The NEW ENGLA ND JOURNAL of MEDICINE

Perspective June 20, 2024

Fundamental s of Medic al E thic s

Ethics and Highly Innovative Research on Brain Diseases

Ethics and Innovative Research on Brain Diseases

Saskia Hendriks, M.D., Ph.D., and Christine Grady, M.S.N., Ph.D.​​

T
he human brain is the object of endless fas- covers that the device company declared
cination, given its centrality to identity and bankruptcy and the needed replacement
parts are no longer available. He is left
many core functions, including production with a defunct implant.
of thoughts, emotions, and actions. Patients may Ongoing clinical trials are test-
ing highly innovative brain im-
therefore attribute distinctive derived from it raise both familiar plants, with aims ranging from
meaning to brain diseases and in- and new ethical challenges. treating opioid addiction to restor-
terventions. The devastating toll A few specific hypothetical ing speech. Mr. P.’s case is, unfor-
of neurologic and psychiatric dis- cases based on existing innovative tunately, not unlike some that have
orders makes seeking knowledge brain research can help illustrate been reported.1 Given the risks
and developing interventions by these challenges. The first relates posed by brain surgery, trials in-
means of brain research an ethi- to post-trial care. volving brain implants typically
cal imperative. Deeper under- Mr. P., who was left quadriplegic enroll patients with severe, treat-
standing of the brain could also after an accident, joins a trial of a ment-resistant conditions. Unsur-
change our notions of what is brain–computer interface (BCI). Intra- prisingly, many participants who
uniquely human and of death, cortical microelectrode arrays are im- benefit want to keep the implant,
agency, responsibility, and other planted in his motor cortex, and percu- which is often the only interven-
concepts underlying fundamental taneous electrodes are inserted in his tion that has worked. For other
societal norms and laws. Our in- arm. The recorded neural activity is participants, explantation of the
creasing ability to record, under- decoded to command his paralyzed arm device would be too risky. But pa-
stand, and directly modify the by electrically stimulating his hand, tients with experimental implants
brain has led research to a new elbow, and shoulder muscles. After re- need ongoing care to maintain the
frontier, where calls are being ceiving 10 hours of training each week benefits, reduce side effects, or
made to protect the right to men- for a year, Mr. P. can cortically com- manage complications (such as
tal self-determination. Despite ex- mand his paralyzed arm. This ability bleeding) that may occur years
citing advances, conducting brain increases his independence, improving after the trial. Determining who
research and appropriately imple- his quality of life. Three years after the is responsible for post-trial care
menting interventions or insights trial, the BCI stops working. Mr. P. dis- requires balancing participants’ in-

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PERS PE C T IV E Ethics and Innovative Research on Brain Diseases

Selected Considerations and Responsibilities Related to Post-Trial Care after Brain-Implant Trials.*

Professionals or Organizations Considerations and Responsibilities

Research teams
Research institutions
Device manufacturers
Funders
Reviewers (IRBs, FDA)
Identify post-trial research-related risks, discomforts, and benefits by mapping out the patient
journey in reasonably foreseeable scenarios (e.g., whether the device is commercialized).
Identify continuing health care needs related to study participation.
Minimize research-related post-trial risks and enhance potential benefits when designing
the device, the study, and long-term care plans for former participants with implants.
Describe post-trial care needs and plans in protocols for review by the IRB, the funder, and
the FDA.
Ensure that the informed consent process adequately informs patients about what happens
after trials end (see “Reviewers” below for elements to be included).
Within reasonable limits, ensure that appropriate referrals are made or remain available to
provide necessary care that only the researchers can provide.
Consider contributing to critical unmet post-trial needs by waiving fees, providing financial
support within limits, or both.
Minimize research-related post-trial risks and enhance potential benefits when designing the
device, the study, and long-term care plans for former participants with implants.
If hardware or software is incompatible with commercially available options, make a reasonable
number of hardware replacements available (e.g., produce them up front) and provide soft-
ware updates for a reasonable time.
Consider contributing to critical unmet post-trial needs by providing financial support within
limits.
Establish industry standards to maximize compatibility where possible.
Request long-term plans and assess them.
Consider contributing to critical unmet post-trial needs by providing financial support within
limits.
Assess the adequacy of informed consent forms’ description of what happens after trials end,
including reasonably foreseeable post-trial risks, discomforts, and benefits, continuing medi-
cal care needs related to study participation, plans to provide or facilitate this care, and costs
resulting from having participated in the trial.
Include reasonably foreseeable research-related post-trial risks and benefits in the trial’s risk–
benefit analysis; ensure that these risks are also sufficiently minimized.

