Ethical Commitments, Principles, and Practices Guiding Intracranial Neuroscientific Research in Humans

Ethical Commitments, Principles, and Practices Guiding

Intracranial Neuroscientific Research in Humans

Ashley Feinsinger

1,15

Nader Pouratian

2,15,16

Hamasa Ebadi

Ralph Adolphs

3,4

Richard

Andersen

Michael S. Beauchamp

Edward F Chang

Nathan E. Crone

Jennifer

L. Collinger

Itzhak Fried

Adam Mamelak

Mark Richardson

Ueli Rutishauser

Sameer A. Sheth

Nanthia Suthana

9,13

Nitin Tandon

Daniel Yoshor

NIH Research

Opportunities in Humans Consortium

Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California,

90095, USA

Department of Neurological Surgery, UT Southwestern Medical Center, Dallas, Texas, 75390,

USA

Departments of Psychology and Neuroscience, California Institute of Technology, Pasadena,

California, 91125 USA

Department of Biology, California Institute of Technology, Pasadena, California, 91125, USA

Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania,

Philadelphia, Pennsylvania, 19104, USA

Department of Neurosurgery, UC San Francisco, San Francisco, California, 94143, USA

Department of Neurology, Johns Hopkins University, Baltimore, Maryland, 21287, USA, 15260,

USA

Department of Physical Medicine and Rehabilitation, University of Pittsburgh, Pittsburgh,

Pennsylvania, 15260, USA

Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles,

California, 90095, USA

Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, California, 90048 USA

Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School,

Boston, Massachusetts, 02114, USA

Corresponding Author and Lead Contact:

Nader Pouratian, MD PhD, Department of Neurological Surgery, UT Southwestern

Medical Center, 8353 Harry Hines Blvd MC8855, Dallas, Texas, 75390, (214) 648-9320, Nader.pouratian@utsouthwestern.edu.

Author Contributions

A.F. and N.P. led discussions, abstracted principles, and drafted, edited, and finalized the manuscript. H.E. documented discussions

and edited the manuscript. All other authors significantly contributed to content and perspectives and edited the manuscript.

Declaration of Interests

SS is a consultant for Boston Scientific, Neuropace, and ZimmerBiomet. NP is a consultant for Abbott Laboratories. NT is a surgical

committee member for the Medtronic SLATE trial.

Publisher's Disclaimer:

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our

customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review

of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered

which could affect the content, and all legal disclaimers that apply to the journal pertain.

HHS Public Access

Author manuscript

Neuron

. Author manuscript; available in PMC 2023 January 19.

Published in final edited form as:

Neuron

. 2022 January 19; 110(2): 188–194. doi:10.1016/j.neuron.2021.11.011.

Author Manuscript

Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, 77030 USA

Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at

UCLA, Los Angeles, California, 90095, USA

Department of Neurosurgery, University of Texas Houston, Houston, Texas, 77030, USA

Equal Contribution

Lead Contact and Corresponding Author

Summary

Leveraging firsthand experience, BRAIN-funded investigators conducting intracranial human

neuroscience research propose two fundamental ethical commitments: (1) maintaining the

integrity of clinical care and (2) ensuring voluntariness. Principles, practices, and uncertainties

related to these commitments are offered for future investigation.

eTOC blurb

Investigators conducting intracranial neuroscientific research have real-world experience

considering neuroethical challenges. Here, a consortium of investigators offer two overriding

ethical commitments: 1.Maintain the integrity of clinical care and 2.Ensure the voluntariness of

participation. Guiding ethical principles and practical examples of implementation, including areas

of disagreement and future directions, are highlighted.

Keywords

Neuroethics; Ethics; Intracranial Research; Human Neuroscience; Human Neurophysiology;

Investigators

Several neurosurgical interventions require intracranial electrodes for either diagnostic or

therapeutic purposes, providing unique opportunities to conduct basic intracranial human

neuroscience research (henceforth referred to as intracranial research). This research has

significantly advanced our understanding of human brain function across multiple domains,

including language, sensorimotor function, memory, and emotional and affective processing

(

Collinger

et al

., 2014

;

Kirkby

et al

., 2018

;

Mosher

et al

., 2021

). Notably, intracranial

research is not intended to provide near-term therapeutic benefit to participants or other

patients. While invasive human research is not unique to neurosurgery, the lack of

therapeutic benefit, the vulnerability of patient populations with neurological or psychiatric

diagnoses, the rarity of access to intracranial data, and the common occurrence of clinician-

investigators necessitate ethical scrutiny. However, to date, non-therapeutic intracranial

research has garnered little ethical discussion (

Chiong

et al

., 2018

;

Hendriks

et al

., 2019

;

Mergenthaler

et al

., 2021

Two recent publications are of immediate relevance (

Hendriks

et al.

