Advancing Basic Science for Humanity
The next application deadline for the BRAIN Initiative Advanced Postdoctoral Career Transition Award to Promote Diversity (K99/R00) is February 10, 2020 (resubmission deadline is March 10, 2020).
Fostering diversity in the scientific research workforce is a key element of the NIH strategy to identify, develop, support, and maintain the quality of our scientific human capital. Research shows that diverse teams working together outperform homogenous ones. Scientists and trainees with different backgrounds and points of view bring innovation and creativity to solving complex scientific problems. Diversity enhances scientific discovery, which is why NINDS, along with the other NIH Institutes and Centers participating in the BRAIN Initiative, is strongly committed to enhancing diversity in the biomedical workforce.
The funding opportunity announcement (FOA) for one part of this effort, the NIH BRAIN Initiative Advanced Postdoctoral Career Transition Award to Promote Diversity (K99/R00), has been reissued. The program is designed to enhance scientific research workforce diversity and promote retention and advancement of a strong cohort of highly-skilled, well-trained, NIH-supported independent investigators from diverse backgrounds working in BRAIN Initiative research priority areas. Twenty outstanding researchers to date have received the NIH BRAIN Initiative K99/R00 award — learn more about current awardees here.
The award is intended for individuals who have no more than five years of postdoctoral experience at the time of the initial or resubmission application and who require at least 12 months of mentored research training and career development before transitioning to an independent tenure-track or equivalent faculty position.
For this announcement, institutions are encouraged to identify candidates who will enhance diversity as described in Notice of NIH’s Interest in Diversity, which include members of underrepresented racial or ethnic groups, individuals with disabilities, those from disadvantaged backgrounds, and women. The reissued funding announcement also falls under the new NIH Extension Policy for Eligibility Window for Pathway to Independence Awards (K99/R00), which allows applicants to extend the eligibility time window for new application submission or resubmission due to childbirth (one-year extension), medical concerns, disability, and other reasons. Most extension requests are reviewed on a case-by-case basis. For more details on K99/R00 eligibility extensions, please view information under the “Career Planning” tab here.
Information about applications can be found under RFA-NS-19-043 (independent clinical trial not allowed) and RFA-NS-19-044 (independent clinical trial required). Additional resources, including a technical assistance webinar, are available at https://braininitiative.nih.gov/brain-programs/training.
The next deadline for the application is February 10, 2020, and standard dates apply after that. The upcoming resubmission deadline is March 10, 2020. Applications to previous FOAs (PAR-18-813 and PAR-18-814) can also be resubmitted for the March deadline.
Those interested in applying for this award may send scientific or career development questions to BRAINDIVERSITYK99R00@nih.gov.
BRAIN Initiative investigators can now offer feedback on a new NIH-wide data sharing policy that will likely impact ongoing and future neuroscience research. The draft NIH policy for data management and sharing is open for public comment until Jan 10, 2020.
Advancements in high-speed computing and massive data storage capabilities have enabled the collection of larger datasets than ever before. Interdisciplinary collaborative projects funded by the BRAIN Initiative are generating complex and multidimensional data; making the preservation, analysis, and sharing of datasets a pervasive issue. Many of those in the biomedical research community agree that data archiving and sharing augments research reproducibility and could enhance scientific discovery.
Earlier this year, the NIH Institutes and Centers participating in the BRAIN Initiative addressed data sharing needs by releasing a new data sharing policy focused on building an informatics infrastructure. This policy requires researchers to submit their data to archives, create a resource sharing plan, and include costs for data organization and archiving in grant applications.
Ensuring that data sharing policies reflect current data and research practices, however, is not a challenge unique to brain research. Just last year, the NIH solicited feedback from researchers and the public on what to include in a new NIH-wide data sharing policy. Most individuals who submitted comments supported the practice of data sharing and the importance of planning for where, when, and how scientific data should be managed and shared. However, commenters expressed concerns about a ‘one-size-fits-all’ policy and the potential burden of data sharing on the research community.
Recently, the NIH incorporated these suggestions into a draft overarching data management and sharing policy. In early November, a Draft NIH Policy for Data Management and Sharing was released for public comment. The draft policy applies to all NIH-funded research that results in the generation of scientific data. Rather than standardizing data practices across all scientific fields, the policy would require researchers to submit and follow a plan detailing how they will integrate data management and sharing into their research program. The NIH also encourages researchers to consider the legal, technical, and ethical factors that may limit data preservation and sharing.
Most scientists broadly support the idea that free and open data dissemination will accelerate biomedical research by allowing many more individuals to access and analyze large datasets. Given the enormity and diversity of datasets, as well as growing support of open data by the scientific community, data archiving and sharing has quickly become a reality that researchers cannot ignore.
The final NIH policy for data sharing will likely impact all NIH-funded researchers (including those funded by BRAIN). Therefore, BRAIN investigators are encouraged to weigh in on the draft policy. Those interested in commenting on the draft policy can do so via an easy and secure web-based portal. To ensure consideration, responses must be submitted by Jan 10, 2020. To further engage the community, the NIH will soon hold a webinar on the draft policy.
In a recent paper published in JAMA Neurology, a collaborative team of ethics and neuroscience experts highlight key ethical issues surrounding neural device research and provide points to consider for researchers and others working in this space.
Human research is fundamental to the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative®’s goals of understanding the brain and developing treatments for brain disorders. Scientists supported by the BRAIN Initiative are rapidly developing modern tools to monitor and regulate brain activity. This research involves the new and expanded use of invasive and noninvasive neural devices in humans, bringing important ethical considerations to light.
To ensure that BRAIN-funded neural device research is done ethically, one goal of the BRAIN Initiative’s Neuroethics Working Group (NEWG) – a group of experts in neuroethics and neuroscience – is to anticipate ethical questions that arise as technology advances. For example, the NEWG recently published eight guiding neuroethical principles for BRAIN Initiative research. Building upon these overarching principles, in October 2017 the NIH brought together neuroethics and bioethics experts, neuroscientists, and clinicians to discuss and offer input on the ethical issues surrounding neural device research in humans. For details on this discussion, please view the videocast of the NEWG workshop on this topic.
