Returning Individual Research Results from Digital Phenotyping in Psychiatry.

Psychiatry is rapidly adopting digital phenotyping and artificial intelligence/machine learning tools to study mental illness based on tracking participants' locations, online activity, phone and text message usage, heart rate, sleep, physical activity, and more. Existing ethical frameworks for return of individual research results (IRRs) are inadequate to guide researchers for when, if, and how to return this unprecedented number of potentially sensitive results about each participant's real-world behavior. To address this gap, we convened an interdisciplinary expert working group, supported by a National Institute of Mental Health grant. Building on established guidelines and the emerging norm of returning results in participant-centered research, we present a novel framework specific to the ethical, legal, and social implications of returning IRRs in digital phenotyping research. Our framework offers researchers, clinicians, and Institutional Review Boards (IRBs) urgently needed guidance, and the principles developed here in the context of psychiatry will be readily adaptable to other therapeutic areas.

An Ethics Checklist for Digital Health Research in Psychiatry: Viewpoint.

BACKGROUND: Psychiatry has long needed a better and more scalable way to capture the dynamics of behavior and its disturbances, quantitatively across multiple data channels, at high temporal resolution in real time. By combining 24/7 data-on location, movement, email and text communications, and social media-with brain scans, genetics, genomics, neuropsychological batteries, and clinical interviews, researchers will have an unprecedented amount of objective, individual-level data. Analyzing these data with ever-evolving artificial intelligence could one day include bringing interventions to patients where they are in the real world in a convenient, efficient, effective, and timely way. Yet, the road to this innovative future is fraught with ethical dilemmas as well as ethical, legal, and social implications (ELSI). OBJECTIVE: The goal of the Ethics Checklist is to promote careful design and execution of research. It is not meant to mandate particular research designs; indeed, at this early stage and without consensus guidance, there are a range of reasonable choices researchers may make. However, the checklist is meant to make those ethical choices explicit, and to require researchers to give reasons for their decisions related to ELSI issues. The Ethics Checklist is primarily focused on procedural safeguards, such as consulting with experts outside the research group and documenting standard operating procedures for clearly actionable data (eg, expressed suicidality) within written research protocols. METHODS: We explored the ELSI of digital health research in psychiatry, with a particular focus on what we label "deep phenotyping" psychiatric research, which combines the potential for virtually boundless data collection and increasingly sophisticated techniques to analyze those data. We convened an interdisciplinary expert stakeholder workshop in May 2020, and this checklist emerges out of that dialogue. RESULTS: Consistent with recent ELSI analyses, we find that existing ethical guidance and legal regulations are not sufficient for deep phenotyping research in psychiatry. At present, there are regulatory gaps, inconsistencies across research teams in ethics protocols, and a lack of consensus among institutional review boards on when and how deep phenotyping research should proceed. We thus developed a new instrument, an Ethics Checklist for Digital Health Research in Psychiatry ("the Ethics Checklist"). The Ethics Checklist is composed of 20 key questions, subdivided into 6 interrelated domains: (1) informed consent; (2) equity, diversity, and access; (3) privacy and partnerships; (4) regulation and law; (5) return of results; and (6) duty to warn and duty to report. CONCLUSIONS: Deep phenotyping research offers a vision for vastly more effective care for people with, or at risk for, psychiatric disease. The potential perils en route to realizing this vision are significant; however, and researchers must be willing to address the questions in the Ethics Checklist before embarking on each leg of the journey.

Emerging ethical issues raised by highly portable MRI research in remote and resource-limited international settings.

