BRAIN 2015 Blog of Blogs

Summary

This 'BRAIN 2015 Blog' will aggregate the best blog posts from the BRAIN Initiative community. We repost open access blogs .... and we summarize other selected blog posts.

Bloggers include:
Tom Insell, NIMH Director
Walter Koroshetz, NINDS Director
Tom Kalil, OSTP Technology and Innovation Deputy Director
James Olds, NSF Assistant Director BIO Directorate
Hank Greely, At large member Multi-Council Working Group

June – August 2015

The Brain’s Critical Balance

Director’s Blog July 29, 2015
Tom Insel, Director NIMH and co-Director of the BRAIN Inititative

We have reached an interesting moment in our quest to understand how the brain works. Our current tools generate an abundance of data, but we are not sure how to turn this data into knowledge. In some ways, neuroscience today is where physics was half a century ago. The physicist Steven Weinberg reminds us, “Rather than being starved for data fifty years ago, we were deluged by data we could not understand. Progress when it came was generally initiated by theoretical advances, with experimentation serving as a referee between competing theories and providing occasional healthy surprises.” While we don’t have a unified field theory of the brain, some of the early projects in the BRAIN Initiative are providing models of how behavior emerges from brain activity.  One of the first grants issued by the BRAIN Initiative supported scientists at NIMH and the University of Maryland to understand how the activity of individual neurons is integrated into larger patterns of brain activity. This work builds on the observation that in nature, order sometimes emerges out of the chaos of individual interacting elements.

This month, the NIMH team, led by Dietmar Plenz, reported that what might seem like chaotic, “noisy” firing of individual neurons in fact organizes across the brain in ways that can distinguish anesthetized and awake states and eventually could help distinguish healthy from disordered brain function.3 In awake rats the sporadic firing of individual neurons spontaneously organizes into avalanches, or cascades of activity within groups of neurons. Tracking neuronal firing using 2-photon imaging, which reveals the activity of individual cells in a behaving animal, the team found that avalanches were absent while the rats were anesthetized, but emerged as they awaken. While prior research in humans and animals has noted the presence of neuronal avalanches in the brain, this is the first link between the emergence of avalanches, the activity of excitatory neurons, and awakening. This finding depended not only on advanced imaging using genetically encoded fluorescent calcium sensors, but the ability to analyze complex patterns of neuronal firing.

Importantly, the frequency and magnitude of avalanches occur in a ratio that is consistent from small scale to large (reminiscent of fractals, repeating patterns that mirror themselves at every scale). This order in neuronal activity bursts, reflected in the above ratio, echoes a universal organizational pattern in nature, now observed in systems as diverse as social networks, power grids, economic systems, and the internet. Avalanche organization emerges as the many individual elements in each system engage in precisely balanced interactions. In the brain, the pace of neuronal avalanches depends on a balance between “excitatory” activity that causes neurons to fire, and “inhibitory” activity that prevents firing. Too much excitatory activity, and the system veers off balance, as in epilepsy, and possibly psychiatric disorders. It appears that the healthy brain is poised at “criticality,” ensuring the optimal ability to respond to the environment without tipping into instability.

There is an increasing recognition that understanding the brain in health and disease is going to require methods to make sense of the interactions of thousands, if not millions, of interacting, ever-changing assemblies of genes, proteins, and cells that form the circuits encoding our experience of the world. The BRAIN Initiative, beyond providing tools to measure, visualize, and monitor brain activity, is supporting scientists to develop a unifying framework and underlying principles for understanding how the estimated 86 billion neurons in the human brain act, en masse and in split second time frames, to enable consciousness and behavior.

References

Weinberg S. Physics: What We Do and Don’t Know.  The New York Review of Books. November 7, 2013.

Bak P. How Nature Works. Oxford. Oxford University Press. 1997.

Bellay T, Klaus A, Seshadri  S, Plenz D. Irregular spiking of pyramidal neurons organizes as scale-invariant neuronal avalanches in the awake state.  eLIFE. 2015 Jul 7;4. doi: 10.7554/eLife.07224.

New Award Creates Stable Funding for Outstanding Neuroscience Investigators

Director’s Messages July 16, 2105
by Walter Koroshetz, Director of NINDS and co-Director of the BRAIN Inititative

As NINDS Director, my goal is to optimize the progress of basic, translational, and clinical neuroscience research. One issue that slows the pace of discovery is that, rather than directly engaging in research, many principal investigators spend a great deal of their time writing and administering grant proposals. This is a consequence not only of the current constrained budget climate, but also of the fact that NIH grants fund individual projects that are relatively short in duration.

We feel that it is time to free up smart, talented people with innovative ideas to focus their time and effort on doing excellent science. To empower investigators to use their time more productively, NINDS is piloting a new funding mechanism – the Research Program Award (RPA) (see FAQs). Rather than funding a single project, an RPA will support an NINDS investigator’s overall research program for up to eight years. This initial pilot program aims to fund up to 30 investigators in FY 2016 who have demonstrated strong potential to do high impact science. The announcement describing this new award was released July 15 for an application deadline of Oct 6.  For further information about the RPA, see the blog post from our Extramural Director Robert Finkelstein.