, 2019

Chiong

al.

, 2018

). Hendriks

et al

. discuss ethical frameworks for neural device research aimed at

developing novel clinical/therapeutic applications, which is distinct from the current focus.

Chiong

et al

. address ethical considerations for intracranial electrophysiology research but

Feinsinger et al.

Page 2

Neuron

. Author manuscript; available in PMC 2023 January 19.

Author Manuscript

acknowledge the need for broader input to capture variability across institutions. Using

Chiong

et al

. (2018)

as an initial point of discussion, investigators from the Research

Opportunities in Humans (ROH) Consortium, a group of more than 30 investigators funded

by the NIH BRAIN Initiative to conduct intracranial research, developed explicit ethical

commitments and areas of consensus related to intracranial research. We discuss these

commitments, the principles they give rise to, and the associated practices used across

settings, noting areas of uncertainty for future study. The goal for these contributions is

to offer a framework for critically evaluating and refining future practices in intracranial

research.

This work is the product of a series of discussions within the ROH consortium,

which includes clinician-scientists (neurosurgeons and neurologists) and neuroscientists.

Additionally, two NIH funded ethicists, who do not conduct intracranial research but

interview patients-participants, participated in guiding the discussions and drafting this

Neuroview. The common elements of ROH research are (i) the goal of scientific

understanding of human brain function, (ii) absence of near-term therapeutic intent, and (iii)

use of intracranial recordings and/or stimulation in human subjects requiring neurosurgical

intervention. In some cases, research involves utilizing data recorded from therapeutically

implanted devices, such as intracranial recordings during deep brain stimulator surgery

(

Mosher

et al.

, 2021

). In other cases, recordings are obtained from patients undergoing

clinically indicated surgeries with little or no modification of the clinical procedure, such as

intracranial monitoring for epilepsy (

Forseth

et al

., 2020

;

Kornblith

et al.

, 2017

). Finally, in

some instances, patients undergo a neurosurgical procedure as part of an investigational

device trial, such as implantation of a Utah array for brain computer interface (BCI)

investigations (

Collinger

et al.

, 2014

Ethical discussions of this research should integrate input from all stakeholders, including

patients, families, clinician-investigators, non-clinician investigators, non-investigator

clinicians (e.g., epileptologists), funding and regulatory agencies, ethicists, device

manufacturers, and society. Each group’s experiences provide insight into different

dimensions of the research. Without intending to privilege any one perspective, this report

offers the ethical views of investigators who conduct intracranial research and whose

perspectives are relatively under-represented in the literature. Investigators have substantial

first-hand experience (i) practically managing ethical considerations, (ii) driving research

from design to management, and (iii) interacting with other stakeholders. Because of these

experiences, they can provide insights into how ethical principles might be formulated to

best facilitate ethical practice across study contexts.

Ethical Commitments, Principles, and Practices

The ROH consortium offers the following two overarching ethical commitments as overt

affirmations of their obligations and as foundations of an approach to ethical intracranial

research:

Maintaining the integrity of clinical care and space.

Ensuring the voluntariness of participation in intracranial research.

Feinsinger et al.

Page 3

Neuron

. Author manuscript; available in PMC 2023 January 19.

Author Manuscript

These commitments, which align with the Belmont Report’s principles of Beneficence and

Respect for Persons, are further motivated by (i) the tension between exploiting a rare

clinical opportunity and protecting a vulnerable participant population and (ii) the potential

conflict created by the rewards, often in the form of grants, that drive this research. In the

authors’ view, the following principles and shared practices (as detailed in Table 1) are

essential for conducting ethical intracranial research.

Maintaining the Integrity of Clinical Care and Space

Prioritizing the integrity of clinical care—maintaining that care be guided by fundamental

clinical principles—requires practices to ensure that care is not compromised, purposefully

or inadvertently.

