Posts tagged BRAIN Initiative
Articles and news from the latest research reports.
BRAIN initiative is underway, funding new ways to map cells, circuits
Scientists will aim to capture the workings of the human brain in comprehensive recordings, to watch the brain while in motion and to reimagine the world’s most complex biological organism as a buzzing network of interlocking circuits with the award of $46 million in study grants announced Tuesday.
The announcement marks the first concrete steps taken under the Obama administration’s BRAIN Initiative, short for Brain Research Through Advancing Innovative Neurotechnologies. Unveiled in April 2013, the initiative is a planned 12-year effort to spur new understanding of the brain in sickness and in health by improving technologies used to map, record, probe and stimulate its workings.
President Obama has sought $110 million for the BRAIN initiative in 2014 and $200 million for the 2015 fiscal year, which begins on Wednesday, with future years’ funding to be worked out. He has likened the initiative to the Human Genome Project, which has dramatically deepened understanding of the roles played by nearly 25,000 genes that make up human DNA, and has advanced medicine along a wide front.
On Tuesday, Obama administration officials revealed which researchers and universities will carry out the first federally funded projects under the initiative’s banner, naming more than 100 investigators in 15 states and several countries.
Seeing the inner workings of the brain made easier by new technique
Last year Karl Deisseroth, a Stanford professor of bioengineering and of psychiatry and behavioral sciences, announced a new way of peering into a brain – removed from the body – that provided spectacular fly-through views of its inner connections. Since then laboratories around the world have begun using the technique, called CLARITY, with some success, to better understand the brain’s wiring.
However, Deisseroth said that with two technological fixes CLARITY could be even more broadly adopted. The first problem was that laboratories were not set up to reliably carry out the CLARITY process. Second, the most commonly available microscopy methods were not designed to image the whole transparent brain. “There have been a number of remarkable results described using CLARITY,” Deisseroth said, “but we needed to address these two distinct challenges to make the technology easier to use.”
In a Nature Protocols paper published June 19, Deisseroth presented solutions to both of those bottlenecks. “These transform CLARITY, making the overall process much easier and the data collection much faster,” he said. He and his co-authors, including postdoctoral fellows Raju Tomer and Li Ye and graduate student Brian Hsueh, anticipate that even more scientists will now be able to take advantage of the technique to better understand the brain at a fundamental level, and also to probe the origins of brain diseases.
This paper may be the first to be published with support of the White House BRAIN Initiative, announced last year with the ambitious goal of mapping the brain’s trillions of nerve connections and understanding how signals zip through those interconnected cells to control our thoughts, memories, movement and everything else that makes us us.
"This work shares the spirit of the BRAIN Initiative goal of building new technologies to understand the brain – including the human brain," said Deisseroth, who is also a Stanford Bio-X affiliated faculty member.
Eliminating fat
When you look at the brain, what you see is the fatty outer covering of the nerve cells within, which blocks microscopes from taking images of the intricate connections between deep brain cells. The idea behind CLARITY was to eliminate that fatty covering while keeping the brain intact, complete with all its intricate inner wiring.
The way Deisseroth and his team eliminated the fat was to build a gel within the intact brain that held all the structures and proteins in place. They then used an electric field to pull out the fat layer that had been dissolved in an electrically charged detergent, leaving behind all the brain’s structures embedded in the firm water-based gel, or hydrogel. This is called electrophoretic CLARITY.
The electric field aspect was a challenge for some labs. “About half the people who tried it got it working right away,” Deisseroth said, “but others had problems with the voltage damaging tissue.” Deisseroth said that this kind of challenge is normal when introducing new technologies. When he first introduced optogenetics, which allows scientists to control individual nerves using light, a similar proportion of labs were not initially set up to easily implement the new technology, and ran into challenges.
To help expand the use of CLARITY, the team devised an alternate way of pulling out the fat from the hydrogel-embedded brain – a technique they call passive CLARITY. It takes a little longer, but still removes all the fat, is much easier and does not pose a risk to the tissue. “Electrophoretic CLARITY is important for cases where speed is critical, and for some tissues,” said Deisseroth, who is also the D.H. Chen Professor. “But passive CLARITY is a crucial advance for the community, especially for neuroscience.” Passive CLARITY requires nothing more than some chemicals, a warm bath and time.