Early BRAIN Breakthroughs

Director’s Blog June 22, 2015
Tom Insel, Director NIMH and co-Director of the BRAIN Inititative

I don’t usually keep count of scientific breakthroughs, but right now we are on a streak of findings from the BRAIN Initiative that, if my count is correct, looks like one a week for the past five weeks. BRAIN is the Brain Research through Advancing Innovative Neurotechnologies Initiative. This is the public and private effort, first announced by President Obama in April 2013, to develop the next generation of tools to understand the brain. New tools should reveal not only a new understanding of the brain, but new approaches to brain disorders and ultimately new treatments.

One of the early goals of the BRAIN Initiative is a “parts list” for the brain. While we have a pretty good idea of the various cell types in most organs, for the brain we still lack a comprehensive list of the kinds of cells and how many of each kind of cell should be present. This is a surprisingly hard problem, partly because of the sheer numbers and diversity of cell types in the human brain. In mid-May, Evan Macosko and his colleagues at Harvard and MIT reported on Drop-seq, a new technique for single cell analysis.1 Drop-seq is a high throughput system for identifying cell types by the genes they express using bar-coded beads in microscopic droplets. The system is fast (processing 10,000 cells in 12 hours) and inexpensive (less than 7 cents per cell). As a test case, the team studied over 44,000 cells in the mouse retina and identified 39 cell types, consistent with previous reports using far more labor- intensive methods.

Another goal of the BRAIN Initiative is to move from correlational studies to causal or mechanistic studies of brain function. By delivering genetically altered receptors or channels into the brain, cells and circuits can be turned on or off with great precision, allowing a better test of causal mechanisms. Optogenetics is one version of this approach, using a pulse of light from an implanted laser to control the activity of individual cells deep in the brain. Another version, sometimes called chemogenetics, uses the Designer Receptor Exclusively Activated by Designer Drugs or DREADD technology which targets a genetically engineered receptor to a specific cell type. Because this receptor can only be activated by a designer drug that activates no other receptor, specific cell types can be influenced more precisely than is possible with natural receptors and current drugs. Last month Bryan Roth and his colleagues at the University of North Carolina reported on a new generation of DREADDs, based on the kappa-opioid receptor but activated by a pharmacologically inert drug.  This new designer receptor reduces neuronal activity, meaning that DREADDS can be used for bidirectional control of neuronal circuits.2

Next generation imaging has been a major effort in the first year of the BRAIN Initiative. Early last month, Lihong Wang and his colleagues at Washington University and Texas A&M University reported on a new form of non-invasive imaging called photoacoustic microscopy.3 With this novel technique, single capillaries and the oxygenation of blood can be visualized in the brain through the intact skull of a mouse. This method achieves much higher spatial and temporal resolution than any current method for in vivo brain imaging through the skull. While still in development, photoacoustic imaging could be a new modality for human brain imaging in the future.

In addition to imaging, direct recording of brain signals is ripe for a revolution.  Developing new ways of recording brain signals will require engineering, materials science, nanotechnology, and a lot of luck. Charles Lieber, an NIH Pioneer Awardee, and his team at Harvard just described syringe-injectable electronics.4 This technique involves injecting a polymer net that is a soft, conductive electrode array covering the cortex for direct recording. Their first experiments in mice show that this approach can be used to record from and stimulate thousands of cells. Presumably a similar approach could someday be used to record from human cortex without major neurosurgery.

Will the BRAIN Initiative allow paralyzed people to walk? If we could understand brain signals well enough to “hack” them, could we use these signals to drive an interface that could allow someone with a spinal cord injury to grasp or walk? If this seems like science fiction, check out this video  of work from Andy Schwartz at the University of Pittsburgh.

Perhaps even more amazing was a report last month from Richard Andersen and his colleagues at CalTech, entitled “Decoding motor imagery from the posterior parietal cortex of a tetraplegic human.”5In contrast to previous studies demonstrating that signals from the motor cortex can drive a robotic arm, this new report uses a posterior part of the brain associated with attention and intention. Electrodes implanted in this region were capable of driving a robotic arm to reach and grasp, including signals that controlled both left and right sides. The goal, of course, is to use brain signals to drive the person’s own limbs, not robotic limbs, but these early successes with robotic arms suggest that the codes for controlled movements can be channeled perhaps from multiple areas of the cortex and that getting people out of wheelchairs could be one of the achievements of the BRAIN Initiative.

This is still the very beginning of what President Obama called “the next great American project.” None of us can quite imagine where the BRAIN Initiative will lead, but the first year has already revealed more progress than any of us could have expected. Freeman Dyson, speaking of astrophysics, noted that “New directions in science are launched by new tools much more often than by new concepts.” 6Judging from this first year, it appears this insight will hold true for neuroscience as well.

References

1 Macosko EZ et al. Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets.  Cell. 2015 May 21;161(5):1202-14. doi: 10.1016/j.cell.2015.05.002.

2 Vardy E et al, A New DREADD…, Neuron, May 2015

3 Yao J et al. High-speed label-free functional photoacoustic microscopy of mouse brain in action.  Nat Methods. 2015 May;12(5):407-10. doi: 10.1038/nmeth.3336. Epub 2015 Mar 30.

4 Liu J et al. Syringe-injectable electronics.  Nat Nanotchnol. 2015 Jun 8. doi: 10.1038/nnano.2015.115. [Epub ahead of print]

5 Aflalo T et al. Neurophysiology. Decoding motor imagery from the posterior parietal cortex of a tetraplegic human.  Science. 2015 May 22;348(6237):906-10. doi: 10.1126/science.aaa5417.