1. Clinical care and research should be uncoupled, such that care be neither

compromised by nor conditional on research participation, and this must be

communicated to patients.

The temporal and spatial relationship between clinical care and research may raise concerns

that care and research are interdependent, and that the decision to participate will influence

care. For example, conducting experiments in the operating room (OR) during deep brain

stimulator implantation or in the epilepsy monitoring unit (EMU) in patients undergoing

intracranial monitoring for seizures can make it difficult for patients to distinguish the

separability of the two efforts. We must not only assure patients that care is not conditional

on participation, but also that the care of those who participate is guided by principles of

best clinical practice. When clinical care is inherent to the research (such as implantation of

intracranial arrays for BCI), it is particularly important to ensure optimal clinical care as part

of the investigation.

Improving patient comprehension of the ways in which clinical care is distinct from research

may promote this goal. Protocols for doing so may depend on the relative spatial and

temporal correlation of clinical care and research, with closer correlations deserving explicit

attention. All investigators agreed that the informed consent language must explicitly state

that clinical care will not be compromised (regardless of participation).

Several programs separate clinical and research consents in time, space, and personnel,

including having a non-investigator clinician obtain clinical consent or having someone

other than the physician-investigator obtain research consent. Multiple centers have

independently arrived at an approach akin to the “hybrid model,” in which the clinician-

investigator introduces the research and risks but research consent and further discussion is

obtained by a non-clinician investigator (

Grady, 2019

). When the surgical procedure is done

for the purpose of research (e.g., implants for BCI research) (

Collinger

et al.

, 2014

), a more

complex multi-step process was described, including pre-consent discussions of procedures

with investigators, review of risks and benefits with the neurosurgeon, meetings with

neuropsychologists, and a formal consent process with an investigator. These approaches

do not preclude the clinician from being available to answer questions about risk, but still

create separation.

Feinsinger et al.

Page 4

Neuron

. Author manuscript; available in PMC 2023 January 19.

Author Manuscript

In some cases, the clinician-investigator may be best suited to explain risks and help patient-

participants understand the study in the context of the parent neurosurgical procedure.

Investigators noted that absence of the clinician-investigator in the consent process may

give the appearance of fragmentation between clinical and research teams. Moreover, in

some jurisdictions, a physician must administer consent for any device study with greater

than minimal risk. Ultimately, the approach to consent must be customized based on study

factors, local resources, infrastructure, and regulations; a uniform approach should not be

dictated, as long as the distinction between clinical care and research is explicit.

In addition to the written consent, some investigators suggest verbally conveying the

separation of clinical care and research, repeating this at multiple times, as a reminder

not only to patients, but also clinicians, investigators, and allied health professionals. Several

investigators verbally reconsent immediately prior to initiating research studies (e.g., in

the OR or EMU) to ensure that patient-participants understand their clinical care is not

contingent upon participation before beginning. This is important, as the patient-participant

may accumulate more information and opinions about their potential participation.

Additionally discussed but uncommonly used practices include reading out loud the parts

of consent relating to this critical notion, seeking a verbal affirmation, or requesting

a “teach back”. While others have discussed teach back (

Mergenthaler,

et al

., 2021

future work should focus on identifying study-specific considerations about teach back

(including whether the efficacy of teach back varies and what content should be “taught

back”) and include patient-participant input. A supplementary standardized video may be

helpful, providing a purposeful timeout, an independent voice to amplify the separation, and

communication to patient-participants that they are part of a larger research community.

2. While clinician-investigators have dual roles, their role as clinician should be placed

above their role as investigator, and this duality must be communicated to patients.

Patients sometimes express, “I trust my doctors and the research team”, “they’ve done so

much for me, I want to give back”, and “I will do anything to help my doctors”. These

suggest that the dual role of clinician-investigator can affect motivation for participation.

The need to provide the best clinical care for patients and the need to be scientifically

productive in response to federal funding initiatives creates a conflict. Explicit discussion

of these roles can emphasize that the clinician recognizes and prioritizes their role as the

treating physician.

Disclosure of this duality should at least appear in the written informed consent, and

many investigators also routinely include a verbal disclosure. One investigator noted,

“It lends credibility to the fact that physician-investigators are thinking about this and

trying to be principled about their role as a researcher and their role as a physician.”