Many groups have begun to apply CLARITY to probe brains donated from people who had diseases like epilepsy or autism, which might have left clues in the brain to help scientists understand and eventually treat the disease. But scientists, including Deisseroth, had been wary of trying electrophoretic CLARTY on these valuable clinical samples with even a very low risk of damage. “It’s a rare and precious donated sample, you don’t want to have a chance of damage or error,” Deisseroth said. “Now the risk issue is addressed, and on top of that you can get the data very rapidly.”
Fast CLARITY imaging in color
The second advance had to do this rapidity of data collection. In studying any cells, scientists often make use of probes that will go into the cell or tissue, latch onto a particular molecule, then glow green, blue, yellow or other colors in response to particular wavelengths of light. This is what produces the colorful cellular images that are so common in biology research. Using CLARITY, these colorful structures become visible throughout the entire brain, since no fat remains to block the light.
But here’s the hitch. Those probes stop working, or get bleached, after they’ve been exposed to too much light. That’s fine if a scientist is just taking a picture of a small cellular structure, which takes little time. But to get a high-resolution image of an entire brain, the whole tissue is bathed in light throughout the time it takes to image it point by point. This approach bleaches out the probes before the entire brain can be imaged at high resolution.
The second advance of the new paper addresses this issue, making it easier to image the entire brain without bleaching the probes. “We can now scan an entire plane at one time instead of a point,” Deisseroth said. “That buys you a couple orders of magnitude of time, and also efficiently delivers light only to where the imaging is happening.” The technique is called light sheet microscopy and has been around for a while, but previously didn’t have high enough resolution to see the fine details of cellular structures. “We advanced traditional light sheet microscopy for CLARITY, and can now see fine wiring structures deep within an intact adult brain,” Deisseroth said. His lab built their own microscope, but the procedures are described in the paper, and the key components are commercially available. Additionally, Deisseroth’s lab provides free training courses in CLARITY, modeled after his optogenetics courses, to help disseminate the techniques.
Brain imaging to help soldiers
The BRAIN Initiative is being funded through several government agencies including the Defense Advanced Research Projects Agency (DARPA), which funded Deisseroth’s work through its new Neuro-FAST program. Deisseroth said that like the National Institute of Mental Health (NIMH, another major funder of the new paper), DARPA “is interested in deepening our understanding of brain circuits in intact and injured brains to inform the development of better therapies.” The new methods Deisseroth and his team developed will accelerate both human- and animal-model CLARITY; as CLARITY becomes more widely used, it will continue to help reveal how those inner circuits are structured in normal and diseased brains, and perhaps point to possible therapies.
Other arms of the BRAIN Initiative are funded through the National Science Foundation (NSF) and the National Institutes of Health (NIH). A working group for the NIH arm was co-led by William Newsome, professor of neurobiology and director of the Stanford Neurosciences Institute, and also included Deisseroth and Mark Schnitzer, associate professor of biology and of applied physics. That group recently recommended a $4.5 billion investment in the BRAIN Initiative over the next 12 years, which NIH Director Francis Collins approved earlier this month.
In addition to funding by DARPA and NIMH, the work was funded by the NSF, the National Institute on Drug Abuse, the Simons Foundation and the Wiegers Family Fund.
In the brain, the number of neurons in a network may not matter
Last spring, President Obama established the federal BRAIN Initiative to give scientists the tools they need to get a dynamic picture of the brain in action.
To do so, the initiative’s architects envision simultaneously recording the activity of complete neural networks that consist of thousands or even millions of neurons. However, a new study indicates that it may be possible to accurately characterize these networks by recording the activity of properly selected samples of 50 neurons or less – an alternative that is much easier to realize.
The study was performed by a team of cognitive neuroscientists at Vanderbilt University and reported in a paper published the week of Feb. 3 in the online Early Edition of the Proceedings of the National Academy of Sciences.
The paper describes the results of an ambitious computer simulation that the team designed to understand the behavior of the networks of hundreds of thousands of neurons that initiate different body movements: specifically, how the neurons are coordinated to trigger a movement at a particular point in time, called the response time.
The researchers were surprised to discover that the range of response times produced by the simulated population of neurons did not change with size: A network of 50 simulated neurons responded with the same speed as a network with 1,000 neurons.
For decades, response time has been a core measurement in psychology. “Psychologists have developed powerful models of human responses that explain the variation of response time based on the concept of single accumulators,” said Centennial Professor of Psychology Gordon Logan. In this model, the brain acts as an accumulator that integrates incoming information related to a given task and produces a movement when the amount of information reaches a preset threshold. The model explains random variations in response times by how quickly the brain accumulates the information it needs to act.