* Adapted from Hendriks et al.1 Research institutions, device manufacturers, and funders could consider operationalizing finan-
cial support for post-trial care by means of a specific insurance policy or a fund for research-related post-trial care, which may
have some advantages (e.g., spreading financial risk). FDA denotes Food and Drug Administration, and IRB institutional review
board.

terests with potential deterrent
effects on industry and the possi-
ble reduction of funds available
for developing new treatments.
Although post-trial care is a chal-
lenge with other types of implants
as well, investigators, funders,
research institutions, and device
manufacturers generally have more
post-trial responsibilities for brain
implants, given the interests of
patients with severe, treatment-
resistant conditions in keeping a
beneficial device, the high risks
involved in both maintaining and
removing the implant, and the
novelty of brain devices (e.g., in-
surers are less likely to cover them,
and hardware compatibility stan-
dards are not yet established).1
For most trial participants who
benefit from a brain implant and
lack treatment alternatives, it’s
inappropriate to require explanta-
tion when the trial ends. Investi-
gators, funders, research institu-
tions, and device manufacturers
should address key unmet post-
trial needs and ensure that in-
formed consent regarding post-
trial plans is adequate (see table).1
Proper planning may mitigate
potential negative effects on for-
mer research participants who are
are dependent on hardware or
services when companies fold or
stop supporting a device, or when
clinician-investigators become un-
available (because they retire or
change institutions, for example).
A second sample scenario fea-
tures the decoding of the human
brain.
Ms. T. is a healthy volunteer in a
study aiming to reconstruct language
from neural activity recorded using
functional magnetic resonance imag-
ing ( fMRI). While in the fMRI ma-
chine, Ms. T. listens to stories and
imagines telling stories. During one ex-
ercise, she imagines telling her husband
that she wants a divorce. At her next
visit, the researcher asks, “Is everything
OK with your marriage?”