In their paper published in JAMA Neurology, authors emphasize three main areas of ethical challenges in neural device research: 1. Analysis of risk; 2. Informed consent; and 3. Posttrial responsibilities to research participants.
Analysis of risk
Human research with invasive or non-invasive neural devices is rarely void of risk. Before using devices for research purposes, authors encourage scientists to analyze risk by determining the type and extent of risk for each proposed study (DHEW, 1979). In the paper, authors recommend that scientists assess risk from six sources, including 1. Risks related to surgery; 2. Device hardware; 3. Stimulation; 4. The nature of research; 5. Privacy and security; and 6. Financial burden. Importantly, although surgical and hardware risks are unique to invasive neural devices, invasiveness alone is not sufficient to determine risk.
Authors highlight that both invasive and non-invasive neural devices have other, sometimes lesser emphasized risks. Because brain circuit activity forms the basis of everyday human experiences (e.g., perception, thought, emotion, action) neural devices may have unique risks related to mental states and personal identity. For instance, deep brain stimulation (DBS) may negatively affect cognition and involve ‘atypical’ risks such as effects on personality, mood, behavior, and altered perceptions of identity, authenticity, privacy, and agency (Klein et al., 2016; Schupbach et al., 2006). According to authors, these ‘atypical’ risks require special attention because they are poorly understood, variable, and unpredictable. In evaluating risks, they recommend that overall, the risks of a study should ultimately be justified by the possible therapeutic benefit to the participant and the importance of knowledge to be gained.
Informed consent is essential to protect the rights of human research participants. Because neural device research can affect the brain in predictable and unpredictable ways, typical informed consent challenges in clinical research can be exacerbated in neural device research.
Researchers using neural devices must inform participants about “reasonably foreseeable” emerging or atypical risks associated with a neural device. This is particularly difficult because individuals may have diverse preferences and value systems, explain authors. For example, some participants may perceive neural stimulation as enhancing their sense of empowerment, while others may see stimulation as undermining their level of control (Gilbert, O’Brien, & Cook, 2018; Klein et al., 2016). What can be done to ensure that these risks are appropriately disclosed? Authors encourage researchers to draw upon experience in disclosing adverse effects from neuropharmacological studies and utilize a multidisciplinary team to figure out appropriate consent language.
Further, authors discuss how informed consent can be impeded by the link between brain disorders and making or communicating decisions. Complex experimental information and disorders that impair cognition may hinder a participant’s capacity to make an informed choice. Participants may also feel pressured to participate in research studies. For example, they may already have a clinical relationship with their neurosurgeon who is also the study investigator and find it difficult to decline. Authors propose that researchers and institutional review boards (IRBs) can alleviate these pressures by providing patients with alternative communication tools (e.g., written communication or using pictures), ensuring that patients understand that research participation is voluntary and will not jeopardize clinical care, and by providing them with a different investigator (other than their surgeon) with whom to discuss the study.
Posttrial responsibilities to research participants
Once a trial ends, participants may leave a study with specific posttrial needs related to trial participation (see Figure below). This ethical issue can be complicated in neural device research. Individuals who participate in a neural device study may have long-lasting, lifelong changes – such as a permanent brain implant – that impact their future. They may need medical care and equipment for device maintenance (e.g., battery replacement) long after study participation. Costs of maintenance, repairs, and device removal are also an issue: clinical trials involving invasive devices and funders do not always cover these costs and health insurance plans often deny coverage for experimental devices. In fact, no definitive ethical or regulatory frameworks, nor standard practices, exist for posttrial responsibilities in neural device research (Lázaro-Muñoz, Yoshor, Beauchamp, Goodman, & McGuire, 2018), state authors.
Authors suggest that researchers, funders, and device manufacturers anticipate and make plans for participants’ posttrial needs. Prior to beginning a study, IRBs and participants should be well-informed and consent to potential needs, risks, complexities, and costs of posttrial care. Complex neural devices, such as DBS, may make participants particularly vulnerable. Researchers should provide participants with experts who can assist them with device technicalities. Authors also propose creating a registry to track long-term outcomes of neural devices, such as adverse effects and costs. Overall, authors recommend that researchers, device manufacturers, funders, and health care institutions share responsibility for clarifying responsibilities in posttrial care. Neural devices will continue to be improved for years to come. Therefore, ongoing efforts to clarify researcher and funder responsibilities for posttrial care are essential to align posttrial responsibilities with proper research entities.The light blue timeline shows the development of a neural device, and the brown timeline depicts scenarios in which participants may have posttrial needs. Recommendations for researchers and funders are shown in dark blue boxes.
Advancements in neurotechnology have the potential to outpace existing ethics guidelines. Therefore, it is critical that current ethical frameworks for neural device research evolve with advancements in neurotechnology. With this publication, authors hope to help scientists, clinicians, IRBs, and funders involved in research with neural devices navigate the novel ethical concerns raised by using these emerging neurotechnologies in humans.
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
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
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
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
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
NINDS Director Walter J. Koroshetz, NIMH Director Joshua A. Gordon, NICHD Director Diana W. Bianchi, NIA Director Richard Hodes, NIAAA Director George Koob, NCCIH Director Helene Langevin, NIBIB Director Bruce J. Tromberg, NIDCD Director Debara L. Tucci, NEI Acting Director Santa Tumminia, NIDA Director Nora D. Volkow, ORWH Director Janine A. Clayton, and OBSSR Director William T. Riley.
There’s a lot to be excited about when it comes to the BRAIN Initiative, especially now that the NIH ACD BRAIN Initiative Working Group 2.0, and the BRAIN Neuroethics Subgroup (BNS) have delivered their final reports. The BRAIN Initiative is a collaborative effort between multiple federal research agencies and ten NIH Institutes, funded by the U.S. Congress through the 21st Century Cures Act. In the six years since the inception of the BRAIN Initiative, a tremendous number of scientific advances have generated exciting new tools for exploring neural circuits that underlie brain function. For instance, BRAIN-funded scientific advances include: new probes for recording and perturbing the activity of neurons and neuronal ensembles (e.g., improved DREADDs, genetically-encoded sensors for dopamine and calcium); advances in single-cell genomic profiling (e.g., Drop-seq); microscopy (e.g., Swept Confocally-Aligned Planar Excitation Microscopy (SCAPE) and 3-photon microscopy); and human neuroimaging (e.g., calcium sensors for direct readout of neural activity by MRI). These new tools are already contributing to an advanced understanding of how brain circuit activity enables behavior.
