related potential (ERP)  30
dynamic EEG synchronization  29f evidence-​based medicine
functional and dynamic imaging  27–​8 chronic cerebrospinal venous insufficiency
independent component analysis (ICA)  27 experience  264–​73
limitations to be overcome  28 comparisons, psychiatric neurosurgery  256
neural basis of volition  394 extended mind hypothesis (EMH)  108–​23
with sonoelectric tomography  149 (cognitive) enhancement  118–​19
source mixing of signals  32–​3, 34f neuroethical issues  111–​13
spontaneous magnetoencephalography autonomy  112–​15, 124
synchrony 26 potential conflicts of interest  115
electromyography (EMG)  28 privacy of thought  115–​17
emerging technologies  3–​14 Otto and Inga  108–​9
ethical, legal, and social implications
(ELSI) 3 Facebook users, privacy-​seeking
multiple morally contested areas  4–​5 behavior 117
neuroimaging  15–​53 First Nations Canada  455–​76
shared analytic framework  8–​11, 10t Albertan tar sands projects  458
siloed research and analysis  6–​8 Alzheimer’s disease and  464
engineering model of medicine  135–​7 bridging ethical foundations  466–​9
division of labor  135 colonization, context of change  457–​9
fixing frame  136–​7 engaging in research of the brain  461–​3
moral responsibility, limitations  136–​7 environmental impacts on neurological
enhancement  411–​25 health  459–​61
clinical implications of enhancement  418–​19 ethics and neuroethics  464–​5
comparative table for the definition of fracking 458
enhancement  414–​15t hydro-​electric projects  470
ethical considerations  423–​5 mental illness  460
ideals 414t mercury contamination and  458, 459, 460, 462
anthropocentric ideal  415 mistrust (historical)  461–​2
clinical ideal  415t, 416, 418–​23 proper legal recognition  470
graphic representations  422–​3f study of the brain  462–​3
objective ideal  415, 418 terminology 470
posthuman agenda  418 way forward  470
therapy vs enhancement  412–​13, 418, 535 folk psychology  479
views Food and Drug Administration, humanitarian
additionality view  413 device exemption  256
beyond therapy view  413 football, codes/​rules  515
improvement view  413 fracking, First Nations people and  458
umbrella view  413 free moral agency  388–​410
environmental neuroethics  426–​54 behavioral and brain-​based research as
brain/​mental health risks  427–​33, 446–​7 empowerment  399–​400
burden of human illness, policy implications  437 conscious control of action vs unconscious
change, ecological affect  461 influence on action  395–​6
conceptual issues  443–​4 conscious volition vs free and determined
conflict of interest and bias  446–​7 volition 394
evidence  445–​6 contribution of behavioral and brain science to
future research  443–​7 understanding 400f
generational justice and social fallacies: assumption  1, objectivist,
responsibility  437–​9 essentialist, dualist metaphysics vs
methodologies  445–​6 intersubjectivist, nonessentialist, nondualist
principles and frameworks  439–​43 metaphysics 401–​3
638