Smaller, more affordable, and more portable MRI brain scanners offer exciting opportunities to address unmet research needs and long-standing health inequities in remote and resource-limited international settings. Field-based neuroimaging research in low- and middle-income countries (LMICs) can improve local capacity to conduct both structural and functional neuroscience studies, expand knowledge of brain injury and neuropsychiatric and neurodevelopmental disorders, and ultimately improve the timeliness and quality of clinical diagnosis and treatment around the globe. Facilitating MRI research in remote settings can also diversify reference databases in neuroscience, improve understanding of brain development and degeneration across the lifespan in diverse populations, and help to create reliable measurements of infant and child development. These deeper understandings can lead to new strategies for collaborating with communities to mitigate and hopefully overcome challenges that negatively impact brain development and quality of life. Despite the potential importance of research using highly portable MRI in remote and resource-limited settings, there is little analysis of the attendant ethical, legal, and social issues (ELSI). To begin addressing this gap, this paper presents findings from the first phase of an envisioned multi-staged and iterative approach for creating ethical and legal guidance in a complex global landscape. Section 1 provides a brief introduction to the emerging technology for field-based MRI research. Section 2 presents our methodology for generating plausible use cases for MRI research in remote and resource-limited settings and identifying associated ELSI issues. Section 3 analyzes core ELSI issues in designing and conducting field-based MRI research in remote, resource-limited settings and offers recommendations. We argue that a guiding principle for field-based MRI research in these contexts should be including local communities and research participants throughout the research process in order to create sustained local value. Section 4 presents a recommended path for the next phase of work that could further adapt these use cases, address ethical and legal issues, and co-develop guidance in partnership with local communities.

Concise Review: Human-Animal Neurological Chimeras: Humanized Animals or Human Cells in an Animal?

Blastocyst complementation is an emerging methodology in which human stem cells are transferred into genetically engineered preimplantation animal embryos eventually giving rise to fully developed human tissues and organs within the animal host for use in regenerative medicine. The ethical issues surrounding this method have caused the National Institutes of Health to issue a moratorium on funding for blastocyst complementation citing the potential for human cells to substantially contribute to the brain of the chimeric animal. To address this concern, we performed an in-depth review of the neural transplantation literature to determine how the integration of human cells into the nonhuman neural circuitry has altered the behavior of the host. Despite reports of widespread integration of human cell transplants, our review of 150 transplantation studies found no evidence suggestive of humanization of the animal host, and we thus conclude that, at present, concerns over humanization should not prevent research on blastocyst complementation to continue. We suggest proceeding in a controlled and transparent manner, however, and include recommendations for future research with careful consideration for how human cells may contribute to the animal host nervous system. Stem Cells 2019;37:444-452.

Litigation risks despite guideline adherence for acute spinal cord injury: time is spine.

OBJECTIVE: Current guidelines do not specify timing for management of acute spinal cord injury (aSCI) due to lack of high-quality evidence supporting specific intervals for intervention. Randomized prospective trials may be unethical. Nonetheless, physicians have been sued for delays in diagnosis and intervention. METHODS: The authors reviewed both the medical literature supporting the guidelines and the legal cases reported in the Westlaw and Lexis Advance databases from 1972 to 2018 resulting in awards or settlements, to identify whether surgeons are vulnerable to litigation despite the existence of guidelines not mandating specific timing of care. RESULTS: Timing of intervention was related to claims in 59 (36%) of 163 cases involving SCI. All 22 trauma cases identified cited timing of intervention, sometimes related to delayed diagnosis, as a reason for the lawsuit. The mean award of 10 cases in which the plaintiffs' awards were disclosed was $4,294,384. In the majority of cases, award amounts were not disclosed. CONCLUSIONS: Because conduct of a prospective, randomized trial to investigate surgical timing of intervention for aSCI may not be achievable, evidence-based guidelines will be unlikely to mandate specific timing. Nonetheless, surgeons who unreasonably delay intervention for aSCI may be at risk for litigation due to treatment delay. This is increasingly likely in an environment where "complete" SCI is difficult to verify. SCI may at some point be recognized as a surgical emergency, as brain injury generally is, despite a lack of prospective randomized trials supporting this implementation, challenging the feasibility of the US trauma infrastructure to provide care for these patients.

Parsing the Behavioral and Brain Mechanisms of Third-Party Punishment.