In fact, BRAIN-sponsored advances stood out as some of the highlights at the 2019 Annual Meeting of the Society for Neuroscience, the largest gathering of brain scientists in the world. Events there included a mini-symposium and a busy social highlighting BRAIN neurotechnologies, neuroethics sessions, a meeting of the BRAIN Initiative Alliance, a planning session for the International Brain Initiative, and myriad talks and poster presentations. Through these events, scientists highlighted the support of the BRAIN Initiative in developing game-changing tools and resources, many of which are already beginning to be distributed to the wider basic neuroscience community. Even now, these BRAIN Initiative technologies are impacting clinical research. BRAIN-funded studies include a clinical trial of an experimental brain device, developed in the lab of Dr. Nader Pouratian, that enables blind patients to better distinguish light and motion, and a new method developed by Dr. Edward Chang and his team to use brain activity to reconstruct human speech. With these scientific advances and many others, the BRAIN Initiative has truly made spectacular progress.
Building on this considerable progress, the NIH BRAIN Initiative in the coming years is poised to lead to tremendous advancements. Accordingly, the NIH has recently completed a year-long effort to revise the strategic plan guiding the BRAIN Initiative. In 2013, a working group of the Advisory Committee to the NIH Director (ACD) outlined strategic priorities to guide the BRAIN Initiative in BRAIN 2025, a scientific vision that coalesced support for BRAIN across the neuroscience community and has been embraced by BRAIN partners both nationally and internationally. The BRAIN 2025 report emphasized that the Initiative would need to adapt in response to a changing scientific landscape. As such, the ACD convened a new group of external experts in April 2018 to review the progress of the BRAIN Initiative and identify new gaps and opportunities, given the rapid advancements that have occurred.
Drs. Catherine Dulac and John Maunsell co-chaired this group of external scientific experts, the NIH ACD BRAIN Initiative Working Group 2.0, and presented their findings at the June 2019 meeting of the ACD, following up in a teleconference on October 21, 2019. The report, From Cells to Circuits, Toward Cures, encompasses over a year of the group’s tireless efforts. The group reported that NIH should continue to advance the BRAIN Initiative through projects centered in single or small teams of laboratories. They emphasized that the BRAIN Initiative needs to continue to attract and leverage the expertise of diverse scientists, including engineers, geneticists, chemists, mathematicians, physicists, computational scientists, and basic and clinical neuroscientists to develop more powerful tools to map, monitor, and modulate neural circuits. In addition, the group saw the unique opportunity of the BRAIN Initiative to take on ambitious team science projects for achieving research goals that will transform the future of neuroscience and lead to new treatments for neuro/mental/substance use disorders. A balanced approach of individual lab research and team science will propel BRAIN Initiative research into the future. Finally, to collectively accelerate the pace of scientific discovery, the 2.0 Working Group suggested increased resources devoted to data harmonization and sharing, technology dissemination, clinical translation, training, public engagement, and neuroethics.
As the BRAIN Initiative moves forward, it must do so responsibly and ethically. Thus, in parallel with the BRAIN Initiative Working Group 2.0 activities, the BRAIN Neuroethics Subgroup (BNS) examined the challenges that face investigators, the medical community, and society as a whole as we develop new abilities to precisely monitor and modulate brain activity and predict behavior. Drs. James Eberwine and Jeffrey Kahn co-chaired this group of external experts, which detailed their findings in the complementary report, The BRAIN Initiative and Neuroethics: Enabling and Enhancing Neuroscience Advances for Society, at the June and October ACD meetings. The report focuses on enhancing the integration of neuroscience and neuroethics, providing additional resources for addressing neuroethics issues and opportunities, assessing the development and use of innovative animal and neural-circuit model systems, establishing guidelines for the neuroscience data ecosystem, and initiating conversations and collaborations to address neuroscience applications beyond biomedical and clinical contexts.
Dr. Francis Collins, NIH Director, accepted the ACD endorsed reports, and NIH will carefully consider how to integrate both sets of findings in future BRAIN Initiative priorities and investments. We are thrilled that such thoughtful and hard work went into tackling these complicated and challenging issues, and we thank the co-chairs and members of both working groups for their diligent efforts over the last year and a half. The groups’ presentations to the ACD can be viewed here. Fiscal year 2019 saw over 180 new NIH BRAIN awards, with NIH support for more than 270 investigators and a total budget of almost $425 million; as such, these reports could not be more timely. At NIH, we are immediately and enthusiastically developing an implementation strategy guided by the work of the 2.0 Working Group and BNS. The discussions surrounding the next phase of the BRAIN Initiative – its opportunities and potential – leave us nothing short of excited to see what the second half of the Initiative brings.
The recent conference for the Society for Neuroscience gave many BRAIN Initiative-funded researchers the chance to showcase their newly developed technologies that are helping to drive neuroscience forward. Nearly 30,000 people from 75 countries attended the meeting, held October 19-23 in Chicago, Illinois.
Recent success stories from BRAIN-funded investigators include: Dr. Matthew Tantam’s lab engineered genetically-fluorescent sensors that allow for high-resolution, real-time, and live-cell imaging of ATP dynamics; Dr. Anne Churchland and team showed that animals execute expert decisions while performing richly varied, uninstructed movements that profoundly shape neural activity, as measured by two-photon imaging and Neuropixels electrophysiological probes; a clinical trial of an experimental brain device, developed in the lab of Dr. Nader Pouratian, enables blind patients to better distinguish light and motion; and a new method developed by Dr. Edward Chang and team use brain activity to reconstruct human speech. With these scientific advances and many others, the BRAIN Initiative has made important progress in advancing our understanding of the brain.
