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.

Outcome measurement in functional neurological disorder: a systematic review and recommendations.

OBJECTIVES: We aimed to identify existing outcome measures for functional neurological disorder (FND), to inform the development of recommendations and to guide future research on FND outcomes. METHODS: A systematic review was conducted to identify existing FND-specific outcome measures and the most common measurement domains and measures in previous treatment studies. Searches of Embase, MEDLINE and PsycINFO were conducted between January 1965 and June 2019. The findings were discussed during two international meetings of the FND-Core Outcome Measures group. RESULTS: Five FND-specific measures were identified-three clinician-rated and two patient-rated-but their measurement properties have not been rigorously evaluated. No single measure was identified for use across the range of FND symptoms in adults. Across randomised controlled trials (k=40) and observational treatment studies (k=40), outcome measures most often assessed core FND symptom change. Other domains measured commonly were additional physical and psychological symptoms, life impact (ie, quality of life, disability and general functioning) and health economics/cost-utility (eg, healthcare resource use and quality-adjusted life years). CONCLUSIONS: There are few well-validated FND-specific outcome measures. Thus, at present, we recommend that existing outcome measures, known to be reliable, valid and responsive in FND or closely related populations, are used to capture key outcome domains. Increased consistency in outcome measurement will facilitate comparison of treatment effects across FND symptom types and treatment modalities. Future work needs to more rigorously validate outcome measures used in this population.

Stigma and functional neurological disorder: a research agenda targeting the clinical encounter.

Stigma against patients with functional neurological disorder (FND) presents obstacles to diagnosis, treatment, and research. The lack of biomarkers and the potential for symptoms to be misunderstood, invalidated, or dismissed can leave patients, families, and healthcare professionals at a loss. Stigma exacerbates suffering and unmet needs of patients and families, and can result in poor clinical management and prolonged, repetitive use of healthcare resources. Our current understanding of stigma in FND comes from surveys documenting frustration experienced by providers and distressing healthcare interactions experienced by patients. However, little is known about the origins of FND stigma, its prevalence across different healthcare contexts, its impact on patient health outcomes, and optimal methods for reduction. In this paper, we set forth a research agenda directed at better understanding the prevalence and context of stigma, clarifying its impact on patients and providers, and promoting best practices for stigma reduction.

Localization and function of dopamine receptors in the subthalamic nucleus of normal and parkinsonian monkeys.

The subthalamic nucleus (STN) receives a dopaminergic innervation from the substantia nigra pars compacta, but the role of this projection remains poorly understood, particularly in primates. To address this issue, we used immuno-electron microscopy to localize D1, D2, and D5 dopamine receptors in the STN of rhesus macaques and studied the electrophysiological effects of activating D1-like or D2-like receptors in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys. Labeling of D1 and D2 receptors was primarily found presynaptically, on preterminal axons and putative glutamatergic and GABAergic terminals, while D5 receptors were more significantly expressed postsynaptically, on dendritic shafts of STN neurons. The electrical spiking activity of STN neurons, recorded with standard extracellular recording methods, was studied before, during, and after intra-STN administration of the dopamine D1-like receptor agonist SKF82958, the D2-like receptor agonist quinpirole, or artificial cerebrospinal fluid (control injections). In normal animals, administration of SKF82958 significantly reduced the spontaneous firing but increased the rate of intraburst firing and the proportion of pause-burst sequences of firing. Quinpirole only increased the proportion of such pause-burst sequences in STN neurons of normal monkeys. In MPTP-treated monkeys, the D1-like receptor agonist also reduced the firing rate and increased the proportion of pause-burst sequences, while the D2-like receptor agonist did not change any of the chosen descriptors of the firing pattern of STN neurons. Our data suggest that dopamine receptor activation can directly modulate the electrical activity of STN neurons by pre- and postsynaptic mechanisms in both normal and parkinsonian states, predominantly via activation of D1 receptors.

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.

Neuroethics guidance documents: principles, analysis, and implementation strategies.

Innovations in neurotechnologies have ignited conversations about ethics around the world, with implications for researchers, policymakers, and the private sector. The human rights impacts of neurotechnologies have drawn the attention of United Nations bodies; nearly 40 states are tasked with implementing the Organization for Economic Co-operation and Development's principles for responsible innovation in neurotechnology; and the United States is considering placing export controls on brain-computer interfaces. Against this backdrop, we offer the first review and analysis of neuroethics guidance documents recently issued by prominent government, private, and academic groups, focusing on commonalities and divergences in articulated goals; envisioned roles and responsibilities of different stakeholder groups; and the suggested role of the public. Drawing on lessons from the governance of other emerging technologies, we suggest implementation and evaluation strategies to guide practitioners and policymakers in operationalizing these ethical norms in research, business, and policy settings.

Extrastriatal D2-like receptors modulate basal ganglia pathways in normal and Parkinsonian monkeys.