This acknowledgement also reassures others not involved in the research that clinician-

investigators recognize the conflict and are committed to protecting the role as a clinician.

Wording may include explicit dissociation, such as “I am telling you about this as a

researcher, not as your doctor.”

Feinsinger et al.

Page 5

Neuron

. Author manuscript; available in PMC 2023 January 19.

Author Manuscript

While some have proposed that treating clinicians should not be investigators, the ROH

(clinicians and non-clinicians alike) proposed that such prohibition would thwart progress,

especially in some situations where the treating clinician is the most qualified person

to carry out the research and understand the risks and benefits. Furthermore, clinicians

have important relationships with patient populations, and prohibiting their participation in

research may adversely affect patient welfare.

3. Non-clinician members of the research team who interact with patient-participants

require instruction on bedside interactions with patients and on the surgical methods and

risks.

Health professionals receive explicit training on maintaining respect for the clinical

environment and patient communication. Non-clinician investigators may be responsible

for discussing research procedures with clinical dimensions with which they are not familiar,

and this introduces challenges for maintaining the integrity of clinical care. Non-clinician

investigators who are interacting with patient-participants or who are otherwise working in

clinical spaces should therefore receive formal training on conduct and communication in

the clinical environment.

Few teams had implemented formal training for non-clinicians. Current practices include

having non-clinician investigators observe clinical procedures and research studies

before interfacing with patient-participants. Investigators endorsed the potential value of

standardized training (such as standardized videos that are often used in the clinical setting)

on topics ranging from bedside interactions to relevant surgical and research methods. A

certification process was considered potentially valuable but requires further research.

4. The decision to use intracranial modalities in clinical care should not be influenced by

scientific considerations unless the scientific study itself is the reason for the intracranial

intervention.

The clinical decision about whether to use invasive methods should not be influenced by

scientific considerations unless the intervention itself is driven by research. Investigators

agree that it may be appropriate to modify the method (e.g., using modified electrodes with

microwires, higher density arrays, or additional electrodes) with detailed informed consent.

Other examples include temporary discontinuation of therapy (e.g., turning off a brain

stimulator to enable research studies) or consumption of clinical resources that can modify

clinical care (e.g., battery power or time in clinic or the OR). Critically, besides considering

interval risks, the ultimate therapeutic goals of the surgery cannot be compromised by

research-related modifications.

Several centers ensure that clinicians not involved in the conduct of research confirm

the clinical need for intracranial interventions. For example, neurologists not involved

in research convene to determine the clinical need for surgery. However, depending on

the center and program, all treating clinicians may be involved in the research program.

Alternative strategies include encouraging participants to discuss the study with other

physicians and involving a Data Safety Monitoring Board (DSMB), which includes

Feinsinger et al.

Page 6

Neuron

. Author manuscript; available in PMC 2023 January 19.

Author Manuscript

physicians who are not invested in the research goals and are charged with guarding the

participants’ interests.

Ensuring the Voluntariness of Participation in Intracranial Neuroscientific

Studies

Some of the practices above (e.g., assurance of care and research uncoupling, discussion

of dual roles) are also motivated by a concern for patient misunderstanding and undue

influence. These concerns are particularly relevant in this potentially vulnerable population.

The remaining ethical principles and practices are intended to supplement those above to

further promote voluntariness.

5. Informed consent procedures should be specifically designed to account for the

potential for neurological injury, the high rate of clinician-investigators, and patient

population vulnerabilities.

Given the surgical context in which these studies are carried out, targeted consent practices

are essential for promoting voluntariness of participation. As previously detailed, practices

for consenting include having both a written and verbal consent (and reconsent) and

employing “hybrid consents.” Many investigators also value providing an opportunity to

involve family in the consenting process, to the extent that participants desire it, and giving

participants a robust opportunity to discuss participation with non-investigator clinicians.

Given the complexities of these studies, consent may require significantly more time.

In contrast to study and site-specific communications, standardized videos could provide

an external voice on portions of the consent process, including the goals of the research,

patient rights to withdraw, and the community involved in the research. Training videos are

ubiquitous in medical care to ensure familiarity with and understanding of a broad range

of topics, from financial conflicts of interest to personal protective equipment usage. It is

important that standardized videos should not be used instead of personal discussions and

that their value is verified, as done in other clinical areas (

Christensen

et al.