BRAIN-related events at Neuroscience 2019 included a mini-symposium, a social, neuroethics sessions, and a myriad of talks and poster presentations. For instance, the National Institutes of Health (NIH) presented a poster on Sunday, highlighting how the agency has been contributing to funding and strategic planning for the BRAIN Initiative. The NIH provides several avenues of funding at multiple career levels in order to promote the development of cutting-edge technology. Along with other federal and private institutions, the NIH participates in the BRAIN Initiative Alliance to help communicate BRAIN advances and helps host an annual meeting for all researchers funded by BRAIN.
All of the BRAIN-associated activities at Neuroscience 2019 allowed scientists to highlight how the BRAIN Initiative has helped support the development of game-changing tools and resources. Many of these new technologies are already beginning to be distributed to the wider neuroscience community.
A primary objective of the BRAIN Initiative is to disseminate tools to other researchers in order to accomplish the Initiative’s research goals. Dr. Walter Koroshetz, Director of the National Institute of Neurological Disorders and Stroke (NINDS), chaired a mini-symposium on Saturday that highlighted the work of BRAIN-funded scientists. “BRAIN Initiative: Cutting-Edge Tools and Resources for the Community” featured six researchers who have developed and disseminated new technology that is helping to drive neuroscience forward.
“We are preparing and entering the second half of the BRAIN Initiative,” said Dr. Koroshetz. “The focus remains the same: to understand how brain circuit function enables everything we do, and how disordered brain circuits contribute to neurological, mental, and substance use disorders.”The panelists and moderator of the BRAIN Initiative mini-symposium at Neuroscience 2019 (from left to right): Drs. Loren Frank, Jeff Lichtman, Kathleen Gates, Alison Barth, Kristen Harris, James Trimmer, and Walter Koroshetz.
Jeff Lichtman, PhD, of Harvard University, showcased his BRAIN-funded work to develop and share tools to allow researchers to better visualize neural connections. His talk, “A Facility to Generate Connectomics Information,” described how his lab uses serial section electron microscopy to get a highly accurate view of the location of cells and synapses within a 3D volume. His team has used this technique to view the overarching patterns of connectivity of different cell types within the human cortex. Dr. Lichtman also shares his devices and computer infrastructure with other labs so that other neuroscience investigators can do their own studies on connectivity with other types of brain tissue.
The next talk, “High-Throughput Methods for Fluorescence-Based Connectomics,” featured new tools to better visualize synapses. Alison L. Barth, PhD, of Carnegie Mellon University, described connecting anatomical data with functional data to better understand how brain circuits change over time, following learning, or in disease states. Her lab has developed genetically-expressed fluorescent labeling reagents and software programs that can accurately detect different types of synapses at high resolution. The Barth lab and colleagues share some of these technologies through sites like Addgeneand GitHub.
How does the hippocampus retrieve sensory information that is stored in different regions across the brain in order to construct a memory? The lab of Loren Frank, PhD, of the Kavli Foundation, HHMI, and the University of California, San Francisco, has been developing new devices to help answer this question. In order to get large-scale recordings of brain activity, Dr. Frank and colleagues have developed a new type of very thin, flexible polymer probe. When paired with the lab’s innovative algorithms, these probes can simultaneously capture readings from 1024 electrodes in order to better understand how entire populations of neurons communicate with each other. Their technology also enables investigators to collect stable brain recordings over the course of several months.
Kristen Harris, PhD, of the University of Texas at Austin, presented “Enhanced Resolution of 3DEM Analysis of Synapses.” Her lab has developed new techniques for 3D imaging, including combining tilt tomography and electron microscopy in order to get better resolution of cell borders. The Harris lab has also developed a collection of software and protocols to more accurately visualize and measure the structure of synapses. Many of these tools, as well as public datasets, are available to other researchers at 3DEM.org.
How can connectivity information be used to help people? Kathleen Gates, PhD, from the University of North Carolina at Chapel Hill, discussed a new method for identifying patterns of connectivity among different subsets of people. Her talk, “Introducing an Unsupervised Classification Tool: Separating Individuals Based on Within- or Between Network Functional Brain Activity,” described a cutting-edge tool, Group Iterative Multiple Model Estimation (GIMME), that is able to accurately separate people into subgroups based on brain functional connectivity maps. The Gates lab offers several software and data analysis packages, a GitHub page, and online tutorials to other interested researchers.
The final talk, “Renewable Recombinant Immunolabels Developed and Validated for BRAIN Research,” was by James Trimmer, PhD, of the University of California, Davis. His lab’s goal is to create, validate, and disseminate effective and low-cost monoclonal antibodies to be used by the neuroscience community. Additionally, the Trimmer lab is in the process of cloning and validating recombinant antibody fragments that can be expressed from plasmids for in vitro antibody production, which makes it easier to use and share validated, mutation-free antibody clones. So far, his lab has distributed over 60,000 vials of monoclonal antibodies, has made available 500 validated hybridoma cell lines, and has disseminated 100 recombinant monoclonal antibody-expressing plasmids through Addgene.
Brain Initiative Alliance Social
Many researchers turned out on Sunday night for “Tools & Tech: A BRAIN Initiative Alliance Social,” an event that fostered new collaborations and facilitated access to cutting-edge tools for people in the neuroscience community.
Several researchers presented software programs designed to better capture, process, or use neuroscience data. One such tool was cytoNet, software developed by the Amina Ann Qutub lab from the University of Texas, San Antonio. This web-based program measures the spatial organization of cells in 2D culture to get a better sense of how cell networks change over time or in response to certain stimuli. “This is software that captures cell community through microscope images,” said Dr. Arun Mahadevan, who helped develop this technology over the course of his PhD at Rice University.
Other software at the social included tools from the Translational NeuroEngineering lab at the University of Minnesota, which uses real-time recordings of brain signals paired with automated stimulation in order to manipulate communication between two brain regions, and Neurodata Without Borders, an ecosystem of tools that helps store, consolidate, process, and analyze large neurophysiology datasets.