6 Dyson F. Imagined Worlds. Cambridge, MA: Harvard University Press, 1997.

The BRAIN Like You’ve Never Seen It Before!

Posted by Tom Kalil and James Olds on June 12, 2015 at 01:45 PM EDT

BRAIN Awareness

Director’s Blog March 18, 2015
Tom Insel, Director NIMH and co-Director of the BRAIN Inititative

Curator’s note: To view all Tom Insell’s BRAIN related posts, go to this BRAIN 2015 post.

After what seems like an endless winter along the East Coast, we have reached what Emily Dickinson famously called the “month of expectation.” And, of course, March is also the time each year we celebrate Brain Awareness Week, the annual celebration of neuroscience with school visits, community lectures, and lab tours to talk about the brain. A list of Brain Awareness events can be found at http://www.dana.org/brainweek/ , where you will also find that March 16-22 is the week for related public events around the world.

Who would have imagined a decade ago that brain science would have become so popular? Not only has President Obama proclaimed the BRAIN  Initiative as the “next great American project,” there are related projects in the European Union, Israel, Canada, Australia, and Japan. We expect a brain project in China to be announced soon. The private sector has joined in as well, from big companies like GE to new companies like Inscopix. Google has shifted a team from mapping roads and traffic to mapping the intricacies of neuronal connections. Apple has announced a research kit for Parkinson’s disease. And Facebook is hiring computational neuroscientists to develop brain-computer interfaces.

All this excitement does not mean that Brain Awareness Week is superfluous. This year, this is a good time to note a few recent advances. In a few months, the Human Connectome Project  will complete its multimodal study of 1,200 healthy adults, including 300 twin pairs. Already, data on over 500 subjects have been made public, creating an unprecedented treasure trove for students who want to explore individual variation in brain pathways. Like the Human Genome Project that created a fundamental map of our genetic sequence, the Human Connectome Project will provide a reference atlas of macro-level brain connections that can be used to study development, diseases, and species differences. Developmental connectomes and disease connectome projects will follow soon.

What’s new from the BRAIN Initiative? The first 58 projects funded by the NIH have launched recently. One project will use wireless nano-stents as sensors to form a vast network in the brain’s blood vessels, developing a GPS map for traffic across the complex networks of the active brain. Another will use focused ultrasound to activate deep brain structures non-invasively. Projects for new imaging tools include attempts to increase spatial resolution one hundred-fold and a method to capture regional activity in active, ambulatory subjects. We don’t know if any of these high risk projects will succeed, but the BRAIN Initiative, like the Apollo program—another great American project—is an opportunity to push the boundaries of how we study this frontier, in this case inner space rather than outer space.

Moving forward, the NIH BRAIN Initiative will develop new tools for invasive recording and stimulating brain activity in patients with neurological disorders. We will be expanding our current efforts to define the different types of brain cells and brain circuits, as well as developing new tools for large-scale recording and decoding of brain circuit activity. BRAIN will be developing a new arm for training scientists in the use of new technologies. And BRAIN will be reaching out to small companies to join the project.

Brain Awareness Week is especially important for NIMH. On behalf of ten institutes at NIH, we are co-leading the BRAIN Initiative along with the National Institute of Neurological Disorders and Stroke. We think that tools that can decode the language of the brain at the speed of thought can also help us diagnose and ultimately treat mental disorders. If mental disorders can be defined as circuit disorders, what some have called “connectopathies,” one of the fruits of the BRAIN Initiative will be the tools to define mental disorders with greater precision. In addition to yielding biomarkers of brain circuit activity, the BRAIN Initiative may ultimately provide non-invasive tools to tune circuits, creating new treatments. Admittedly, this may require a decade of progress not just a “month of expectation.” Brain Awareness Week is an excellent time to celebrate this exciting quest.

Investing in Research to Help Unlock the Mysteries of the Brain

On April 2, 2013, President Obama launched the Brain Research through Advancing Neurotechnologies (BRAIN) Initiative, a Grand Challenge designed to revolutionize our understanding of the human brain. Since then, the BRAIN Initiative has grown to include five Federal agencies. The BRAIN Initiative remains a top priority for the Administration, which is why the President’s 2016 Budget proposes increasing funding for the BRAIN Initiative from about $200 million in FY 2015 to more than $300 million in FY 2016.

This increased investment will support a wide range of interdisciplinary projects aimed at developing and applying cutting-edge technologies to create a dynamic picture of the brain in action, providing the critical knowledge base for researchers seeking new ways to treat brain disorders. These projects include the following Agency efforts:

  • National Institutes of Health: NIH will support a diverse set of projects, including developing new devices to record and modulate activity in the human nervous system and revolutionizing human neuroimaging technologies to understand how individual cells and complex neural circuits interact in time and space.
  • Defense Advanced Research Projects Agency: DARPA will focus on leveraging brain-function research to alleviate the burden of illness and injury and provide novel, neurotechnology-based capabilities for military personnel and civilians alike. In addition, DARPA is working to improve researchers’ abilities to understand the brain by fostering advancements in data handling, imaging, and advanced analytics.
  • National Science Foundation: NSF will focus on generating an array of physical and conceptual tools needed to determine how healthy brains function over the lifespan of an organism, including humans. NSF will also focus on the development and use of these tools to produce a comprehensive understanding of how thoughts, memories, and actions emerge from the dynamic actions of the brain.
  • Intelligence Advanced Research Projects Activity: IARPA will focus on applying breakthroughs in neuroscience to advance understanding of cognition and computation in the brain. In addition, IARPA will test and validate non-invasive neural interventions that have the potential to significantly improve adaptive reasoning and problem solving.
  • Food and Drug Administration: FDA will focus on enhancing the transparency and predictability of the regulatory landscape for neurological devices. FDA’s efforts will also include a new program that would speed the availability of certain medical devices that address unmet public health needs while ensuring that patients receive high-quality, safe, and effective medical devices, including those that treat brain disorders.