Meanwhile, neuroscientists have related response time to measurements of single neurons. “Twenty years ago we discovered that the activity of particular neurons resembles the accumulators of psychology models. We haven’t understood until now how large numbers of these neurons can act collectively to initiate movements,” said Ingram Professor of Neuroscience Jeffrey Schall.
No one really knows the size of the neural networks involved in initiating movements, but researchers estimated that about 100,000 neurons are involved in launching a simple eye movement.
“One of the main questions we addressed is how ensembles of 100,000 neuron accumulators can produce behavior that is also explained by a single accumulator,” Schall said.
“The way that the response time of these ensembles varies with ensemble size clearly depends on the ‘stopping rules’ that they follow,” explained co-author Thomas Palmeri, associate professor of psychology. For example, if an ensemble doesn’t respond until all of its member neurons have accumulated enough activity, then its response time would be slower for larger networks. On the other hand, if the response time is determined by the first neurons that react, then the response time in larger networks would be shorter than those of smaller networks.
Another important factor is the degree to which the ensemble is coordinated. “The more the ensemble is coordinated, the more the collective resembles a single accumulator. What has been unknown is how much coordination is necessary for the ensemble to act in unison, ” said Bram Zandbelt, a post-doctoral fellow and lead author on the paper.
To address this problem, the researchers developed a new type of computer simulation, one that models the collective behavior of different numbers of accumulators given different amounts of variation in the rates of accumulation. The simulation took a tremendous amount of computer power. Even using Vanderbilt’s in-house supercomputer at the Advanced Computing Center for Research & Education, Zandbelt was limited to modeling networks containing 1,000 neurons.
The researchers found that the networks did not produce realistic response times if responses were initiated when only a few or almost all of the simulated neurons finished accumulating, or if the simulated neurons had very different accumulation rates. However, the networks produced realistic response times over a broad range of stopping rules and similarity in accumulation rates, showing that within these broad constraints, size doesn’t matter. “We were surprised to discover that the networks behaved with a remarkable uniformity except under extreme assumptions,” said Schall.
“As far as the response time goes, the bottom line is that we found that the size of the neural network doesn’t matter under a large set of conditions. If this is true for networks ranging from 10 to 1,000 neurons, it should also hold for networks of 10,000 to 100,000 neurons,” Palmeri said.
Nanoscale neuronal activity measured for the first time
A new technique that allows scientists to measure the electrical activity in the communication junctions of the nervous systems has been developed by a researcher at Queen Mary University of London.
The junctions in the central nervous systems that enable the information to flow between neurons, known as synapses, are around 100 times smaller than the width of a human hair (one micrometer and less) and as such are difficult to target let alone measure.
By applying a high-resolution scanning probe microscopy that allows three-dimensional visualisation of the structures, the team were able to measure and record the flow of current in small synaptic terminals for the first time.
“We replaced the conventional low-resolution optical system with a high-resolution microscope based on a nanopipette,” said Dr Pavel Novak, a bioengineering specialist from Queen Mary’s School of Engineering and Materials Science.
“The nanopipette hovers above the surface of the sample and scans the structure to reveal its three-dimensional topography. The same nanopipette then attaches to the surface at selected locations on the structure to record electrical activity. By repeating the same procedure for different locations of the neuronal network we can obtain a three-dimensional map of its electrical properties and activity.”
The research, published (Wednesday 18 September) in Neuron, opens a new window into the neuronal activity at nanometre scale, and may contribute to the wider effort of understanding the function of the brain represented by the Brain Activity Map Project (BRAIN initiative), which aims to map the function of each individual neuron in the human brain.
(Source: qmul.ac.uk)
"BigBrain" Study Provides Most Detailed 3-D Map of the Brain Yet
A landmark three-dimensional digital reconstruction of a complete human brain, called the BigBrain, shows the brain anatomy in microscopic detail at a spatial resolution of 20 micrometers—smaller than the size of one fine strand of hair.
The reconstruction, published in the 21 June issue of the journal Science, exceeds the resolution of all existing reference brains presently in the public domain, and will be made freely available to the broader scientific community.
The fine-grained anatomical resolution of the BigBrain will allow scientists who use it to gain insights into the neurobiological basis of cognition, language, emotions and other processes, according to the study. The anatomical tool yielded by the researchers will serve as an atlas for neurosurgery and provide a framework for research in many directions, including enhanced understanding of brain diseases, such as Alzheimer’s disease.