Some investigators showcased new electrodes and probes (see image below). “We’re using 3D printing to make the next generation of brain probes,” said Sandy Ritchie, a PhD candidate at Carnegie Mellon University. She works in the Advanced Manufacturing and Materials Laboratory, led by Dr. Rahul Panat, which is innovating new manufacturing techniques to solve neuroscience problems. This team can very quickly produce microelectrode arrays that allow scientists to access layers of the brain that were previously out of reach. Dr. Panat said that these probes “can increase the recording density by one order of magnitude, allow greater customization, and integrate stimulation with recording in three dimensions.”Courtesy of the Panat Lab
A team of researchers from the University of Michigan presented silicon electrodes paired with LEDs for in vivo research that could provide close to single-neuron stimulation. This technology, as well as several other tools, is being disseminated across the neuroscience community through the Multimodal Integrated NeuroTechnology (MINT) NeuroNex program.
Still more groups built new hardware that can change the way researchers interact with the brain. Scientists from the University of Minnesota, Twin Cities, in the Biosensing and Biorobotics Laboratory led by Dr. Suhasa Kodandaramaiah, developed a robotics platform that can perform microsurgeries on mice. Craniobot is a useful tool for implementing very precise, delicate procedures (see image below). The robot’s software is open-source and the hardware can be built for under $1,500 using protocols from the lab and materials from Amazon. This lab has also developed “See-Shells,” transparent polymer mouse skulls that enable long-term brain imaging.Courtesy of the Kodandaramaiah Lab
This social helped engage the community and brought together researchers across multiple disciplines in order to make new connections, educate people about the advances being made through the BRAIN Initiative, and help scientists find new tools, resources, and opportunities for advancing neuroscience research.
Neuroethics at Neuroscience 2019
Neuroethics is a field that studies the ethical, legal, and societal implications of neuroscience. Nita Farahany, JD, PhD, professor at Duke University, President of the International Neuroethics Society, and a member of the NIH BRAIN Initiative’s Neuroethics Working Group (NEWG), gave the annual David Kopf Lecture on Neuroethics at Neuroscience 2019. She challenged attendees to consider the ethical, legal, and social ramifications of proliferation of technologies to access functioning of the human brain. Dr. Farahany described various devices that currently can measure mood and decode simple numbers, shapes, or words a person is saying, hearing, or seeing. She also discussed various instances where corporations are already using such devices to monitor their employees, to determine access to desirable consumer goods, and to monitor school children. Dr. Farahany shared data suggesting that people don’t fully understand the capabilities or implications of these evolving brain-recording technologies. She argued for a pro-active broad deliberation on how to protect what she refers to as ‘cognitive liberty’, in a potential future where neurotechnology is in widespread use.
Dr. Khara Ramos, Director of the Neuroethics Program at NINDS, presented the poster “Neuroethics: An Essential Partner to Enhance the NIH BRAIN Initiative” at Neuroscience 2019. Her presentation highlighted how neuroethics can serve to anticipate and address ethical questions raised by neuroscience research and that integrating neuroethics into a neuroscience research project can be a powerful way to maximize positive impact of the research. New tools and technologies that are being used to study the brain may raise important neuroethical challenges. For example: If collecting and sharing neural data is crucial, how does this intersect with protecting participants’ privacy? How do patients’ and investigators’ perceptions of the risks and benefits of data sharing align or differ?
The NIH has a multi-part strategy to help manage the neuroethical implications of the development and application of BRAIN-funded tools and technologies. This Neuroethics program includes funding neuroethics research projects, hosting workshops that focus on neuroethical considerations in specific areas of BRAIN-funded research, and managing the NEWG, who have published guidance on key ethical challenges associated with BRAIN-funded research. “I hope this is just the beginning of a culture change, in that neuroethics will become a routine part of neuroscience training programs, and neuroscientists will become quite comfortable with integrating neuroethics into their research programs,” Dr. Ramos said.
Dr. Winston Chiong, Associate Professor, University of California, San Francisco, and a member of the NIH BRAIN NEWG, co-chaired with Dr. Ramos the Neuroethics Social at Neuroscience 2019. This event was open to all conference attendees and highlighted the ways in which researchers and educators could incorporate neuroethics concepts into various stages of neuroscience training. Featured guests from multiple institutions helped attendees explore how training programs, facilities, and laboratories could use neuroethics education to help researchers better pursue the ethical dimensions of their neuroscience work.
The BRAIN Initiative Beyond Neuroscience 2019
Many new reagents, imaging devices, probes, protocols, data processing packages, and software tools are now available to the neuroscience community due to the investments of the BRAIN Initiative. This initiative will continue to fund cutting-edge research into new tools and resources and offer opportunities for scientists to form collaborations that allow them to apply these tools to new research questions.
Staying up to date on the latest BRAIN Initiative advancements is possible thanks to the work of the BRAIN Initiative Alliance (BIA), a group consisting of the National Institutes of Health, the National Science Foundation, the Intelligence Advanced Research Projects Activity, the Food and Drug Administration, Kavli Foundation, Simons Foundation, Allen Institute, and the Institute of Electrical and Electronic Engineers. Scientists wishing to learn more can visit www.braininitiative.org/ for more information on funding opportunities, BRAIN Initiative goals, and updates on new research, or follow the BIA on Facebook (https://www.facebook.com/usBRAINInitiative/) or Twitter (https://twitter.com/USBrainAlliance).
This update can also be found on the BRAIN Initiative Alliance website.
Two BRAIN Initiative scientists – Dr. Jin Hyung Lee and Dr. James Eberwine – are recipients of the NIH Director’s Pioneer Award, originally established in 2004 to fund scientists from all career stages who propose “pioneering” research with broad scientific implications beyond their field.
As part of the National Institutes of Health (NIH) Common Fund, the High-Risk, High-Reward Research Program recently awarded 93 recipients from different biomedical, social, and behavioral science fields distinct awards for their original and innovative research. This program focuses on proposals that normally would be deemed too premature or risky in the traditional peer-review process, despite their relevance to the NIH’s mission. The four awards included the NIH Director’s Pioneer Award (11 awards), the NIH Director’s New Innovator Award (60 awards), the NIH Director’s Transformative Research Award (9 awards), and the NIH Director’s Early Independence Award (13 awards). The 93 funded grants total nearly $267,000,000.