UNLABELLED: The evolved capacity for third-party punishment is considered crucial to the emergence and maintenance of elaborate human social organization and is central to the modern provision of fairness and justice within society. Although it is well established that the mental state of the offender and the severity of the harm he caused are the two primary predictors of punishment decisions, the precise cognitive and brain mechanisms by which these distinct components are evaluated and integrated into a punishment decision are poorly understood. Using fMRI, here we implement a novel experimental design to functionally dissociate the mechanisms underlying evaluation, integration, and decision that were conflated in previous studies of third-party punishment. Behaviorally, the punishment decision is primarily defined by a superadditive interaction between harm and mental state, with subjects weighing the interaction factor more than the single factors of harm and mental state. On a neural level, evaluation of harms engaged brain areas associated with affective and somatosensory processing, whereas mental state evaluation primarily recruited circuitry involved in mentalization. Harm and mental state evaluations are integrated in medial prefrontal and posterior cingulate structures, with the amygdala acting as a pivotal hub of the interaction between harm and mental state. This integrated information is used by the right dorsolateral prefrontal cortex at the time of the decision to assign an appropriate punishment through a distributed coding system. Together, these findings provide a blueprint of the brain mechanisms by which neutral third parties render punishment decisions. SIGNIFICANCE STATEMENT: Punishment undergirds large-scale cooperation and helps dispense criminal justice. Yet it is currently unknown precisely how people assess the mental states of offenders, evaluate the harms they caused, and integrate those two components into a single punishment decision. Using a new design, we isolated these three processes, identifying the distinct brain systems and activities that enable each. Additional findings suggest that the amygdala plays a crucial role in mediating the interaction of mental state and harm information, whereas the dorsolateral prefrontal cortex plays a crucial, final-stage role, both in integrating mental state and harm information and in selecting a suitable punishment amount. These findings deepen our understanding of how punishment decisions are made, which may someday help to improve them.

Public Perceptions of Neurotechnologies Used to Target Mood, Memory, and Motor Symptoms.

Background: Advances in the development of neurotechnologies have the potential to revolutionize treatment of brain-based conditions. However, a critical concern revolves around the willingness of the public to embrace these technologies, especially considering the tumultuous histories of certain neurosurgical interventions. Therefore, examining public attitudes is paramount to uncovering potential barriers to adoption ensuring ethically sound innovation. Methods: In the present study, we investigate public attitudes towards the use of four neurotechnologies (within-subjects conditions): deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), pills, and MRI-guided focused ultrasound (MRgFUS) as potential treatments to a person experiencing either mood, memory, or motor symptoms (between-subjects conditions). US-based participants (N=1052; stratified to be nationally representative based on sex, race, age) were asked about their perceptions of risk, benefit, invasiveness, acceptability, perceived change to the person, and personal interest in using these neurotechnologies for symptom alleviation. Results: Descriptive results indicate variability between technologies that the U.S. public is willing to consider if experiencing severe mood, memory, or motor symptoms. The main effect of neurotechnology revealed DBS was viewed as the most invasive and risky treatment and was perceived to lead to the greatest change to who someone is as a person. DBS was also viewed as least likely to be personally used and least acceptable for use by others. When examining the main effects of symptomatology, we found that all forms of neuromodulation were perceived as significantly more beneficial, acceptable, and likely to be used by participants for motor symptoms, followed by memory symptoms, and lastly mood symptoms. Neuromodulation (averaging across neurotechnologies) was perceived as significantly riskier, more invasive, and leading to a greater change to person for mood versus motor symptoms; however, memory and motor symptoms were perceived similarly with respect to risk, invasiveness, and change to person. Conclusion: These results suggest that the public views neuromodulatory approaches that require surgery (i.e., DBS and MRgFUS) as riskier, more invasive, and less acceptable than those that do not. Further, findings suggest individuals may be more reluctant to alter or treat psychological symptoms with neuromodulation compared to physical symptoms.

Ethical, legal, and policy challenges in field-based neuroimaging research using emerging portable MRI technologies: guidance for investigators and for oversight.

