A proportion of diabetic patients experience chronic pain that is frequently refractory to treatment with conventional analgesics. Experimentally diabetic animals exhibit a range of behavioral abnormalities indicative of pain, and can be used to model human painful diabetic neuropathy. Studies suggest that pain during diabetes is not associated with structural damage to the peripheral nerves, and biochemical amplification of nociceptive processing may be of importance. The formalin test is used to measure spinal sensitization in animals. Diabetic rats exhibit exaggerated flinching during this test, in addition to increased constitutive spinal expression of cyclooxygenase-2 (COX-2) protein. Studies were designed to establish causality between increased spinal COX-2 activity and formalin hyperalgesia in diabetic rats. Rats with one, two or four weeks of streptozotocin-induced diabetes exhibited significantly increased levels of spinal COX-2 protein and activity, along with exaggerated paw flinching in response to 0.5% paw formalin injection. Increased flinching of diabetic rats was attenuated by intrathecal pre-treatment with a selective COX-2 inhibitor immediately prior to formalin injection, confirming the involvement of COX-2 activity in formalin hyperalgesia observed in diabetic rats. We hypothesized that glucose flux through the polyol pathway in the central nervous system (CNS) causes elevated spinal COX-2 expression and formalin hyperalgesia in diabetic rats. Chronic treatment with insulin or ICI222155, an aldose reductase inhibitor (ARI) previously shown to cross the blood-brain barrier (BBB) and prevent formalin-evoked hyperalgesia in diabetic rats, prevented elevated spinal COX-2 protein and activity in diabetic rats. In contrast, the ARI IDD676 showed efficacy against AR activity only in the peripheral nervous system, and had no effect on elevated spinal COX-2 or hyperalgesia to paw formalin injection, despite demonstrating efficacy against indices of peripheral nerve dysfunction. In the spinal cord, aldose reductase (AR) expression was observed solely in oligodendrocytes, which also expressed COX-2. These data suggest that activity of AR in spinal oligodendrocytes may be a primary initiating factor linking hyperglycemia with hyperalgesia in diabetic rats. Further, CNS targeting of ARIs may be important in treating painful diabetic neuropathy in patients

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.

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.

The overarching goal of the NIH BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative is to advance the understanding of healthy and diseased brain circuit function through technological innovation. Core principles for this goal include the validation and dissemination of the myriad innovative technologies, tools, methods, and resources emerging from BRAIN-funded research. Innovators, BRAIN funding agencies, and non-Federal partners are working together to develop strategies for making these products usable, available, and accessible to the scientific community. Here, we describe several early strategies for supporting the dissemination of BRAIN technologies. We aim to invigorate a dialogue with the neuroscience research and funding community, interdisciplinary collaborators, and trainees about the existing and future opportunities for cultivating groundbreaking research products into mature, integrated, and adaptable research systems. Along with the accompanying Society for Neuroscience 2019 Mini-Symposium, "BRAIN Initiative: Cutting-Edge Tools and Resources for the Community," we spotlight the work of several BRAIN investigator teams who are making progress toward providing tools, technologies, and services for the neuroscience community. These tools access neural circuits at multiple levels of analysis, from subcellular composition to brain-wide network connectivity, including the following: integrated systems for EM- and florescence-based connectomics, advances in immunolabeling capabilities, and resources for recording and analyzing functional connectivity. Investigators describe how the resources they provide to the community will contribute to achieving the goals of the NIH BRAIN Initiative. Finally, in addition to celebrating the contributions of these BRAIN-funded investigators, the Mini-Symposium will illustrate the broader diversity of BRAIN Initiative investments in cutting-edge technologies and resources.

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.