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PE R S PE C T IV E
Although this case is hypotheti-
cal, researchers have used neu-
ral-network language models to
reconstruct continuous language
from cortical semantic representa-
tions recorded using fMRI.2 They
created intelligible word sequences
capturing the meaning of perceived
speech, imagined speech, and si-
lent videos — an advance with po-
tential restorative and augmentative
applications. Notably, this study
involved decoding an earlier stage
of language production than have
most previous efforts, which fo-
cused on the action stage (which
occurs in the motor cortex). The
new focus has potential clinical ad-
vantages (e.g., for Broca’s aphasia)
but probably also reduces patients’
control over what’s conveyed. Re-
searchers are exploring applica-
tion of the decoder with more lim-
ited subject-specific training data
(http://videocast​.­nih​.­gov/​­watch=​
­54090). If it becomes possible to
apply it on data collected for other
purposes (e.g., resting-state fMRI
data in public archives), there will
be privacy concerns.
Besides questions about con-
ducting studies ethically, research
that advances our ability to use
brain data (data recorded about
the structure, activity, or function
of the brain) to make sensitive
inferences about individuals and
groups (about thought patterns,
emotional states, and risk for cer-
tain diseases, for example) raises
ethical questions related to long-
term effects and potential mis-
use.3 Furthermore, many types of
brain data are unique to each per-
son (e.g., functional brain connec-
tivity) or allow reconstruction of
faces (e.g., MRI), which can be
matched to publicly available pic-
tures using facial recognition soft-
ware and arouse concerns about
reidentifiability.
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Ethics and Innovative Research on Brain Diseases
As the science advances, com-
mercial interest in neurotechnol-
ogies grows. Big Tech companies
such as Meta and Microsoft are
developing consumer neurotech-
nologies that may ultimately find
widespread use.3 Neurotechnolo-
gies may someday become the key
way that people interface with
their electronic devices. This pos-
sibility raises questions about what
future scientists, companies, and
governments could learn about
people from our brains, how that
information will be used, and
what the effects will be on indi-
viduals and communities.3 Psycho-
logical testing, digital traces, and
digital phenotyping already permit
some inferences about people’s
unspoken mental states, beliefs,
and mental health, but neurosci-
entific advances may significantly
increase what anyone with access
to brain data can infer about indi-
vidual people. And beyond pro-
viding or withholding initial con-
sent, people whose brain data
are collected may have little con-
trol over the breadth of infer-
ences that can be drawn about
them — which may have major
effects on people’s freedom, and
perhaps their authenticity (if con-
cerns about brain monitoring lead
people to adjust their thoughts
and behaviors). Some commenta-
tors have called mental privacy
“our last bastion of freedom.”3
The challenge is to promote
valuable neuroscience innovations
while minimizing risks. First, we
believe more legal protections
against harmful uses of brain data
(e.g., for discriminatory purposes)
are needed.3 Researchers should
consider using controlled-access
databases for sharing high-risk
brain data. Second, professional
societies can promote best prac-
tices in technology design to re-
nejm.org June 20, 2024
duce risks (e.g., storing only pro-
cessed, not raw, data) and best
practices in informed consent.
Third, the public should be in-
formed about potential benefits
and risks of sharing brain data so
they can make informed choices
when managing commercial neu-
rotechnologies.
Finally, current oversight struc-
tures are limited. Entities such as
institutional review boards and
the Food and Drug Administra-
tion review particular studies, but
not potential bigger-picture ef-
fects and implications of research.
Individual institutions often lack
the authority, expertise, or proce-
dures to consider technologies’
wider impact. The purview of the
Novel and Exceptional Technolo-
gy and Research Advisory Com-
mittee (NExTRAC) of the Nation-
al Institutes of Health is beyond
individual studies, but its scope
and authority are limited. To fill
this gap, an independent advisory
body could be created to consid-
er long-term effects of potential-
ly disruptive fields of research,
identify research directions and
types of research to be avoided
given their potential for misuse,
and make recommendations to
researchers, institutions, funders,
and regulators. Any resulting
boundaries or safeguards should
be grounded in science, incorpo-
rate public input, and align with
community values.
A third useful sample case can
be found in work on neural or-
ganoids.
Dr. M., a neuroscientist studying hu-
man neural organoids, is excited about
the fast pace of research in creating 3D
models of human brain tissues. Given
the lack of good options for studying