The BRAIN Initiative is further supported by non-Federal partners. Major foundations, private research institutions, universities, and patient advocacy organizations have committed over $240 million to the BRAIN Initiative. In addition, members of the National Photonics Initiative, regional clusters like the Pacific Northwest Neuroscience Neighborhood, and companies such as GE, GlaxoSmithKline, and Inscopix have joined this effort through commitments of more than $30 million in research and development investments.

We want to hear about other activities that align with the goals of the BRAIN Initiative! If your organization is pursuing new or expanded activities that advance our understanding of the brain, tell us by emailing brain@ostp.gov.

Learn more:

  • Fact Sheet: Obama Administration Proposes Over $300 Million in Funding for The BRAIN Initiative.

Monica Ramirez Basco is Assistant Director for Neuroscience, Mental Health, and Broadening Participation at the White House Office of Science and Technology Policy.

Robbie Barbero is Assistant Director for Biological Innovation at the White House Office of Science and Technology Policy.

January – December 2014

The BRAIN Initiative and Grand Challenge Scholars

On Tuesday, September 30, OSTP hosted the White House BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Conference. The BRAIN Initiative seeks to revolutionize our understanding of the human brain by mapping the brain, linking neural activity to behavior, and integrating computation with neuroscience experiments. Last week, former competitive snowboarder Kevin Pearce shared why the BRAIN Initiative has personal meaning for him, demonstrating the real positive impact that the Initiative has on individuals. The BRAIN Conference was held to highlight recent progress on the President’s BRAIN Initiative, and to look ahead at the tools and technologies that still need to be envisioned and created to meet the goals of the BRAIN Initiative.  The conference participants included representatives from the academic research community, national laboratories, philanthropic foundations, companies, and other key contributors across America that have aligned their research goals with the Initiative.

Several students from the National Academy of Engineering Grand Challenge Scholars Program were also invited to participate. Students selected for this prestigious, nationwide program may become some of the next generation’s top scholars. OSTP invited two of them, Kevin Mauro from Duke University and Kaleia Kramer from Arizona State University, to share their experiences from the conference.

What are your thoughts on the BRAIN initiative?

Kevin: The BRAIN Initiative is a much-needed kickstarter for research into the neurosciences. It’s likely that many of the problems facing our understanding of the brain will have multiple solutions, each with its own pros and cons. An overwhelming amount of funding is still needed, but I believe all of this funding is both necessary and will produce tremendous results.  Additionally, I think people underestimate the mark scientific advancements can leave on our culture. The fact that, fifty years later, people are still inspired by the United States’ moon landing is a sign that if U.S. were to lead the charge into understanding the brain, it could very well carry our reputation as a global scientific leader into the 21st century. Endeavors like the BRAIN Initiative are a way for our government to encourage research into the neurosciences.

Kaleia: The BRAIN initiative has provided a means for collaboration between multiple institutions and seeks to advance our understanding of the brain, revolutionizing our approach to research. As someone who researches the brain areas involved with motor control, and seeks to continue this research after graduating, I was thrilled to hear the announcement of the BRAIN Initiative. Its potential to solve some of our biggest questions about the brain will assist in our ability to understand and treat patients less invasively and more effectively. In addition, since the call to action from the Obama Administration, there has been a larger push toward conversation and collaboration between research groups.

What can students do to advance the goals of the BRAIN initiative? What advice would you give them?

Kaleia: Students who desire to advance the goals of the BRAIN initiative or engage on other scientific challenges of the 21st century should develop research questions related to their scientific challenges of interest. Fundraising is another way to advance research, as well as working with philanthropies that donate to the advancement of neuroscience and other scientific challenges of the 21st century. For students pursuing neuroscience, engineering, and other fields related to the BRAIN Initiative, I would recommend joining a research laboratory early in their undergraduate career and learn as much as possible prior to starting a project. The past two years I’ve spent in my laboratory have been invaluable, and I have directly applied most of my coursework to the development and execution of research questions in the laboratory. Also, students shouldn’t afraid to become involved prior to college in pre-college research programs, philanthropies, or even shadowing major researchers or companies involved in the BRAIN Initiative. There is no limit to what you can learn, regardless of your age, and never stop asking questions.

Kevin: The best way to become a valuable member in nearly any scientific field is to learn to code. Software developers are needed across all types of industry (private, university, government). It has been my experience that nearly every lab could use another pair of hands to perform data analysis or machine learning techniques that you can learn with at least some coding background.  There are practically an infinite number of ways to learn to code, most of them you can do in your free time.  If you want to stay in the realm of biology, try e-mailing a science laboratory at your school expressing interest. Of course, take advantage of the Grand Challenge Scholars Program if it’s offered at your school. It really does give you a great mindset on to plan your future.