, 2020

). Limited

resources were seen as the primary barrier to developing such videos.

6. Consenting to research may require different cognitive and decision-making capacities

than consenting for care, and consent protocols may need to reflect this.

Consenting to clinically indicated surgery is rooted in a personal neurological or psychiatric

concern, while consenting to participate in non-therapeutic research may require additional

levels of abstraction. The latter requires understanding the purpose and benefits of the

study, neither of which are rooted in the individual’s condition, and which involve notions

(e.g., societal benefit) that patients may not fully understand. The cognitive impairments

often seen in patient-participants with Parkinson disease or epilepsy may differentially

affect clinical vs. research consent capacity, and these patient population vulnerabilities

may inadvertently lead to misunderstandings. No investigators reported using tools to

separately assess capacity for research consent, but suggested practices include asking

patient-participants to specifically express understanding of research-related risks and goals.

Future work, including engagement with patient-participants, might better determine which

Feinsinger et al.

Page 7

Neuron

. Author manuscript; available in PMC 2023 January 19.

Author Manuscript

study features are most critical and how to assess abilities to comprehend those study

features (e.g., benefits to society despite the lack of direct benefit).

7. Patients have the right to refuse or stop participation in research at any time and

should be reminded of this right at appropriate intervals in meaningful ways.

Study participants have the right to refuse participation over any time frame and in any

setting, whether before initial consent or at any time after consenting to participation.

This right is often explicitly detailed in the written informed consent and research participant

bill of rights. Some expressed interest in standardized language that could be used

across studies, but also acknowledged that institutional review boards may enforce certain

local requirements that supersede this desire. Other practices include explicitly offering

participants multiple opportunities to voluntarily withdraw, on a timescale relevant to the

study, whether during regular intervals during a 20–30 minute intraoperative experiment or

daily during an EMU stay. BCI studies often include multiple checkpoints over periods of

weeks prior to the neurosurgical procedure, and for longer studies, some investigators have

included informal and formal reconsent. Reconsenting or withdrawing opportunities may

be particularly important for patient-participants in multi-day EMU stays, as their medical

and psychiatric status can change quickly. Non-investigator clinician guidance is critical

for understanding the continued appropriateness of participation of patient-participants in

research. Further research is needed, in close concert with patient input, on the most

effective ways to provide study-specific opportunities to withdraw.

Such opportunities may require different approaches, as simply repeating the right to

withdraw may be insufficient. Understanding how patients can be made to feel comfortable

withdrawing is crucial, particularly during research in the OR, where the context is unique

and may add additional factors to their decision-making.

Promoting the right to withdraw also requires perceptiveness about hesitation or

postponements. Postponements may be an indirect way of withdrawing, overshadowed

by concerns of disappointing the clinic or research team, or they may be a sign that

patients have unanswered questions and concerns. Investigators found value in having both

clinician and non-clinician investigators engage in these discussions with patients, since

patients may worry about disappointing clinicians but also more readily express clinical

concerns to them. Practices for managing repeated postponements include asking permission

to re-approach the patient for participation at a later time, offering an open-ended discussion

about concerns, and offering patients an explicit opportunity to withdraw.

III. Conclusions and Future Directions

This Neuroview proposes an initial ethical framework for intracranial research from the

perspectives of investigators. It aims to supplement other perspectives and provide practical

implementations for discussion. Crucially, the framework acknowledges the need for study-

specific practices as well as patient-participant input.

Feinsinger et al.

Page 8

Neuron

. Author manuscript; available in PMC 2023 January 19.

Author Manuscript

The focus on investigator perspectives is purposeful, in part because investigators must

take responsibility for the ethical conduct of their research. This report is not inclusive

of all investigator viewpoints nor exhaustive of neuroethical issues. Notably, the author-

investigators are all NIH-funded US-based investigators, and future work should consider

comparative perspectives across geographies. Further work should also include expanded

input of non-investigator clinicians that care for these patient populations longitudinally

(e.g., psychiatry, epileptology), and most critically, involve patients themselves. Looking

forward, we hope to encourage collaboration between investigators and ethicists across

multiple topics, including post-trial obligations, data-sharing, and the overall value of

intracranial research.