human brains, these models may revo-
lutionize the field’s understanding of
brain development, function, and dis-
2135
 PERS PE C T IV E
ease. Journalists, institutional officials,
and ethicists challenge Dr. M. to ad-
dress what should happen if evidence
of consciousness or sentience emerges in
organoids. Dr. M., like many neurosci-
entists, doubts that organoid conscious-
ness or sentience is likely to develop and
believes that even if it emerges, its level
would be comparable to that of insects
and therefore of limited moral relevance.
Derived from pluripotent stem
cells, brain organoids are collec-
tions of neural cells that can de-
velop in a manner similar to that
of fetal brains; assembloids are
combined organoids that have
formed interregional connections.
Despite limitations of size and
complexity, along with other scien-
tific challenges, neural organoids
can receive sensory inputs, send
functional outputs, and exhibit
synchronized electrical activity.
Work with brain assembloids, for
example, enabled researchers to
identify genes associated with
neurodevelopmental disorders that
inhibit cortical circuit develop-
ment, possibly ultimately facilitat-
ing therapeutic efforts.4
As organoids and assembloids
become more analogous to hu-
man brains,
An audio interview
with Christine Grady both their sci-
is available at NEJM.org entific poten-
tial and related ethical challenges
increase. If future organoids devel-
Sustaining and Scaling Up Street Medicine
Health Care beyond Clinic Walls — Sustaining and Scaling Up
Street Medicine
Michael Liu, M.Phil., Sahil Sandhu, M.Sc., Brett J. Feldman, M.S.P.A.S., P.A.-C., and David G. Munson, M.D.​​
R oughly 650,000 people expe-
rience homelessness at any
given time in the United States,
of whom approximately 40% are
unsheltered, according to a point-
2136
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Ethics and Innovative Research on Brain Diseases
oped morally relevant capacities
such as sentience or conscious-
ness, they would have to be man-
aged in new ways. Developing
methods to detect such capacities
is therefore important. In addition,
best practices for donors’ in-
formed consent for brain organoid
research should be defined, given
that preliminary studies suggest
that some donors have moral
qualms about such research and
want to be able to decide whether
to consent to specific future uses
of brain organoids derived from
their tissues.5 Organoid research
oversight is currently limited, and
the field must establish guidelines,
including checkpoints to help re-
searchers determine when a line
has been crossed or additional
oversight is needed. Periodic as-
sessment of research programs by
an independent advisory body may
also be appropriate.
Brain research has enormous
promise but raises ethical chal-
lenges that require more than sim-
ple regulatory compliance. Ethics
are inextricably interwoven with
science. Value-laden considerations,
which are plentiful in brain re-
search, influence decisions about
what research to support, how to
conduct it, and how to implement
its findings. Thoughtful incorpo-
ration of ethics can enhance the
in-time count conducted by the
Department of Housing and Ur-
ban Development during January
2023. The unsheltered homeless
population has reached its largest
n engl j med 390;23 nejm.org June 20, 2024
The New England Journal of Medicine
scientific value of brain research,
advance participants’ interests,
and help align the application of
findings with societal values.
The series editors are Bernard Lo, M.D.,
Debra Malina, Ph.D., Genevra Pittman,
M.P.H., and Stephen Morrissey, Ph.D.
The views expressed in this article are
those of the authors and do not represent
those of the National Institutes of Health,
the Department of Health and Human Ser-
vices, or the U.S. government.
Disclosure forms provided by the authors
are available at NEJM.org.
From the Department of Bioethics, Na-
tional Institutes of Health Clinical Center,
Bethesda, MD.
This article was published on June 15, 2024,
at NEJM.org.
1. Hendriks S, Hsu N, Beckel-Mitchener
AC, Ngai J, Grady C. Continuing trial re-
sponsibilities for implantable neural devic-
es. Neuron 2023;​111:​3143-9.
2. Tang J, LeBel A, Jain S, Huth AG. Seman-
tic reconstruction of continuous language
from non-invasive brain recordings. Nat
Neurosci 2023;​26:​858-66 .
3. Farahany NA. The battle for your brain:
defending the right to think freely in the age
of neurotechnology. New York:​St. Martin’s
Press, 2023.
4. Meng X, Yao D, Imaizumi K, et al. As-
sembloid CRISPR screens reveal impact of
disease genes in human neurodevelopment.
Nature 2023;​622:​359-66.
5. MacDuffie KE, Stein JL, Doherty D, et
al. Donor perspectives on informed con-
sent and use of biospecimens for brain or-
ganoid research. Stem Cell Reports 2023;​
18:​1389-93.
DOI: 10.1056/NEJMp2310377
Copyright © 2024 Massachusetts Medical Society.
Ethics and Innovative Research on Brain Diseases
size since national reporting be-
gan in 2007 (see graph). People
who are unsheltered lack safe
and stable housing, and many of
them reside in locations that are