How would you describe NAE Grand Challenge Scholars Program?

Kevin: Grand Challenges are a list of “dares” from an older generation to ours. We are dared to reverse-engineer the brain, we are dared to secure cyberspace, we are dared to prevent nuclear terror. This list is about nothing other than the pursuit of something that will last beyond our lifetimes, and trickle down in the history lessons taught to future generations. The 14 National Academy of Engineering Grand Challenges for Engineering aren’t just a call to those already in the field of science. They’re a call to anyone passionate about scientific innovation and the grand impacts it can have on our lives.

Kaleia: The Grand Challenge Scholars Program is designed to address these NAE Grand Challenges and prepare students to solve the problems of the 21st century. Grand Challenge Scholars are required to choose one of the 14 Grand Challenges for Engineering and fulfill five program components related to their grand challenge of interest. These components include two semesters of research experience, an interdisciplinary curriculum, entrepreneurship, a global dimension, and service learning.

How did you get involved in the National Academy of Engineering (NAE) Grand Challenge Scholar Program?

Kevin: I became involved in the NAE Grand Challenge Scholar (GCS) program through my dean at Duke University. The GCS program appealed to me because of its interdisciplinary approach. For example, many engineering programs across the country focus only on academics and if students are lucky, a research or industry component too. As a member of the GCS program, I’m required to have academic, global, research, service, and entrepreneurial components to my application. Coming into college I never expected that I would want to start a company once I graduated. However, the GCS program has done exactly that — I have an idea for a start-up that I will likely pursue after college thanks to the ‘push’ that the GCS program gave me.

Kaleia: Watching my best friend in high school suffer from Reflex Neurovascular Dystrophy was heartbreaking and inspired me to pursue neuroscience as well as biomedical engineering in hopes of finding a means of alleviating the pain that she was experiencing. Since her recovery, I have maintained my drive to pursue this research and better understand this disorder, as well as other aspects of the brain. When I started my freshman year of college at Arizona State University as a biomedical engineer, I was enthusiastic about not only the Biomedical Engineering Department’s neural engineering focus, but also their encouragement of undergraduate research. After joining Dr. Marco Santello’s Neural Control of Movement Laboratory, I discovered the Grand Challenge Scholars Program and their rounded and holistic approach to engineering education. Since I already planned on focusing on neural engineering, I was delighted to discover that one of the National Academy of Engineering’s Grand Challenge areas was Reverse-Engineering the brain, which I am currently pursuing.

Tell us about your NAE Grand Challenge work/research.

Kaleia: Motor control is essential for daily functions; although we know a lot about what we can do with motor control, we still lack the understanding of how it works. For the past two years I have been working with a team to try to understand the roles of different areas of the brain in planning, learning, and executing movement. This is done using a Transcranial Magnetic Stimulation (TMS) machine to create virtual lesions, inhibit, excite, and monitor cortical activity in areas related to motor control, planning, and execution. Using transcranial direct current stimulation as well as TMS, I hope to understand areas involved in both associative learning and dual task interference. These two areas of research can be later applied not only to a healthy population but to those with Alzheimer’s Disease in hopes of increasing associative learning and prevent dual task interference from affecting quality of daily life.

Kevin: My research is on brain-machine and brain-to-brain interfaces. Basically, I’m building the language that will let our brains talk to computers. One cool example that came from this kind of research is the Walk Again Project at the 2014 World Cup. My lab was able to design a brain-controlled exoskeleton that allowed a paralyzed teenager stand up and kick a soccer ball at the opening ceremony to the World Cup. This kind of “reverse-engineering the brain” is exactly what is promoted by both the BRAIN Initiative and the Grand Challenge Scholars Program.


Want to become more involved with BRAIN? Send your ideas for how the Administration can further the goals of the BRAIN Initiative at brain@ostp.gov and stay up to date at WhiteHouse.gov/BRAIN.

Creating the Next Generation of Tools

Director’s Blog June 11, 2014

Curator’s note: To view all Tom Insell’s BRAIN related posts, go to this BRAIN 2015 post.

Each year at this time, the Kavli Foundation announces its annual scientific prizes. In contrast to the Nobel Prizes, the Kavli Prizes cover three focal areas of science: astrophysics, nanoscience, and neuroscience. Fred Kavli, who died recently, described these prizes as recognizing those who work on “the biggest, the smallest, and the most complex.” This year’s awards in neuroscience, to Brenda Milner, John O’Keefe, and Marcus Raichle, continue the tradition of recognizing those who embrace complexity.

Complexity was also the theme of an extraordinary report released last week by the NIH Advisory Committee to the Director (ACD). Workgroup reports for advisory committees generally are not great summer reading, but this one, which captures not only the complexity but the excitement of brain research, is both insightful and inspiring. The report provides a 12-year plan for the BRAIN Initiative (BRAIN is an acronym for Brain Research through Advancing Innovative Neurotechnologies), what President Obama has called “the next great American project.” We know much less about the brain than any other organ, and yet brain disorders, from autism to Alzheimer’s, are increasing in prevalence, creating a national public health crisis. Recognizing both the urgency and the complexity, the BRAIN report calls for a broad approach, involving a $4.5 billion investment over 10 years beginning in fiscal year 2016, to decode the language of the brain by understanding its circuits.