638 Subject Index

free moral agency  (cont.) health insurance, discrimination based on genetic

fallacies: assumption  2, is–​ought fallacy vs information 153
fact–​value continuum 403–​5 Health Insurance Portability and Accountability Act
free will an illusion  395 (HIPPA) 563
key components  391f health technology, wearable and mobile  80–​107
obedience and  393 HeLa cell line  7
self-​determined action vs action determined by hippocampal function, Alzheimer’s
others  392–​4 disease  289, 289–​91
sense of self vs conglomerate of divergent homelessness, youth  76–​9
wills  396–​7 homeopathy, trust in  560, 561
shaping by group pressures  393 Human Fertilization and Embryology Authority
standard model of autonomy  399 (UK) 10
threats to  390–​8 Human Genome Project  6
see also moral responsibility human rights
functional magnetic resonance imaging instrumentality and  603–​8
(fMRI)  17–​21 legislation, drug and alcohol dependency/​
amblyopia  18–​19 addiction  578–​9
blood oxygenation level-​dependent (BOLD) patient empowerment and  594, 594–​5
contrast 17, 21 social justice and  437
constrained principal component analysis towards an agenda  608–​9
(fMRI-​CPCA)  19–​21 humanitarian device exemptions (FDA)  256
detecting lying and deception  145 humanities, instrumentality  607
event-​related fMRI analyses  17, 18 hypnosis  197–​213
hemodynamic response (HDR) shape  20–​1 lay hypnosis  208
injury outcome prediction  187 procedure hypnosis  207–​9
repetition suppression/​fMRI adaptation  18 self-​hypnosis  201, 204, 205
task-​based fMRI signal reliability and shaping experience at onset of interaction  205–​7
validity  20–​2 see also pain management
hypothalamic–​pituitary–​adrenal axis (HPA), stress
gambling addiction  580 response and  397
neurobiology claimed/​adopted in legal
context  579–​82 immunomodulatory therapies, tradeoffs  135
Gamma Knife® radiosurgery  239–​40, 243, 253–​6 impulse control disorders (Nevada)  582
adverse effects  245 incidental findings (IFs) on neuroimaging  6, 54–​69
minimal invasiveness  255 children included in research  376–​7
numbers 252 clinically significant IFs  57–​8
generational justice, and social responsibility  437–​8 defined 54
Genetic Information Nondiscrimination Act disclosure of medically actionable, re-​contact  383
(GINA)  153, 155, 563 future importance  65
genetic risk impact  61–​3
Alzheimer’s disease  302 prevalence of IFs  59–​60
brain disease model of addiction (BDMA)  499–​500 public expectations  63–​5
behavioral genetics  574–​6 scale of problem  55–​63
German Association for Psychiatry, Psychotherapy large projects  55
and Psychosomatics, obsessive–​compulsive service use and cost of follow-​up  61–​2
disorder (OCD) and  253 types of IFs  56–​7
German National Cohort  55 incompetent adults  377–​87
Global Alliance for Genomics and Health, data consent, assent, and dissent  380–​3
sharing 385 ethical intersectionality, results and incidental
global mental health  591–​600 findings in Canada  381–​2
10:90 research gap 591 inclusion in research  378–​83
disease and wellness  593–​4 industrial chemicals and pesticides  429–​31, 446
human diversity and neurodiversity  596 information, obligation of clinician, engineering
human rights and patient empowerment  594 model  134–​7
naturalist and empirical approach  592–​3 Institute of Medicine and National Research
government biases  446 Council 5
institutional care  609
Harvard Medical School, definition of brain institutional review boards (IRBs)  75, 77–​8
death 324, 358 instrumentality and human rights  603–​8
headline-​driven science, reducing research interactive capacity  328–​9
authority 560 International Classification of Diseases (ICD-​10)   477
 639

Subject Index 639

Internet information, tagging of Internet-​connected MacArthur Competence Assessment Tool for