One of the prestigious awards, the NIH Director’s Pioneer Award, was granted to two scientists who are actively involved in the BRAIN Initiative: Dr. Jin Hyung Lee and Dr. James Eberwine. The NIH Director’s Pioneer Award was originally established in 2004 to fund scientists from all career stages who proposed “pioneering” research with broad scientific implications beyond their field. As consideration for the award, ground-breaking proposals included research with substantial departures from previously or currently funded research. Dr. Lee and Dr. Eberwine will be individually awarded $700,000 for five years to fund their innovative research.
Jin Hyung Lee, Ph.D., Associate Professor of Neurology, Neurosurgery, Bioengineering and Electrical Engineering at Stanford Medicine, helped pioneer optogenetic functional magnetic resonance imaging (ofMRI). This revolutionary technique combines high-resolution functional MRI with the precision of optogenetic stimulation of specific neuronal populations. Thus, ofMRI can be used to elucidate neural networks across the entire brain. Dr. Lee is a BRAIN Initiative investigator who was awarded an R01 research project grant, which aims to define cell type specific contributions to fMRI signals. Dr. Lee is now focusing her research on the development of new brain-imaging technologies that allow subjects to move about freely.
James (Jim) Eberwine, Ph.D., is the Elmer Holmes Bobst Professor of Systems Pharmacology and Translational Therapeutics at the University of Pennsylvania Perelman School of Medicine. Dr. Eberwine helped pioneer single-cell transcriptome techniques that allow researchers to assess RNAs present in individual cells, and their relative abundance. Ushering in the new era of single cell genomics, Dr. Eberwine and his colleagues’ work aims to quantitatively define both the subcellular localization and the structure of RNAs in each cell. This research also hopes to address what types of RNA structures exist in dendrites and axons and how such structures affect RNA biology (e.g., whether they facilitate stability or degradation). Dr. Eberwine is an active member of the NIH BRAIN Initiative Multi-Council Working Group and NIH BRAIN Initiative Neuroethics Working Group, and he is co-chair of the NIH Advisory Committee to the Director BRAIN Initiative Working Group 2.0 Neuroethics Subgroup. Dr. Eberwine believes that “…this is a great time to be using transformative technologies. The BRAIN Initiative has enabled us to answer many of the questions we’ve been asking for years.” He encourages everyone to study the exciting field of neuroscience – to help elucidate the most complicated organ, the brain.
This update can also be found on the BRAIN Initiative Alliance website.BRAIN Initiative-associated neuroscientists, Dr. James Eberwine (left) and Dr. Jin Hyung Lee (right) were 2 of 11 recipients who received NIH Director’s Pioneer Awards for 2019. Photo credit: NIH Office of Strategic Coordination – The Common Fund.
BRAIN is collaborating with Addgene to develop a plasmid/virus collection that will showcase and promote the dissemination of the diverse molecular tools developed under the NIH BRAIN Initiative. NIH will be seeking investigators who are interested in having their plasmids/viruses featured in the collection.
The NIH BRAIN Initiative encourages the dissemination and sharing of tools and technologies that are developed by its investigators. As part of this goal, BRAIN has collaborated with Addgene to develop a BRAIN Initiative plasmid/virus collection and repository that will showcase the diverse molecular tools developed under the BRAIN Initiative and promote their dissemination.
BRAIN-funded investigators might have an existing collection at Addgene, where they have already deposited BRAIN-funded plasmids/viruses as part of their award’s Resource Sharing Plan. Alternatively, investigators may plan to deposit plasmids/viruses in the near future after publication or completion of their active BRAIN grant.
The BRAIN Initiative collection with Addgene can be viewed here: https://www.addgene.org/collections/brain-initiative/. To start a new plasmid deposit at https://www.addgene.org/deposit/, investigators can include “BRAIN Initiative” in the Depositor Comments field during data entry, or e-mail email@example.com to add their plasmids to the BRAIN Initiative collection.
Investigators with questions about adding their plasmids/viruses to the BRAIN Initiative collection with Addgene may contact Dr. Olivier Berton (firstname.lastname@example.org).
Please join us for exciting BRAIN-relevant events at the annual Society for Neuroscience meeting in Chicago, Illinois (October 19-23, 2019).
There are several exciting BRAIN Initiative happenings at the Society for Neuroscience’s annual conference, which begins tomorrow at the McCormick Place Convention Center (Chicago, Illinois). On Saturday, October 19th from 1:30pm-4:00pm (CST; Room: S406A), there will be a mini-symposium, “BRAIN Initiative: Cutting-Edge Tools and Resources for the Community,” chaired by Dr. Walter Koroshetz, NINDS Director. Speakers include BRAIN-funded investigators: Jeff Lichtman, Alison Barth, Loren Frank, Kristen Harris, Kathleen Gates, and James Trimmer.
The annual BRAIN Initiative Alliance Networking Event will occur on Sunday, October 20th, from 6:30pm-8:30pm (CST) at the Hyatt Regency McCormick Place (Regency Ballroom CDE). This open event, “Tools & Tech: A BRAIN Initiative Alliance Social,” will feature some of the leading toolmakers funded by the U.S. BRAIN Initiative. Through the BRAIN Initiative, a broad array of neuroscience technology and resources – including software, electrophysiological/probes, optics/microscopy, molecular/cellular, chemical/small molecules, and other hardware tools – are becoming available to the research community. For a full list of tools and toolmakers who will be featured at the event, visit https://www.braininitiative.org/events/sfn-social/.
On Saturday and Sunday, come see the latest updates on the NIH BRAIN Initiative and neuroethics activities at the following posters: 1. “Neuroethics: An essential partner to enhance the NIH BRAIN Initiative” (Location/Room: McCormick Place: Hall A. Session Number: 027), and 2. “From cells to circuits toward cures: Updating NIH contributions to the BRAIN Initiative” (Location/Room: McCormick Place: Hall A. Session Number: 026).