Freeman Dyson, a leading astrophysicist, famously said, “New directions in science are launched by new tools much more often than by new concepts.” This is true for neuroscience as much as astrophysics. The Rosetta Stone for the brain will require a new generation of tools that give us the vocabulary, the syntax, and the grammar of the brain. We still do not know the number or types of cells, the basic principles of encoding information, or the rules by which the brain stores and retrieves information. Our tools for recording from circuits capture, at best, hundreds of cells when circuits involve many thousands or millions. Our current approach has been compared to watching a television screen with only a handful of pixels, rather than the millions we require for HDTV. Modern imaging, which yields impressive color images, is also a coarse representation of brain activity. Even the highest resolution imaging scanner for the human brain captures the aggregate activity of about 100,000 neurons in each voxel (think of a voxel as a 3D pixel), when we really want to be measuring the activity of individual neurons or at least much smaller groups of neurons in each voxel. And these scanners work by measuring changes in blood flow or oxygen consumption, a process that is much too slow to monitor brain activity at the speed of thought.

The BRAIN report calls for a new generation of tools for neuroscience. Recognizing that current tools are focusing on the “micro-connectome” to map every connection of a small group of cells or the “macro-connectome” to map activity of the whole brain with neuroimaging, the report focuses on the “meso” scale, the in-between level that includes the circuit activity that may be the most critical for decoding the brain’s language. Developing the tools for neuroscience at this scale will require teams of scientists from many disciplines, especially engineering, materials science, nanotechnology, and computational science. The first wave of grants for the BRAIN Initiative are expected to be awarded this September to launch projects on creating a cell census for the brain, creating new tools for monitoring circuit activity, and planning for the next generation of scanners for imaging the human brain.

In spite of the complexity and the urgency, the price tag of $4.5 billion may elicit sticker shock for some. This is, of course, the budget recommended by the ACD BRAIN working group, not a commitment from NIH. BRAIN funds would be “new money” that does not replace current funding for basic, translational, and applied research at NIH. These funds would need to be proposed by the President and appropriated by Congress. Even over the 10-year timeline, the $4.5 billion is less than what NIH currently spends on neuroscience research each year. And as Cori Bargmann, co-chair of the working group pointed out, $4.5 billion is still “less than the cost of a six pack of beer for every American.” Most of all, BRAIN is an investment in the future – giving us the tools to make progress on brain disorders and inform a deeper understanding of what makes us human.

As a glimpse into what this future might look like, last week brought two other notable neuroscience events from projects that preceded the BRAIN Initiative. The Human Connectome Project released data on the first 500 subjects who have received state-of-the-art brain scans and cognitive assessments. This massive amount of data, unprecedented in human neuroscience, along with the tools to explore it, have been uploaded to the Human Connectome Projectwebsite  . Also last week, the International Neuroimaging Data-sharing Initiative (INDI) announced the public release of the “Consortium for Reliability and Reproducibility (CoRR )” via the 1000 Functional Connectomes Project. This effort has aggregated data from 1629 individuals across 38 cohorts collected at 18 institutions (over 5,000 resting state fMRI scans) to establish benchmark datasets for the evaluation of analytic methodologies, as well as to understand the range of variation for reliability across sites. Datasets will be made available via COINS  an easily searchable informatics platform that was used for collecting the scans. BRAIN projects will follow a similar scenario, making tools and data available to the community as soon as possible.

What Freeman Dyson said about the importance of tools for new directions in science is critically important for NIMH. Biomarkers, new therapies, and preventive strategies for brain disorders, especially for the “connectopathies” that we call mental disorders, will require better tools. NIMH will be co-leading the BRAIN Initiative with our sister institute, the National Institute for Neurological Disorders and Stroke (NINDS). Whether you are a scientist working on synapses or a family member challenged by a mental disorder, the BRAIN Initiative represents a bold commitment by the NIH, offering hope for the development of better tools to enhance our understanding of the brain in health and disease.

January – December 2013

New Views into the Brain

Director’s Blog April 10, 2013
Tom Insel, Director NIMH and co-Director of the BRAIN Inititative

Curator’s note: To view all Tom Insell’s BRAIN related posts, go to this BRAIN 2015 post.

The physicist and mathematician Freeman Dyson once noted, “New directions in science are launched by new tools much more often than by new concepts.”1 This week marks the publication of a new tool that may alter the way we look at the brain. Karl Deisseroth and his colleagues at Stanford University have developed a method they call CLARITY. Yes, CLARITY is an acronym, for Clear Lipid-exchanged Anatomically Rigid Imaging/immunostaining-compatible Tissue hYdrogel. By replacing the brain’s fat with a clear gel, CLARITY turns the opaque and impenetrable brain into a transparent and permeable structure. Most important, the hydrogel holds the brain’s anatomy intact. And because the hydrogel is permeable, the brain can be stained to localize proteins, neurotransmitters, and genes at a high resolution (see images below). Unlike other recent breakthroughs in neuroanatomy, this one can be used in human brains.

This technique is only for post-mortem tissue. And it measures structure not function. But I predict this new tool will revolutionize neuropathology, opening a new era for studying the neural basis of mental disorders. Indeed, in this initial report Deisseroth and his colleagues describe findings from a brain of someone who had died with autism 6 years earlier. With CLARITY they detected an unusual pattern of bridging connections from a particular class of inhibitory cells in this brain. Of course, this finding from a single brain needs to be replicated. The beauty of CLARITY is that other brains can now be tested, even tissue that has been stored for years.