algorithmic 117 Treatment 130
Internet sex addiction  585–​7 magnetic resonance imaging
is–​ought fallacy vs fact–​value continuum, free moral assessment of changes in tissue structure in
agency  403–​5 neurodegenerative diseases  16
basis 15
Jewish law  359 with carbon-​13 nuclei 17
costs caused by patient anxiety  209
law diffusion (dMRI)  37–​40
perceptions of control and responsibility, evolving into a quantitative tool  15
disability 570 fMRI, intrinsic neurophysiological amplitude
see also legal cases network correlations  24–​5
lead intoxication  428 functional (fMRI)  17–​21
legal cases magnetic resonance spectroscopy, brain
American Civil Liberties Union v. James Clapper metabolites 16
(2013) 116 phase information  16
Interior Health Authority (South Similkameen positron emission tomography (PET/​MRI)  22–​4
Health Centre) v. Hospital Employee’s Union quantification of tissue properties  15–​17
(2013) 586 sodium imaging  17
Kellogg Canada Inc v. Bakery, Confectionary, structural (sMRI)  15–​17
Tobacco Workers & Grain Millers (2006)  578 magnetic resonance-​guided focused ultrasound
McKelvey v. Turnage (1988)  478 (MRgFUS)  236, 237, 240–​2
McNeill v. Ontario Ministry of the Solicitor adverse effects  246
General and Correctional Services comparison of techniques  247–​8t
(1998) 582 contraindications 246
Manitoba Government and General Employees’ obsessive-​compulsive disorder (OCD)  243
Union v. Manitoba (2013)  585 reduction of anxiety and depression  244
Manitoba v. Manitoba Government and General magnetoencephalography (MEG) imaging  24
Employees’ Union (2005)  581 default mode network (DMN)  25
Milazzo v. Autocar Connaisseur Inc. (2003)  579 injury outcome prediction  187
Nix v. Hedden (1895)  325 magnetoencephalography/​
Ontario v. Tranchemontagne (2009)  579 electroencephalography (MEG/​EEG)
R. v. Ample Annie’s Itty Bitty Roadhouse analyses of brain signals  27–​37
(2001) 583 quantitative translational
R. v. Belcourt (2010)  573 magnetoencephalography (MEG)  26–​7
R. v. Horvath (1997)  580 spontaneous phase synchrony  25–​6
R. v. H.T. (2010)  585 Mandela, on freedom  388
R. v. Obed (2006)  573 manganese intoxication  429
R. v. Smith (2015)  580, 581 Manhattan Engineer District (Manhattan
Seneca College v. Ontario Public Service Project) 533
Employees Union (2002)  586 media
Traynor v. Turnage (1988)  478 conflicts of interest  557
Winkfield v. Rosen (2015)  359 direct-​to-​consumer advertising
Yellowknife (City) v. Denny (2004)  583 (DTCA)  557–​8, 562
legal fiction, using diagnostic criteria as  324–​5 pressure, compassionate access to antiviral
legally authorized representatives drugs 266
(LARs)  378–​80 public participation in science  265–​6
lesbian, gay, bisexual, and transgender (LGBT), youth self-​assessments  561–​3
and social media  74–​5 websites  560–​1
life-​saving treatment (LST), withdrawal medicalization
decisions 315, 327 addiction concept, describes other compulsive
life/​death distinction see brain death behaviors 578
locked-​in syndrome  185, 609 of deviance in society  479, 572
long QT syndrome  184 mental impairment, clinical ideal  419–​23
long-​term depression (LTD)  487 mercury contamination  428–​9
long-​term potentiation (LTP)  487 First Nations people  458
Lothian Birth Cohort  59 mereology 360
low-​and middle-​income countries (LMICs), global microbiome, research, existence of self and  397–​8
mental health  591–​2 microsurgical ablative procedures see ablative
lumbar spine, magnetic resonance imaging microsurgical procedures
examinations 56 military, professional ethics  545–​6
640