Acknowledgements

The authors gratefully acknowledge the support of NIH BRAIN Initiative program officers and staff who organized

the Research Opportunities in Humans (ROH) Consortium, including Karen David, Jim Gnadt, and Khara Ramos.

We also acknowledge the contributions of other ROH Consortium members who contributed perspectives to the

manuscript. Finally, we acknowledge the patients who have participated in relevant studies that have helped form

the experiences and perspectives included in the current report.

All investigators were supported by BRAIN Initiative and NIH funding, including U01 NS098961 (AF, NP),

R01 MH121373 (AF, NP), U01 NS118739 (UR, AM), U01 NS117765 (EC), U01 NS103082 (NS), U01

NS117838 (NS), R01 MH110831 (AM), P50 MH094258 (Radolphs, AM), U01 NS103780 (RAdolphs), U01

NS113339 (MSB), R01 NS065395 (MSB), U01 NS108922 (JC), U01 NS123125 (JC), U01 NS108930 (IF), R01

NS084017 (IF), U01 NS123127 (Randersen), U01 NS121472 (SS), U01 NS108923 (SS), R01 NS110424 (MR),

U01 NS117836 (MR), U01 NS098969 (MR), R01 NS115929 (NEC), UH3 NS114439 (NEC), U01 DC016696

(NEC), and U01 NS117836 (NEC), U01 NS098981 (NT, NEC). Additional support provided by NSF 1756473

(IF) and California Institute for Regenerative Medicine (CLIN2–12319, AM). SS received funding from McNair

Foundation. RAdolphs received funding from Simons Foundation Collaboration on the Global Brain. NS received

funding from the McKnight Foundation.

References

Chiong W, Leonard MK, and Chang EF (2018). Neurosurgical Patients as Human Research Subjects:

Ethical Considerations in Intracranial Electrophysiology Research. Neurosurgery 83, 29–37.

10.1093/neuros/nyx361. [PubMed: 28973530]

Christensen L, Rasmussen CS, Benfield T, and Franc JM (2020). A Randomized Trial of Instructor-

Led Training Versus Video Lesson in Training Health Care Providers in Proper Donning and

Doffing of Personal Protective Equipment. Disaster Med Public Health Prep 14, 514–520. 10.1017/

dmp.2020.56. [PubMed: 32223776]

Collinger JL, Kryger MA, Barbara R, Betler T, Bowsher K, Brown EH, Clanton ST, Degenhart AD,

Foldes ST, Gaunt RA, et al. (2014). Collaborative approach in the development of high-performance

brain-computer interfaces for a neuroprosthetic arm: translation from animal models to human

control. Clin Transl Sci 7, 52–59. 10.1111/cts.12086. [PubMed: 24528900]

Forseth KJ, Hickok G, Rollo PS, and Tandon N. (2020). Language prediction mechanisms in human

auditory cortex. Nat Commun 11, 5240. 10.1038/s41467-020-19010-6. [PubMed: 33067457]

Grady C. (2019). A Hybrid Approach to Obtaining Research Consent. Am J Bioeth 19, 28–30.

10.1080/15265161.2019.1574493.

Hendriks S., Grady C., Ramos KM., Chiong W., Fins JJ., Ford P., Goering S., Greely HT., Hutchison

K., Kelly ML., et al. . (2019). Ethical Challenges of Risk, Informed Consent, and Posttrial

Responsibilities in Human Research With Neural Devices: A Review. JAMA Neurol. 10.1001/

jamaneurol.2019.3523.

Kirkby LA, Luongo FJ, Lee MB, Nahum M, Van Vleet TM, Rao VR, Dawes HE, Chang EF, and Sohal

VS (2018). An Amygdala-Hippocampus Subnetwork that Encodes Variation in Human Mood. Cell

175, 1688–1700 e1614. 10.1016/j.cell.2018.10.005.

Feinsinger et al.

Page 9

Neuron

. Author manuscript; available in PMC 2023 January 19.

Author Manuscript

Kornblith S, Quian Quiroga R, Koch C, Fried I, and Mormann F. (2017). Persistent SingleNeuron

Activity during Working Memory in the Human Medial Temporal Lobe. Curr Biol 27, 1026–1032.