Researchers are rapidly developing and deploying highly portable MRI technology to conduct field-based research. The new technology will widen access to include new investigators in remote and unconventional settings and will facilitate greater inclusion of rural, economically disadvantaged, and historically underrepresented populations. To address the ethical, legal, and societal issues raised by highly accessible and portable MRI, an interdisciplinary Working Group (WG) engaged in a multi-year structured process of analysis and consensus building, informed by empirical research on the perspectives of experts and the general public. This article presents the WG's consensus recommendations. These recommendations address technology quality control, design and oversight of research, including safety of research participants and others in the scanning environment, engagement of diverse participants, therapeutic misconception, use of artificial intelligence algorithms to acquire and analyze MRI data, data privacy and security, return of results and managing incidental findings, and research participant data access and control.

Brain imaging with portable low-field MRI.

The advent of portable, low-field MRI (LF-MRI) heralds new opportunities in neuroimaging. Low power requirements and transportability have enabled scanning outside the controlled environment of a conventional MRI suite, enhancing access to neuroimaging for indications that are not well suited to existing technologies. Maximizing the information extracted from the reduced signal-to-noise ratio of LF-MRI is crucial to developing clinically useful diagnostic images. Progress in electromagnetic noise cancellation and machine learning reconstruction algorithms from sparse k-space data as well as new approaches to image enhancement have now enabled these advancements. Coupling technological innovation with bedside imaging creates new prospects in visualizing the healthy brain and detecting acute and chronic pathological changes. Ongoing development of hardware, improvements in pulse sequences and image reconstruction, and validation of clinical utility will continue to accelerate this field. As further innovation occurs, portable LF-MRI will facilitate the democratization of MRI and create new applications not previously feasible with conventional systems.

Ethical Issues Posed by Field Research Using Highly Portable and Cloud-Enabled Neuroimaging.

Highly portable, cloud-enabled neuroimaging technologies will fundamentally change neuroimaging research. Instead of participants traveling to the scanner, the scanner will now come to them. Field-based brain imaging research, including populations underrepresented in neuroscience research to date, will enlarge and diversify databases and pave the way for clinical and direct-to-consumer (DTC) applications. Yet these technological developments urgently require analysis of their ethical, legal, and social implications (ELSI). No consensus ethical frameworks for mobile neuroimaging exist, and existing policies for traditional MRI research are inadequate. Based on literature review and ethics analysis of neurotechnology development efforts, Shen et al. identify seven foundational, yet unresolved, ELSI issues posed by portable neuroimaging: (1) informed consent; (2) privacy; (3) capacity to accurately communicate neuroimaging results to remote participants; (4) extensive reliance on cloud-based artificial intelligence (AI) for data analysis; (5) potential bias of interpretive algorithms in diverse populations; (6) return of research results and incidental (or secondary) findings to research participants; and (7) responding to participant requests for access to their data. The article proposes a path forward to address these urgent issues.

The American Public Is Ready to Accept Human-Animal Chimera Research.

We report findings from a new survey of US public attitudes toward human-animal chimeric embryo (HACE) research, designed to compare with recently reported Japanese survey data. We find that 59% of the US public can personally accept the process of injecting human induced pluripotent stem cells into genetically modified swine embryos and having human tissues produced in a pig's body transplanted into a human. This is greater acceptance than in Japan, and there is even strong acceptance among those with strong religious affiliations and who self-identify as conservatives. We argue that strong public support for HACE research, as well as the emerging literature suggesting that humanization of research animals is very unlikely, should compel the NIH to lift its current moratorium on HACE research.

The Legal Implications of Detecting Alzheimer's Disease Earlier.

Early detection of Alzheimer's disease (AD) raises a number of challenging legal questions. In this essay, we explore some of those questions, such as: Is a neurological indicator of increased risk for AD a legally relevant brain state before there are any outward behavioral manifestations? How should courts address evidentiary challenges to the admissibility of AD-related neuroimaging? How should the government regulate the marketing of neuroimaging diagnostic tools? How should insurance coverage for the use of these new tools be optimized? We suggest that many voices and multidisciplinary perspectives are needed to answer these questions and ensure that legal responses are swift, efficient, and equitable.