640 Subject Index

mind performance enhancement/​therapy  535–​9

as blend between brain and algorithm  111 representative international research
defined  109–​10 programs  540–​4t
lying and deception  145 tensions between goals of science and
minimally conscious state (MCS)  187–​8, security  531–​2
307, 310–​13 neonatal care, improvement in intensive care
behavioral criteria  329 techniques  165–​6
fMRI  187–​8 neuroimaging
misdiagnosis 186 advanced neuroimaging techniques,
vs vegetative state  311–​13, 317–​19, 321–​2, 324, children  187–​90
327, 603, 609 emerging technologies  15–​53
minors and incompetent adults  369–​87 neurological disorders
moral responsibility 12% of deaths globally 556
definition of disability and  570–​90 degenerative disease  274–​93
engineering model of medicine  135–​7 amyloid and tau  295
perceived control  576–​8 capacity to value  276–​8
scientific model of addiction  490–​1 psychiatric conditions, marginalization and
self-​control  571 discrimination 608
see also criminal responsibility/​criminality; free neurological, mental health, and substance abuse
moral agency (NMS) disorders  144
multiple constrained minimum-​variance (MCMV) neuromodulation
beamforming  33–​7, 34–​5f defined 132
source mixing  32–​7 engineering model of medicine  134–​7
multiple sclerosis (MS), CCSVI experience  267–​71 role of the clinician  133
multiple-​comparisons problem, and approaches neuroprognostication
(statistics) 37 advanced neuroimaging techniques  187–​90
myelin water imaging  16 severe brain injury in children  180–​96
neuroprosthetics, communication and  610
N-​acetylaspartate  16 neurosurgery, ablative microsurgical
naloxone, inhibition of placebo-​induced procedures  236–​52
analgesia 223 adverse effects  245
National Child Development Study (UK)  63–​4 comparison of techniques  247–​8t
National Commission for the Protection of Human efficacy  242–​4
Subjects of Biomedical and Behavioral publication bias and  240–​1
Research 607 ethical issues  252
National Environmental Policy Act (NEPA)  438 history 238
National Institute on Alcohol Abuse and Alcoholism, see also psychiatric neurosurgery
prioritization of brain disease model of neurotechnologies
addiction (BDMA) treatment over public emerging  3–​14
health policy  506–​7 global mental health and  591–​613
National Institute on Drug Abuse (NIDA), brain as heuristic  610
disease model of addiction (BDMA) and invasive  152–​3
funding  497–​514 neuroethics instrumentality of the humanities  607
National Institutes of Health neuroethics of  603–​5
BRAIN Initiative®  144–​56 research and development see also BRAIN
overemphasis on the brain disease model of Initiative®
addiction (BDMA)  506 targeting brain circuitry  145–​6
National Research Council  533 see also technologies of the extended
review of ethical, legal, and social implications mind (TEMs)
(ELSI) 547 neurotoxicants and neurotoxic agents  428–​33
national security  531–​53 nicotine addiction  582–​5
criteria for development and use of specific Northwestern University’s Center for Behavior
neurotechnology 547 Intervention Technologies (CBITs)  77
devices  535–​6 Nuremberg Code  370
dual-​use research of concern (DURC)  532
ethical issues in historical context  537–​40 obedience, Milgram’s classical experiment  393
ethical, legal, and social issues (ELSI)  534, 547 obsessive-​compulsive disorder (OCD)
ethics of power  546 ablative procedures  238–​43
telic approach  545 anterior capsulotomy  239, 244, 253
neurocognitive science, current and future comparisons of treatment  254
use  538–​40 deep brain stimulation (DBS)  237, 242
 641

