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Neurological, neuropsychiatric, and substance use disorders cause substantial suffering, underscoring the critical need to develop better tools to diagnose and treat them (Greely et al., 2018). One promising area of research involves neural devices, which can be used to record and/or stimulate brain function. To develop and advance neural devices, human studies are needed. These studies are only possible because research participants generously participate. To protect the interests of research participants, trials with neural devices must be conducted ethically. Although there is general guidance on conducting clinical research ethically as well as regulations governing clinical research, recent advantages in neurotechnologies have presented challenges that require further ethical guidance (Goering & Yuste, 2016). 

The NIH BRAIN Initiative is a major funder of research involving new or expanded use of invasive and non-invasive neural devices. Bringing together NIH bioethics and neuroethics groups, as well as neuroscience researchers, clinicians, and ethicists from all over the world, the NIH is supporting an effort to address the ethical challenges associated with these advances. In a recent paper in  JAMA Neurology,  the authors interpret and specify existing ethical frameworks to provide points to consider on challenges related to the analysis of risk, informed consent, and post-trial responsibilities to research participants of neural device studies (Hendriks et al., 2019).  

Analysis of Risk 

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Almost all studies with invasive or non-invasive neural devices pose some risks to research participants. To assess the ethics of each proposed neural device study, determining the type and extent of these risks is fundamental (DHEW, 1979). Neural device research may include risks from at least six sources: risks related to surgery, hardware, stimulation, the nature of research, privacy and security, and financial burdens. These risks are not just relevant to invasive, but also to non-invasive devices (except surgical risks and complications from implanted hardware). As compared to other types of devices (e.g. a prosthetic joint), some of the risks may have special meaning because of the brain’s relation to, for example, mental states and identity. Indeed, neural stimulation may involve so-called ‘atypical’ risks: effects on personality, mood, behavior, and perceptions of identity, authenticity, privacy, and agency (Klein et al., 2016; Schupbach et al., 2006). These ‘atypical’ risks are complex, in that they can be experienced as harmful, beneficial, or even be an explicit goal of treatment. 

For a study to be ethical, the risks to participants should be balanced against therapeutic benefits for participants and the study’s social value. Acceptable levels of risks may be context-dependent, for example, more protections are appropriate for certain vulnerable groups (e.g. children or adults with impaired consent capacity). There is a need for more guidance on acceptable levels of risk of interventions without prospects of therapeutic benefit. For example, how long can neurosurgery for a clinical indication be prolonged to conduct intracranial recordings done purely for research purposes? 

Informed Consent 

Obtaining informed consent entails disclosing relevant information to a decisionally capable person who makes a voluntary decision to enroll in the study (Berg, Appelbaum, Lidz, & Parker, 2001). While informed consent is important to protect and respect research participants (DHEW, 1979), there are still practical and theoretical challenges in obtaining informed consent. Some of these challenges are exacerbated in neural device research – two of these will be highlighted here.  

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As in other types of trials, participants in neural device trials must be informed about, among others, ‘reasonably foreseeable’ risks and benefits. One of the challenges in neural device research is that it may involve ‘atypical’ risks (e.g. personality changes). Determining what and how to disclose information about atypical risks is complicated, because individual preferences and values can influence how participants or their families might perceive certain changes. For example, whereas neural stimulation is perceived by some participants as enhancing their authenticity and sense of

empowerment, other participants perceive it as undermining their authenticity or level of control (Gilbert, O’Brien, & Cook, 2018; Klein et al., 2016). In navigating these challenges, researchers may draw on experience from a multidisciplinary team and experience with disclosing similar types of side effects from neuropharmacological therapies (e.g. dopamine agonists).   

Similar to many other types of research, potential neural device research participants may experience certain pressures to participate. For example, in neural device studies, potential research participants may already have a clinical relationship with the neurosurgeon who is also the investigator. In these cases, patients may find it difficult to decline to participate in research. Furthermore, the limited number of effective treatment options for many nervous system disorders may lead patients to perceive research as their only option. It is still a matter of debate in research ethics when such pressures undermine voluntariness (Appelbaum, Lidz, & Klitzman, 2009; Roberts, 2002). Researchers and institutional review boards (IRBs) should be sensitive to concerns about potential pressures on patients and may, for example, underline that research participation is a choice, or offer potential participants the opportunity to discuss the study with another person than the clinician with whom they have an existing relationship.  

Post-trial responsibilities 

After a trial ends, research participants for whom the neural device was effective may benefit from continued access to the device and related care. For example, patients with implanted devices may need long-term maintenance (e.g. battery replacement) or device removal. Lacking access to post-trial care may expose former research participants to risks. However, invasive device trials do not always cover the costs of, for example, device removal or replacing a depleted battery after the trial ends. Some funders lack mechanisms for supporting post-trial care and health insurance plans may deny coverage for investigational devices. There are no definitive ethical or regulatory frameworks, or even standard practices, regarding the extent of post-trial responsibilities for neural devices (Lázaro-Muñoz, Yoshor, Beauchamp, Goodman, & McGuire, 2018).  