Finally, remember to use the Neuroscience Meeting Planner and annual meeting mobile app and search for keyword, “BRAIN Initiative,” for many more talks, presentations, and events related to BRAIN.
The MacArthur Foundation has announced this year’s roster for their annual “genius” grant, including two researchers whose diligent and innovative work is part of the BRAIN Initiative.
Drs. Vanessa Ruta and Joshua Tenenbaum are two neuroscientists among the esteemed 26 fellows for 2019 whose work encompasses a broad expanse of topics ranging from writing, to music, geochemistry, criminal justice reform, and neuroscience.
Since 1981, The John D. and Catherine T. MacArthur Foundation has granted fellowships to over 1000 artists and scholars in the form of a significant financial stipend to empower these individuals to continue their ground-breaking work, such as understanding the fundamental neural principles that underlie the perception of the visual world (Doris Tsao) and expanding the conventions of musical theater to reflect cultural diversity in America (Lin-Manuel Miranda). The award is a no-strings-attached investment to “talented individuals who have shown extraordinary originality and dedication in their creative pursuits and a marked capacity for self-direction,” according to the Foundation.
Each of this year’s grantees will receive $625,000 over five years to fund their work, removing any financial barriers to creative exploration and innovation. For the two BRAIN Initiative scientists selected, the genius grant is a momentous accolade that recognizes their exceptional creativity, significant contributions to the neuroscience community, and potential to continue their innovative scientific research.
Vanessa Ruta, Ph.D., Professor at The Rockefeller University, New York, NY, uses the fruit fly Drosophila melanogaster to discern neural circuit programming in innate and learned behaviors. Ruta’s lab investigates the individual neuronal circuits that change with experience and evolve to modify future behavior. Ruta is part of the Kavli Neural Systems Institute, which fosters collaboration among Rockefeller’s dynamic community of scientists to generate new knowledge about the brain. Her National Institutes of Health (NIH) BRAIN Initiative project involves dissecting the role of the neurotransmitter dopamine in learning and behavior. She has also received an R35 Research Program Award from the National Institute of Neurological Disorders and Stroke (NINDS). The goal of the NINDS R35 program is to allow an investigator whose record of research achievement demonstrates the ability to make major contributions to neuroscience, the freedom to embark on ambitious, creative, and/or longer-term research projects, without the constraints of specific aims.
Joshua Tenenbaum, Ph.D., Professor at Massachusetts Institute of Technology (MIT), Cambridge, MA, investigates the computational basis of learning, judgment, perception, and other cognitive processes. Tenenbaum is a contributing researcher to the Intelligence Advanced Research Projects Activity (IARPA)’s BRAIN Initiative program called Machine Intelligence from Cortical Networks (MICrONS), which seeks to revolutionize machine learning by reverse-engineering the algorithms of the brain. The program is expressly designed as a dialogue between data science and neuroscience. Tenenbaum has also received funding support from two additional federal agencies involved in the BRAIN Initiative: the National Science Foundation and the Defense Advanced Research Projects Agency (DARPA).
This update can also be found on the BRAIN Initiative Alliance website.BRAIN Initiative neuroscientists, Vanessa Ruta (left) and Joshua Tenenbaum (right), receive 2019 MacArthur fellowships. Photo credit: John D. and Catherine T. MacArthur Foundation
Manipulating neural activity while measuring physiology in awake mice … Discovery of the brightest green fluorescent protein homolog to date … Assessing mouse neural dynamics with optoacoustic imaging … Establishing new open cloud services for brain data …
Repeated imaging of awake mice with multiple imaging modalities yields neural, microscopic, and mesoscopic data
Functional magnetic resonance imaging (fMRI) is widely used to non-invasively study human brain activity. However, how the underlying physiology of individual brain and blood vessel cells generates the fMRI signals is not well understood. Performing invasive cellular measurements that are not currently possible in humans and non-invasive imaging in mice provides a bridge to understand the cellular underpinnings of fMRI. Researchers have now demonstrated the feasibility of doing repeated non-invasive and invasive imaging in unanesthetized mice. Dr. Anna Devor and colleagues at the University of California, San Diego devised a protocol to image awake mice using various imaging techniques that ultimately allows for multiscale data generation. Each mouse was imaged using two-photon microscopy, laser speckle contrast imaging, and blood-oxygen level-dependent (BOLD) fMRI. There were several goals of this study, including ensuring that the cranial window implant remained clear, preventing signal artifacts, maintaining the stability of the headpost, allowing for repeated imaging over weeks and months, and conducting behavioral experiments. Genetically-engineered mice expressing inhibitory neurons with the channelrhodopsin-2 optogenetic actuator protein received several different stimuli to compare neural activity across imaging modalities. Using both one and two-photon imaging, insights on the activity of neurons, glial cells, vascular cells, and overall brain metabolics were determined at submicron resolution, as well as glucose and oxygen consumption. BOLD fMRI imaging was also sensitive enough to detect stimulus conditions in specific cortical regions. The authors found a notable increase in neural activity in fully awake versus sedated mice, likely due to decreased blood flow of mice under anesthesia. These results showcase a feasible imaging protocol in which multiple levels of brain data can be elucidated from awake mice, and this protocol could be extended to complex behaviors, such as sensory discrimination or attention. Dr. Devor and her team’s results exemplify how different brain imaging techniques can be synthesized to create a more dynamic and fundamental understanding of the brain.Two-photon imaging of awake mice through long-term glass cranial windows. (C) Imaging of cortical vasculature on Day 1 and Day 28 after cranial window implantation. (D) An image stack generated from two-photon imaging of cortical depth via cranial window.