Subject Index 641

Food and Drug Administration humanitarian as an ethical way forward  227–​9

device exemption  256 as an evolved endogenous healthcare system  224
Gamma Knife® radiosurgery  243, 252 deception and  225–​7
magnetic resonance-​guided focused disease with established biochemical
ultrasound 243, 246 pathways  223–​5
pathogenesis 235 history  215–​16
quick onset of treatment effect  254 mechanisms  219–​23
targets for treatment  238–​9 opiate release and  223
Office of Technology Assessment  9 potential gains in research  228–​9
Ontario, Human Rights Code  577–​8 prejudicial terminology  218–​19
opiate antagonists, long-​acting  489 reward pathways  224
opiates, addiction (Civil War)  535 subjective experience and  229
opioid crisis/​epidemic  203, 208–​9, 488 placebome 225
organ transplantation  324, 339 pollution, air and water  430
dead donor rule’  311, 326–​7 polycyclic aromatic hydrocarbons (PAH)  166–​7
failed 163 American Medical Association (AMA)
rapid death determination  354 professional values  216–​17
Health Resources & Services Administration in practice  216–​17
Division of Transplantation  359 pornography, Internet sex addiction  585–​7
see also brain death positron emission tomography (PET/​MRI)
Orphan Drug Act (1983)  606 imaging  22–​4
18
F-​fluorodeoxyglucose  23
pain/​pain management preclinical detection of Alzheimer’s disease  294–​304
advanced rapport skills  205–​6 President’s Commission for the Study of Ethical
beneficence/​nonmaleficence equation  199–​200 Problems in Medicine Biomedical Behavioral
drug amounts and  201–​2 Research 7
eliciting deleterious behaviors in care President’s Council on Bioethics  315, 320, 538
providers 201 privacy
experience and expectation  199, 202, 204–​5 and confidentiality, wearable and mobile health
healthcare provider-​induced  198 technology  88–​90
hypnotic or imagery-​focused techniques  204 health insurance discrimination, information
inflicting  200–​1 sources 153
language  206–​7 privacy of thought
negative suggestions and  198 extended mind hypothesis (EMH)  115–​18
procedure hypnosis  207–​8 online privacy  115–​16
societal influence  203 prostate-​specific antigen, test dilemma  301
parens patriae doctrine  370 prosthetics
parity principle  109 brain–​machine interface (BMI) for neural
parkinsonism interfaces 139
arsenic and  429, 448 brain–​computer interface (BCI) medicine  125–​6
dementia and  517 cognitive motor dissociation  604
Parkinson’s disease limbs
deep brain stimulation (DBS)  126, 130, 132, 133, control 125, 537
146, 235, 252 handshakes and  137
diet and  435 stroke-​related motor prostheses  127
dopamine and  221 voice and  610
Gamma Knife® radiosurgery  239 psychiatric neurosurgery  235–​63
magnetoencephalography (MEG)  23, 26 ablative procedures  236–​7
pesticides 429 comparison of the different techniques  246–​7t
placebo pathway  221, 223–​4 efficacy, publication bias  241
Pasteur, Louis, vaccination  555 ethical, legal, and social context  249, 252
Pediatric Imaging, Neurocognition, and Genetics ethical issues  236–​7, 252–​3
(PING) Study  167–​8, 167–​9 evidence-​based comparisons  256
personal identity, recognition  171 law enforcement and social control  251
personality-​changing interventions  251 recommendations  255–​8
personalized diagnostics, prognosis, targeted psychopathy, neurobiology vs genetics  574
intervention, and ethical challenges  15–​53 psychotherapies
pesticides  429–​31 evidence-​based and values-​based approaches  592
physician belief, placebo therapy, deception  225–​7 low-​and middle-​income countries (LMICs)  592
Pillow Angel case  420–​1 Public Attitudes to Science, Ipsos Mori poll  555
placebo therapy  214–​34 public engagement activity, bad for career  555
642