CLARITY arrives only a week into the new BRAIN Initiative, announced by President Obama on April 2nd. Yes, BRAIN is another acronym—for Brain Research for Advancing Innovative Neurotechnologies. With some 200 neuroscientists in the East Room of the White House, the President declared, “…there is this enormous mystery waiting to be unlocked, and the BRAIN Initiative will change that by giving scientists the tools they need to get a dynamic picture of the brain in action and better understand how we think and how we learn and how we remember. And that knowledge could be—will be—transformative.”

The President proposed $100 million for the first year of what he called “the next great American project.” NIH, the Defense Advanced Research Projects Agency, the National Science Foundation, and several private laboratories and foundations will be working to develop the next generation of tools for decoding the language of the brain. The NIH BRAIN Initiative  will begin with a planning process to identify the highest priorities and propose some specific short-term and long-term goals.

Recent investments have already built a foundation for this new initiative. As just one example, the Human Connectome Project has increased the resolution of white matter imaging to provide the first detailed “wiring diagram” of the human brain. In one of the first reports from this project, scientists discovered a surprisingly simple 3-dimensional organization of fiber tracts in the human brain.2 The Human Connectome Project has already posted extensive imaging results and cognitive data on a reference cohort of 68 healthy volunteers, on its way to a database of 1200 subjects including 300 twin pairs. (Note to students and early stage scientists: this goldmine of data is waiting for you!)

The new BRAIN Initiative, building on these recent advances, could not come at a better time. Several recent reports have emphasized the increase in prevalence and the increasing costs of brain disorders, from autism to Alzheimer’s disease. The World Health Organization estimates that neuropsychiatric diseases in the developed world are already the leading source of medical disability.3 A recent report from the World Economic Forum projects that health care for mental disorders will account for the greatest expense among health care costs of all non-communicable diseases in the coming decades, greater than cancer, diabetes, and pulmonary disease put together. Given the contribution of mental disorders to these other medical diseases and recognizing our still limited understanding of the brain, you can see why the President called for “this next great American project.”

If CLARITY is a predictor, the next few years could be a period of rapid new insights into brain structure and function. As Dyson said, “new directions in science are launched by new tools.” One can barely begin to imagine how tools like CLARITY will change our concepts of how the brain works in health and disease.

CLARITY provided this 3D view showing a thick slice of a mouse brain’s memory hub, or hippocampus. It reveals a few different types of cells: projecting neurons (green), connecting interneurons (red), and layers of support cells, or glia (blue). Conventional 2D methods require that brain tissue be thinly sliced, sacrificing the ability to analyze such intact components in relation to each other. CLARITY permits such typing of molecular and cellular components to be performed repeatedly in the same brain.
Source:
Kwanghun Chung, Ph.D., and Karl Deisseroth, M.D., Ph.D., Stanford University

CLARITY makes possible this 3D tour of an entire, intact mouse brain. It was imaged using a fluorescence technique that previously could only be performed with thinly-sliced brain tissue, making it difficult to relate micro-level findings to macro-level information about wiring and circuitry.
Source:
Kwanghun Chung, Ph.D., and Karl Deisseroth, M.D., Ph.D., Stanford University

References 1Dyson F. Imagined Worlds. Cambridge, MA: Harvard University Press, 1997. 2Wedeen VJ et al. The geometric structure of the brain fiber pathways. Science. 2012 Mar 30;335(6076):1628-34. doi: 10.1126/science.1215280. 3The Global Burden of Disease: 2004 Update. Geneva, World Health Organization, 2008. 4Bloom DE et al. The Global Economic Burden of Noncommunicable Diseases. Geneva: World Economic Forum, 2011.See press release: Fat-Free See-Through Brain Bares All

Breaking News – White House announces “BRAIN” Initiative

April 2, 2013 by Hank Greely

For more on Hank Greely, at large member of the Multi-Council Working Group, go here.

“Brain Research Through Advancing Innovative Technologies” will be the subject of over $100 million in federal investment.  DARPA will contribute $50 million, NIH $40 million, and NSF $20 million.   They will partner with the Allen Institute ($60 million), Kavli Foundation ($4 million), Salk Institute ($28 million), and Howard Hughes Medical Institute ($30 million).  It’s not clear what all these dollar figures really mean, but it almost certainly beats a poke in the eye with a sharp stick.

BRAIN is to be led by two prominent neuroscientists:  Bill Newsome at Stanford (great scientist, good guy) and Cori Bargmann at Rockefeller University (don’t know her, though know her name).

BRAIN is to have an ethics component, to be handled (initially?) by the President making requests to the President’s Commission for the Study of Bioethical Issues (PCSBI).  PCSBI has at least two members were versed in neuroethics and law and neuroscience:  Nita Farahany and Jonathan Moreno.  In the long run I think any one general bioethics commission won’t prove adequate – I’d prefer “let a hundred flowers bloom,” though that requires water, fertilizer, and (of course) money for those flowers.  But this is astart.

Here’s the White House announcement:  White House.

Here’s a useful NY TImes article about the project:  NYT.

How important this will turn out to be, of course, remains to be seen. It is not a commitment at the level of the Human Genome Project, but there doesn’t seem to be the same kind of target available as there was for the HGP. I’m optimistic – but that’s probably just my brain talking.