Unraveling a “jellyfish’s secret” leads to the characterization of nine previously unknown fluorescent protein homologs
Green fluorescent protein (GFP) and its variants have revolutionized science because of their ability to showcase living complex biological systems at high levels of resolution – including the mammalian brain. However, fluorescent proteins used for research have only been derived from a small number of marine organisms, such as corals and jellyfish. Most fluorescent proteins used in scientific applications arise from the sea anemone Entacmaea quadricolor or the coral Discosoma, because of their ability to emit at longer wavelengths of light. Dr. Nathan Shaner and his team at the University of California, San Diego optically characterized fluorescent proteins from a previously unknown Aequorea (jellyfish) species. The overall goal of this study was to overcome the limitations of the known fluorescent protein scaffolds by identifying, characterizing, and bioengineering fluorescent proteins from more diverse marine organisms with little homology to commonly used fluorescent proteins. After analyzing the transcriptome of A. cf. australis (an Aequorea species most similar to Aequorea australis) in the Great Barrier Reef, the authors identified the brightest fluorescent protein to date – named AausFP1 – with a more than five-fold molecular brightness than enhanced GFP (EGFP). Returning to San Diego, the authors discovered that Aequorea victoria, on exhibit at a local aquarium, also expressed orthologs of AausFP1 that they originally identified in A. cf. australis. Beyond green emitters, these investigations discovered a wide variety of other potentially useful fluorescent proteins, including, for example, purple and blue pigmented chromophores with absorbances ranging from green to the far red. Importantly, several fluorescent variants were superior scaffolds than GFP, meaning that they are more stable in various physiological mammalian conditions (e.g., 37°C). Dr. Shaner and his colleagues’ work emphasizes the importance of characterizing unknown species with the capacity to advance science that may not exist in the future. These discoveries also highlight the value of a highly interdisciplinary approach, including field collection, molecular biology, next-gen sequencing, bioinformatics, protein engineering, microscopy, x-ray chrystallography, and phylogenetics.Fluorescent proteins purified from different Aequorea species. Different fluorescent proteins under (A) white light, (B) 505 nm, (C) 480 nm, or (D) 400 LED illumination. Note that AausFP1 shares 53% homology to avGFP and is currently the brightest fluorescent protein characterized.
Real-time volumetric measurements using optoacoustic imaging of the mouse brain produces macroscopic snapshots of neural activity
Although indirect methods can image brain-wide activity in the mammalian brain, direct methods for visualization of real time activity in vivo have been challenging. Optical methods, for example, may require invasive methods for deeper structures and are limited in area of coverage. Dr. Daniel Razansky and colleagues at the University of Zurich in Switzerland have developed methods to image whole-brain neural activity in real-time using hybrid optoacoustic imaging. Optoacoustic imaging involves using ultrasound waves that are generated from transiently absorbed light. This allows for deeper imaging of the tissue of interest with fields-of-view near 2 cm3 and spatial resolutions of 150 µm – effectively covering the entire mouse brain. The overall goal of this work was to determine the feasibility of real-time volumetric brain imaging of mice with genetically-encoded calcium indicators. These mice express either fast or slow variant calcium indicators that detect neural activity down to the single neuron level. The authors successfully imaged global calcium activity in the brain as well as hemodynamic responses. Of importance, optoacoustic imaging allowed for the capture of brain processes at different time scales and at depths not previously achievable with other noninvasive imaging techniques. Despite formidable background from hemoglobin absorption in brain tissues, optoacoustic imaging was nevertheless sensitive enough to distinguish both slow and fast changes in neuronal calcium signaling. Additionally, optoacoustic imaging recorded stronger calcium changes than the typical fluorescence activity associated with the calcium indicators. Dr. Razansky and his team’s results showcase the practical utility of optoacoustic imaging for viewing deeper brain regions and for conserving spatiotemporal information on vastly different scales, paving the way for even deeper imaging of the mammalian brain in potentially clinically relevant settings.Optoacoustic imaging of neural activity in GCaMP6f-expressing mice in response to a hind paw stimulus. Sequence ranging from t=0 ms of a hind paw stimulus to t=160 ms, t=320 ms, t=480 ms and t=640 ms of (A) fluorescence recorded brain activation maps and (B) 4D optoacoustic recorded brain activation maps at different depths ranging from 0.3 mm to 1.5 mm. Dashed white lines represent functional brain regions.
Establishment of an open diffusion data derivative (O3D) repository of brain data encourages integration, data upcycling, and reproducibility among researchers
Large scale neuroimaging projects, including the Human Connectome Project, the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Adolescent Brain Cognitive Development (ABCD) Study and many others have provided resources for data sharing, reuse, standardization, and secondary data analyses. Dr. Eleftherios Garyfallidis and his team at Indiana University Bloomington have recently developed a unique approach for sharing data and for “data upcycling”, or using data in a manner that is beyond the original scope of research, which has the potential to advance neuroscience and other fields. The project is a web based open diffusion platform that is an open diffusion data derivative (O3D) repository of brain data-derivatives and analysis pipelines. Data derivatives here refer to data that have gone through several analysis iterations. The O3D repository, also known as brainlife.io, was created using diffusion-weighted magnetic resonance imaging (dMRI) data and tractography allowing for structural, anatomical, macroscopic, and microscopic details of the human brain to be preserved under one single digital object identifier (DOI). The O3D repository houses a collection of dMRI files from 12 brains; 3 separate datasets; over 300 tractograms; over 7,000 segmented major tracts, and over 700 matrices (connectivity networks). Thus, researchers who use the O3D repository can choose to upload new data using the same data analysis pipelines. Alternatively, individuals can analyze new data by downloading separate data derivatives in a stepwise fashion. The O3D repository differs from similar data projects as it allows for brain data to be tested and retested for reproducibility purposes. The work of Dr. Eleftherios Garyfallidis and colleagues facilitates collaboration between trainees at all career levels and among members of different scientific disciplines. This work, supported by a joint initiative of the National Institutes of Health and National Science Foundation known as the Collaborative Research in Computational Neuroscience (CRCNS) program, and with support from the National Science Foundation and Microsoft, propels the field of neuroscience into the future of making data understandable, interactive, and accessible for all. For more information, please see an Indiana University press release on this work.Tractograms of the whole human brain. Visualization of whole-brain tractograms generated from three datasets: Stanford University (STN) and the Human Connectome Project (HCP3T and HCP7T). Each dataset uses various reconstruction models, including the deterministic model (DTI), constrained-spherical deconvolution (CSD) deterministic model, and CSD probabilistic model.