10.1016/j.cub.2017.02.013. [PubMed: 28318972]

Mergenthaler JV, Chiong W, Dohan D, Feler J, Lechner CR, Starr PA, and Arias JJ (2021). A

Qualitative Analysis of Ethical Perspectives on Recruitment and Consent for Human Intracranial

Electrophysiology Studies. AJOB Neurosci 12, 57–67. 10.1080/21507740.2020.1866098. [PubMed:

33528320]

Mosher CP, Mamelak AN, Malekmohammadi M, Pouratian N, and Rutishauser U. (2021). Distinct

roles of dorsal and ventral subthalamic neurons in action selection and cancellation. Neuron 109,

869–881 e866. 10.1016/j.neuron.2020.12.025.

Feinsinger et al.

Page 10

Neuron

. Author manuscript; available in PMC 2023 January 19.

Author Manuscript

Highlights

•

Intracranial neuroscience research in humans raises unique neuroethical

issues.

•

Neuroethical commitments and practices of investigators are poorly

characterized.

•

Commitments include protecting the clinical space and ensuring

voluntariness.

•

BRAIN-funded investigators provide guiding neuroethical principles and

practical examples.

Feinsinger et al.

Page 11

Neuron

. Author manuscript; available in PMC 2023 January 19.

Author Manuscript

Feinsinger et al.

Page 12

Table 1.

Ethical Commitments, Principles, and Practices for Basic Neuroscientific Intracranial Research

Commitment

Principles

Example Practices

Maintaining the

integrity of clinical care

and space

1. Clinical care and research should be

uncoupled, such that care be neither

compromised by nor conditional on research

participation, and this must be communicated

to patients.

Current

1. Separate clinical and research consents in time, space, and

personnel

2. Multiple staged meetings to discuss research participation with

both clinicians and non-clinicians.

Proposed

1. Seek verbal confirmation and understanding of separation

described in consent

2. Standardized videos to provide a consistent external voice

describing the separation

2. While clinician-investigators have dual

roles, their role as clinician should be placed

above their role as investigator, and this

duality must be communicated to patients.

Current

1. Include explicit statements of this dual role (and conflict) in

the written informed consent

2. Verbally disclose conflict during study recruitment

3. Non-clinician members of the research

team who interact with patient-participants

require instruction on bedside interactions

with patients and on the surgical methods and

risks.

Proposed

1. Non-clinician investigators attend clinical procedures and

research studies before interfacing with patient-participants.

2. Require standardized training courses or videos on bedside

interactions and surgical and research methods.

4. The decision to use intracranial modalities

in clinical care should not be influenced by

scientific considerations unless the scientific

study itself is the reason for the intracranial

intervention.

Current

1. Clinicians not involved in the research convene via

multidisciplinary conference to determine need for intracranial

monitoring.

2. Encourage participants to discuss study with non-research

related physicians they see regularly

Ensuring the

voluntariness

of participation

in intracranial

neuroscientific studies

5. Informed consent procedures should be

specifically designed to account for the

potential for neurological injury, the high

rate of clinician-investigators, and patient

population vulnerabilities.

Current

1. Include disclosures in both verbal and written consent.

2. “Hybrid consent” process to address conflict of

clinicianinvestigators.

3. Inclusion of family and caregivers in consent process when

appropriate.

Proposed

1. Standardized videos with external perspectives on basic study

information to supplement other discussions.

6. Consenting to research may require

different cognitive and decision-making

capacities than consenting for care, and

consent protocols may need to reflect this.

Proposed

1. Additional intellectual capacity or cognitive assessments

2. Seek explicit confirmation of understanding of goals and risks

of study

7. Patients have the right to refuse or

stop participation in research at any time

and should be reminded of this right at

appropriate intervals in meaningful ways.

Current

1. Offer multiple opportunities to withdraw, at regular intervals

according to the design of the study

2. Include multiple check points for consent over period of weeks

prior to surgical procedure

Proposed

1. Seek acknowledgement of right to withdraw as part of “teach

back”

2. Provide multiple opportunities to discuss concerns with

clinical and non-clinical team, in addition to explicit withdraw

opportunities.

Neuron

. Author manuscript; available in PMC 2023 January 19.