642 Subject Index

Public Health Agency of Canada, First Nations cyberbullying  70–​9

people 457 dementia and  558–​60
public health policies ethical, legal, and social context of psychiatric
prioritization of brain disease model of addiction neurosurgery 250
(BDMA) treatment over  506–​7 headline-​driven science reducing research
value re smoking  506, 509, 558 authority 560
views of addiction, stigma, and discrimination  503–​4 new 71
public participation in science  265–​6 promoting autonomy and empowerment in health
success stories  266–​7 decision-​making  557
publication bias, efficacy of psychiatric social support  432–​3, 435
neurosurgery 241 sociocognitive phenotypes  18
sonoelectric tomography  149
quantitative susceptibility mapping (QSM)  16 speech recognition, auditory brain stem
implants 127
radiofrequency ablation procedures  252 spontaneous network phase synchrony  26
radiosurgery spontaneous neuromagnetic phase locking  25–​6
comparison of techniques  247–​8t static encephalopathy  420–​1
see also Gamma Knife® radiosurgery statistics, multiple-​comparisons problem and
Recombinant DNA Advisory Committee  7 approaches 37
reference class  416–​17 Stockholm Declaration on the Human
regenerative medicine  5 Environment 438
ethical, legal, and social implications (ELSI) and  7 stress response, hypothalamic–​pituitary–​adrenal axis
rehabilitation medicine (HPA) 397
alternative model of consent for stroke
neuromodulation  138–​9 brain–​computer interface (BCI) medicine  127
enabling technology  137–​8 European Co-​operative Acute Stroke Study trial  60
reward circuitry structural magnetic resonance imaging see magnetic
dopamine release  482–​4, 487, 499 resonance imaging
placebo therapy  224
roborat (DARPA)  537 tau aggregation  22–​3
robotics, brain–​computer interface (BCI) tau tracers  23
medicine  125–​6 technologies of the extended mind
Roman Catholic bioethics institute  359 (TEMs)  108, 109–​11
Royal Society, on public engagement activity  555 (cognitive) enhancement  118–​19
global positioning system (GPS) as  110–​11
Sagan Effect  555 intrusions upon privacy of thought  115–​18
science communication  554–​69 new framework for neuroethics  118–​20
headline-​driven, reducing research authority  560 tagging of Internet-​connected algorithmic devices
pre-​Internet vs digital era modes  565t as TEMs  117–​18
progress  563–​4 thalamocortical processing, neurophysiological
science literacy in general population and  556 frameworks  40–​1
security see national security theft, caused by gambling addiction  581–​2
self-​assessments thermal ablation see magnetic resonance-​guided
online 561 focused ultrasound (MRgFUS)
predatory marketing strategy  563 thermocoagulation 252
self-​control see control Three City Study (France)  55
sex addiction (Internet-​based)  585–​7 topological network analysis  19–​20
sleep, rapid eye movement (REM)  333 transcranial electrical stimulation (TES)  536
smart technology see wearable and mobile health transcranial magnetic stimulation (TMS)  127, 536
technology traumatic brain injury (TBI)  149
smoking Turing test  328
autonomy and  162 twin studies  165–​7
control 478 developing brain structure and cognitive
genetic loci associated  482 processing  165–​6
nicotine addiction  582–​4
value of public health policies  506, 509, 558 UK Biobank  55, 62
social influences ultrasound, sonoelectric tomography  149
conformity and  394 Ulysses contracts  258
explicit/​implicit bias and  395–​6 UN Convention on the Rights of the Child  370, 375
social justice, human rights and  437 UN Convention on the Rights of Persons with
social media Disabilities  370, 381, 577
 643

Subject Index 643

UN Office of the High Commissioner  374t vulnerability, youth, and homelessness  70–​9
UN Principles for Older Persons  380t
UN Second World Assembly on Ageing  380t water pollution  430
UNESCO Declaration on Bioethics and Human wearable and mobile health technology  80–​107
Rights 372t, 378 authentic living  98–​100
unresponsive wakefulness syndrome  185 case study: mental health apps  92–​7
urban pollution  430 classifications  82–​7
US Department of Health & Human Services  5 consent  90–​1
US National Institute on Drug Abuse (NIDA)  497 democratization of healthcare  91–​2
US National Institutes of Health BRAIN see BRAIN ethical considerations  87–​92
Initiative® (US National Institutes of Health) examples 81
functionalities  84–​6
vaccination, Pasteur, Louis and  555 privacy and confidentiality  88–​90
value purposes  82–​3
capacity to  276–​8 usage profiles  86–​7
understanding values  279–​84 see also brain–​computer interface (BCI) medicine
vegetative state (unresponsive wakefulness westernized, educated, industrialized, rich, and
syndrome)  185, 309–​10 democratic (WEIRD) populations  596
vestibular schwannomas (aka acoustic neuromas)  31 white coat trance  204
volitional control  392, 491, 495 whole genome sequencing  4–​5
brain–​computer interface (BCI) medicine wholism 333
and 126 World Medical Association (WMA), vulnerable
conscious vs free and determined  394, 401, 405 individuals, research  371t, 373
escaped 477, 480 worried well  593
minimally conscious state (MCS) and  318
neural basis  394 youth homelessness  76–​9
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