Turn right at the cerebellum: President Obama maps the brain

Feb. 21, 2013 by Amanda Rubin

This week, the New York Times reported on a new Obama initiative that, in comparison to gun control or the economy, might seem a little frivolous. It’s called the “Brain Activity Map.”

Three Billion Dollars

The name of the project says it all: The goal is to map the connections in the brain in the same way the Human Genome Project mapped out the genes in human DNA. It’s expected to cost about $3 billion dollars over ten years.

If that seems like a pretty heavy price tag for the American people to take on, especially now, just to let scientist go poke around in the brain, you are right. But you are also wrong. Because the pay off could be tremendous.

Let’s use the Human Genome Project as our comparison. That project cost around the same amount as the Brain Map, coming in just under $4 billion when it was completed ahead of schedule in 2003. But the payoff from that project has been an incredible 150 fold, or $800 billion in 10 years. For any investment, that is a handsome return.

But can we replicate that kind of return? Especially in neuroscience, where scientists would be looking at a single organ, instead of the entire human genome? Absolutely. Alzheimer’s Disease, one of the poster children of neurological dysfunction, is expected to cost Americans $1.1 trillion dollars by 2050. That would create a 500 percent increase in Medicare and Medicaid spending. So the question is not really “is this project worth it?,” but more “Why haven’t we done this already?!”

A Difficult Path to Tread

Independently, scientists have been trying. But mapping the human brain is nothing like mapping the genome. DNA is a single straight line, a clear path. Conversely, following a signal in the brain, from neuron to neuron, is anything but. It is like walking a path that at every step splits in 10,000 directions. Or goes backwards. Or just stops.  As a person learns or forgets, all of a sudden the trail shifts. If that person get Alzheimer’s, whole sections of the path fall into an abyss.

To avoid this overwhelming complexity, scientists have looked at tiny pieces of the map, trying to understand the little part of the network as best they can. In theory, this approach could work, and it has worked for smaller problems. It has cured diseases where only a small piece of the network is being affected. But to understand whole-brain diseases, this approach is too uncoordinated and leaves enormous swaths of “unknown” separating small and growing “knowns.”

Putting Our Heads Together

So we know what we want to do, and we know what we are up against, but is it even possible at this point? What tools do we have? What other tools will we need?

For the latter questions, it depends who you ask.  Gary Marcus, a psychology professor at NYU, writing in the New Yorker blog, has suggested the initiative break itself into five separate projects. Some scientists would decipher the basic elements of neural computation.  Others would try to understand how neurons develop and then change connections over time. Still others would look the connection between genes, circuits, and behavior. And so on.

The trouble with this approach is twofold. First, it misunderstands what neuroscience has achieved. All of the above describe the “known” bits of how the brain works. True, these elements are not completely known, but they are bright lights of knowledge compared to the big black sea of enigma surrounding them.

Second, the Marcus approach misunderstands the way research is conducted and the potential gains from a paradigm shift. Small collaborations of scientists are already at work on the smaller issues mentioned. But for the bigger problems, we need all hands on deck. These are undertakings so data-intensive that Google and Microsoft came together to check that we have the computing power to see them through.  These high-level experiments are going to require fancy new tools, armies of scientists, and the money to keep them all going.

So how to approach this mammoth undertaking? The Europeans have taken one route, building a super-computer simulated brain based on the “knowns” we already have. Their device is trying to simulate everything we know about the brain, down to the neuron. The approach is a bit like modeling in economics, reducing a complicated web to something more manageable. But in biology, where an entire disease can hinge on a single molecular mutation, cutting out the details seems ill advised.

Brawn for the Brain

Assuming Obama’s monolithic “live brain in action” approach is the right one, which I believe it is, the only question left is what are the right tools for implementation. fMRIs, a research tool with a lot of popular press, can’t help us here. It can only look at more macro-level activity, but can’t see individual neurons or smaller parts of the path where all the action is happening.

So, scientists have been developing new tools. Just to see the physical map itself, to distinguish individual neurons from the grey mass, scientists at Harvard developed a technique to individually color neurons. This allows others to create their own wiring maps. This tool, called “Brainbow,” creates some truly stunning photographs, but they are just static images.

A similar technique uses an altered virus to jump from neuron to neuron, which then leaves a trail of where it’s been.  This provides a great way to discover individual paths and networks. It is now being used in a limited way to look at activity as well, the same viruses are being used to turn on and off whole pathways.

But where existing techniques fall short in tracking individual neurons’ activity, scientists are proposing new alternatives. Engineers are imagining wireless microcircuits to report activity to a computer.  Synthetic biologists are hoping to co-opt the neuron’s own machinery. This approach would basically create an in-cell ticker-tape of activity, that would be written out in real time on new strands of DNA.  Each newly created strand would hold 7 days worth of activity, which could later be read by researchers.

Whatever the future holds, it’s going to be complicated, and it’s going to be expensive.  It might unearth issues for ethics and regulation. But, if the Brain Activity Map is able to give Americans even a fraction of the research, health, and economic benefits it promises, it really is a no-brainer.

Amanda Rubin is a first year law student at Stanford, where she is also pursuing a Ph.D. in neuroscience. She is co-president of Stanford’s Interdisciplinary Group in Neuroscience and the Law (SIGNAL) and president of the BioLaw and Health Policy Society.

 

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