According to traditional models of the basal ganglia-thalamocortical network of connections, dopamine exerts D2-like receptor (D2LR)-mediated effects through actions on striatal neurons that give rise to the "indirect" pathway, secondarily affecting the activity in the internal and external pallidal segments (GPi and GPe, respectively) and the substantia nigra pars reticulata (SNr). However, accumulating evidence from the rodent literature suggests that D2LR activation also directly influences synaptic transmission in these nuclei. To further examine this issue in primates, we combined in vivo electrophysiological recordings and local intracerebral microinjections of drugs with electron microscopic immunocytochemistry to study D2LR-mediated modulation of neuronal activities in GPe, GPi, and SNr of normal and MPTP-treated (parkinsonian) monkeys. D2LR activation with quinpirole increased firing in most GPe neurons, likely due to a reduction of striatopallidal GABAergic inputs. In contrast, local application of quinpirole reduced firing in GPi and SNr, possibly through D2LR-mediated effects on glutamatergic inputs. Injections of the D2LR antagonist sulpiride resulted in effects opposite to those of quinpirole in GPe and GPi. D2 receptor immunoreactivity was most prevalent in putative striatal-like GABAergic terminals and unmyelinated axons in GPe, GPi, and SNr, but a significant proportion of immunoreactive boutons also displayed ultrastructural features of glutamatergic terminals. Postsynaptic labeling was minimal in all nuclei. The D2LR-mediated effects and pattern of distribution of D2 receptor immunoreactivity were maintained in the parkinsonian state. Thus, in addition to their preferential effects on indirect pathway striatal neurons, extrastriatal D2LR activation in GPi and SNr also influences direct pathway elements in the primate basal ganglia under normal and parkinsonian conditions.

Building a culture of responsible neurotech: Neuroethics as socio-technical challenges.

Scientists around the globe are joining the race to achieve engineering feats to read, write, modulate, and interface with the human brain in a broadening continuum of invasive to non-invasive ways. The expansive implications of neurotechnology for our conception of health, mind, decision-making, and behavior has raised social and ethical considerations that are inextricable from neurotechnological progress. We propose "socio-technical" challenges as a framing to integrate neuroethics into the engineering process. Intentionally aligning societal and engineering goals within this framework offers a way to maximize the positive impact of next-generation neurotechnologies on society.

Genetic loss of norepinephrine does not alter adult hippocampal neurogenesis in dopamine beta-hydroxylase deficient mice.

Norepinephrine (NE), and specific adrenoceptors, have been reported to influence distinct aspects of adult hippocampal neurogenesis, including latent stem cell activation, progenitor proliferation, and differentiation. These findings are predominantly based on the use of pharmacological approaches in both in vitro and in vivo systems. Here, we sought to assess the consequences of genetic ablation of NE on adult hippocampal neurogenesis, by examining dopamine ß hydroxylase knockout (Dbh -/-) mice, which lack NE from birth. We find that Dbh -/- mice exhibit no difference in adult hippocampal progenitor proliferation and survival. Further, the number of immature newborn neurons, labeled using stage-specific developmental markers within the hippocampal neurogenic niche, was also unaltered in Dbh -/- mice. In contrast, the noradrenergic neurotoxin DSP-4, which had previously been shown to reduce adult hippocampal neurogenesis in rats, also resulted in a decline in hippocampal progenitor proliferation in C57/Bl6N mice. These findings indicate that pharmacological lesioning of noradrenergic afferents in adulthood, but not the complete genetic loss of NE from birth, impairs adult hippocampal neurogenesis in mice.

Alpha2-adrenoceptor blockade accelerates the neurogenic, neurotrophic, and behavioral effects of chronic antidepressant treatment.

Slow-onset adaptive changes that arise from sustained antidepressant treatment, such as enhanced adult hippocampal neurogenesis and increased trophic factor expression, play a key role in the behavioral effects of antidepressants. alpha(2)-Adrenoceptors contribute to the modulation of mood and are potential targets for the development of faster acting antidepressants. We investigated the influence of alpha(2)-adrenoceptors on adult hippocampal neurogenesis. Our results indicate that alpha(2)-adrenoceptor agonists, clonidine and guanabenz, decrease adult hippocampal neurogenesis through a selective effect on the proliferation, but not the survival or differentiation, of progenitors. These effects persist in dopamine beta-hydroxylase knock-out (Dbh(-/-)) mice lacking norepinephrine, supporting a role for alpha(2)-heteroceptors on progenitor cells, rather than alpha(2)-autoreceptors on noradrenergic neurons that inhibit norepinephrine release. Adult hippocampal progenitors in vitro express all the alpha(2)-adrenoceptor subtypes, and decreased neurosphere frequency and BrdU incorporation indicate direct effects of alpha(2)-adrenoceptor stimulation on progenitors. Furthermore, coadministration of the alpha(2)-adrenoceptor antagonist yohimbine with the antidepressant imipramine significantly accelerates effects on hippocampal progenitor proliferation, the morphological maturation of newborn neurons, and the increase in expression of brain derived neurotrophic factor and vascular endothelial growth factor implicated in the neurogenic and behavioral effects of antidepressants. Finally, short-duration (7 d) yohimbine and imipramine treatment results in robust behavioral responses in the novelty suppressed feeding test, which normally requires 3 weeks of treatment with classical antidepressants. Our results demonstrate that alpha(2)-adrenoceptors, expressed by progenitor cells, decrease adult hippocampal neurogenesis, while their blockade speeds up antidepressant action, highlighting their importance as targets for faster acting antidepressants.