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Various arguments support the existence of limited post-trial responsibilities, including considerations related to justice, participants’ interests, respect for persons, and the relationship between researchers and participants. Before a trial starts, researchers, device manufacturers, and funders should consider the needs (linked to study participation) that participants may have after the trial. Furthermore, they should take reasonable steps to facilitate continued access to neural devices that benefit participants.

Participants should be informed about their potential post-trial needs and whether and how these will be provided for. Researchers, device manufacturers, and funders may have further post-trial responsibilities. The extent of these post-trial responsibilities depends on, for example, the financial and opportunity costs of providing care, the risks and benefits for participants, and the vulnerability of participants. Post-trial responsibilities are determined on a case-by-case basis and likely to be more extensive for invasive devices. Continued efforts to clarify researcher and funder post-trial responsibilities in neural device research are needed. 

We hope that the considerations above, described in more detail in the JAMA Neurology paper, are helpful for investigators and others involved in human research with neural devices. We encourage researchers, IRBs, and funders to continue to reflect on the ethical challenges of neural devices and to embrace neuroethics as a way to enhance rigorous science.  

This work and the paper built on a workshop in October 2017. You can watch the workshop here. The workshop was organized by the NIH Clinical Center Department of Bioethics in association with the Neuroethics Working Group of the NIH BRAIN Initiative. 

Disclaimer: The views expressed are the authors’ own and do not reflect those of the National Institutes of Health, the Department of Health and Human Services, or the United States government. 

References

1. Appelbaum, P. S., Lidz, C. W., & Klitzman, R. (2009). Voluntariness of consent to research: a preliminary empirical investigation. Irb, 31(6), 10-14.  
2. Berg, J. W., Appelbaum, P. S., Lidz, C. W., & Parker, L. S. (2001). Informed Consent: Legal Theory and Clinical Practice. 
3. DHEW. (1979). The Belmont Report. Ethical Principles and Guidelines for the Protection of Human Subjects of Research. The National Commission for the Protection of Human Subjects of Biomedical Behavioral Research. Retrieved from https://videocast.nih.gov/pdf/ohrp_appendix_belmont_report_vol_2.pdf 
4. Gilbert, F., O’Brien, T., & Cook, M. (2018). The Effects of Closed-Loop Brain Implants on Autonomy and Deliberation: What are the Risks of Being Kept in the Loop? Camb Q Healthc Ethics, 27(2), 316-325. doi:10.1017/s0963180117000640 
5. Goering, S., & Yuste, R. (2016). On the Necessity of Ethical Guidelines for Novel Neurotechnologies. Cell, 167(4), 882-885. doi:10.1016/j.cell.2016.10.029 
6. Greely, H. T., Grady, C., Ramos, K. M., Chiong, W., Eberwine, J., Farahany, N. A., . . . Serrano, E. E. (2018). Neuroethics Guiding Principles for the NIH BRAIN Initiative. The Journal of Neuroscience, 38(50), 10586-10588.  
7. Hendriks, S., Grady, C., Ramos, K. M., Chiong, W., Fins, J. J., Ford, P., . . . Wexler, A. (2019). Ethical Challenges of Risk, Informed Consent, and Posttrial Responsibilities in Human Research With Neural Devices: A Review. JAMA Neurol. doi:10.1001/jamaneurol.2019.3523 
8. Klein, E., Goering, S., Gagne, J., Shea, C. V., Franklin, R., Zorowitz, S., . . . Widge, A. S. (2016). Brain-computer interface-based control of closed-loop brain stimulation: attitudes and ethical considerations. Brain-Computer Interfaces, 3(3), 140-148. doi:10.1080/2326263X.2016.1207497 
9. Lázaro-Muñoz, G., Yoshor, D., Beauchamp, M. S., Goodman, W. K., & McGuire, A. L. (2018). Continued access to investigational brain implants. Nat Rev Neurosci, 19(6), 317-318. doi:10.1038/s41583-018-0004-5 
10. Roberts, L. W. (2002). Informed Consent and the Capacity for Voluntarism. 159(5), 705-712. doi:10.1176/appi.ajp.159.5.705 
11. Schupbach, M., Gargiulo, M., Welter, M. L., Mallet, L., Behar, C., Houeto, J. L., . . . Agid, Y. (2006). Neurosurgery in Parkinson disease: a distressed mind in a repaired body? Neurology, 66(12), 1811-1816. doi:10.1212/01.wnl.0000234880.51322.16 

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