Assessing the Perceived Value of Neuroethics Questions and Policy to Neuro-Entrepreneurs.

Neuroscience and its findings have deep personal and cultural meaning, so the implications of brain science raise new flavors of ethical issues not covered by traditional bioethics. The field of neuroethics bridges this gap, addressing and responding to the ethical, legal, and social issues intimately related to the evolving landscape of neuroscience. Neuroethical concerns have registered at the highest levels of government. In 2018, an interdisciplinary global neuroethics group working with leading scientists from the International Brain Initiative, a consortium of seven large-scale national-level brain research projects around the globe, published "Neuroethics Questions to Guide Ethical Research in the International Brain Initiatives." The document provides guiding questions to consider throughout the lifecycle of neuroscience research. These questions tackle issues such as identity, morality, cross-cultural differences, privacy, and potential stakeholder involvement in ethical decision-making. In our work with the International Brain Initiative, we noted the important role that the private sector will play in translating and scaling neuroscience for society. We also noticed a gap in communication and collaboration between government, academia and the private sector. These guiding questions were largely co-created with policy makers and academics, so it was unclear how these issues might be received by neuro-entrepreneurs and neuro-industry. We hoped to identify not only common concerns, but also a common language for discussing neuroethical issues with stakeholders outside of government and academia. We used empirical ethics methods to assess the perceived value and attitudes of neuro-entrepreneurs toward neuroethical issues and whether or not these issues align with the process of neuro-innovation. We conducted one-on-one structured interviews with 21 neuro-entrepreneurs in the private sector and used two independent reviewers to analyze for themes. From this preliminary research, we identified key neuroethical themes and processual pain points of neurotech entrepreneurs throughout the innovation process. We also provide a preliminary neuroethics needs assessment for neuro-industry and suggest avenues through which neuroethicists can work with neurotech leadership to build an ethically aligned future. Overall, we hope to raise awareness and provide actionable steps toward advancing and accelerating societally impactful neuroscience.

Prodromes and Preclinical Detection of Brain Diseases: Surveying the Ethical Landscape of Predicting Brain Health.

The future of medicine lies not primarily in cures but in disease modification and prevention. While the science of preclinical detection is young, it is moving rapidly. Preclinical interventions offer hope to decrease the severity of a disease or delay the development of a disorder. With such promise, the research and practice of detecting brain disorders at a preclinical stage present unique ethical challenges that must be addressed to ensure the benefit of these technologies. Direct brain interventions have the potential to impact not just what a patient has but who they are and who they could become. Further, receiving an assessment for a preclinical or prodromal state has potential to impact perceptions about capacity, autonomy and personhood and could become entangled with stigma and discrimination. Exploring ethical issues alongside and integrated into the experimental design and research of these technologies is critical. This review will highlight ethical issues attendant to the current and near future states of preclinical detection across the life span, specifically as it relates to autism spectrum disorder (ASD), schizophrenia, and Alzheimer's disease.

The NIH BRAIN Initiative: Integrating Neuroethics and Neuroscience.

The NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is focused on developing new tools and neurotechnologies to transform our understanding of the brain, and neuroethics is an essential component of this research effort. Coordination with other brain projects around the world will help maximize success.

Ethical Challenges of Risk, Informed Consent, and Posttrial Responsibilities in Human Research With Neural Devices: A Review.

Importance: Developing more and better diagnostic and therapeutic tools for central nervous system disorders is an ethical imperative. Human research with neural devices is important to this effort and a critical focus of the National Institutes of Health Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Despite regulations and standard practices for conducting ethical research, researchers and others seek more guidance on how to ethically conduct neural device studies. This article draws on, reviews, specifies, and interprets existing ethical frameworks, literature, and subject matter expertise to address 3 specific ethical challenges in neural devices research: analysis of risk, informed consent, and posttrial responsibilities to research participants. Observations: Research with humans proceeds after careful assessment of the risks and benefits. In assessing whether risks are justified by potential benefits in both invasive and noninvasive neural device research, the following categories of potential risks should be considered: those related to surgery, hardware, stimulation, research itself, privacy and security, and financial burdens. All 3 of the standard pillars of informed consent-disclosure, capacity, and voluntariness-raise challenges in neural device research. Among these challenges are the need to plan for appropriate disclosure of information about atypical and emerging risks of neural devices, a structured evaluation of capacity when that is in doubt, and preventing patients from feeling unduly pressured to participate. Researchers and funders should anticipate participants' posttrial needs linked to study participation and take reasonable steps to facilitate continued access to neural devices that benefit participants. Possible mechanisms for doing so are explored here. Depending on the study, researchers and funders may have further posttrial responsibilities. Conclusions and Relevance: This ethical analysis and points to consider may assist researchers, institutional review boards, funders, and others engaged in human neural device research.