"It is a common basis for scientific discussions because everybody can work with this brain model," said Science co-author Karl Zilles, senior professor of the Jülich Aachen Research Alliance.
The new reference brain, which is part of the European Human Brain Project, “redefines traditional maps from the beginning of the 20th century,” explained lead author Katrin Amunts from the Research Centre Jülich. Amunts serves as director of the Cecile and Oskar Vogt Institute for Brain Research at the Heinrich Heine University Düsseldorf in Germany.
"The authors pushed the limits of current technology," said Science Senior Editor Peter Stern. Existing reference brains do not probe further than the macroscopic, or visible, components of the brain. The BigBrain provides a resolution much finer than the typical 1 millimeter resolution from MRI studies. "The spatial resolution the researchers achieved exceeds that of presently available reference brains by a factor of 50," said Stern.
"Of course, we would love to have spatial resolution going down to 1 micrometer," said Amunts in a 19 June press teleconference. However, "there are simply no computers at this moment which would be capable to process such data, to visualize this or to analyze it."
To create the detailed brain atlas, Amunts and colleagues took advantage of new advances in computing capacities and image analysis. Using a special tool called a microtome, they carefully cut the paraffin-covered brain of a 65-year-old female into 20 micrometer-thick sections.
The project was “a tour-de-force to assemble images of over 7400 individual histological sections, each with its own distortions, rips and tears, into a coherent 3-D volume,” said Science co-author Alan Evans, a professor at the Montreal Neurological Institute at McGill University in Montreal, Canada.
The sections were mounted on slides, stained to detect cell structures and finally digitized with a high-resolution flatbed scanner so researchers could reconstruct the high-resolution 3-D brain model. It took approximately 1000 hours to collect the data.
The researchers’ future plans for using the map include extracting measurements of cortical thickness to gain insights into aging and neurodegenerative disorders. Eventually, Amunts and colleagues hope to build a brain model at the resolution of 1 micron to capture details of single cell morphology. Detailed brain maps can aid researchers who are exploring the full set of neural connections and real-time brain activity, as scientists discussed recently in a Capitol Hill briefing sponsored by AAAS.
The creation of such a detailed brain map, offering a gateway to unprecedented insights into the brain’s anatomy and organization, was long in the works. “It was a dream for almost 20 years,” Amunts said. “The dream came true because of an interdisciplinary and intercontinental collaboration spanning from Europe to Canada and from neuroanatomy to supercomputing .”
Though not directly related to the BRAIN Initiative announced by President Barack Obama earlier this year, the work by Amunts and colleagues supports the Initiative’s goal of giving scientists the best possible tools with which to obtain a dynamic picture of the brain.
Oscar Wilde called memory “the diary that we all carry about with us.” Now a team of scientists has developed a way to see where and how that diary is written.
Led by Don Arnold and Richard Roberts of USC, the team engineered microscopic probes that light up synapses in a living neuron in real time by attaching fluorescent markers onto synaptic proteins — all without affecting the neuron’s ability to function.
The fluorescent markers allow scientists to see live excitatory and inhibitory synapses for the first time and, importantly, how they change as new memories are formed.
The synapses appear as bright spots along dendrites (the branches of a neuron that transmit electrochemical signals). As the brain processes new information, those bright spots change, visually indicating how synaptic structures in the brain have been altered by the new data.
“When you make a memory or learn something, there’s a physical change in the brain. It turns out that the thing that gets changed is the distribution of synaptic connections,” said Arnold, associate professor of molecular and computational biology at the USC Dornsife College of Letters, Arts and Sciences, and co-corresponding author of an article about the research that appears in Neuron on June 19.
The probes behave like antibodies, but they bind more tightly and are optimized to work inside the cell — something that ordinary antibodies can’t do. To make these probes, the team used a technique known as “mRNA display,” which was developed by Roberts and Nobel laureate Jack Szostak.
“Using mRNA display, we can search through more than a trillion different potential proteins simultaneously to find the one protein that binds the target the best,” said Roberts, co-corresponding author of the article and professor of chemistry and chemical engineering with joint appointments at USC Dornsife and the USC Viterbi School of Engineering.
Arnold and Roberts’ probes (called “FingRs”) are attached to green fluorescent protein (GFP), a protein isolated from jellyfish that fluoresces bright green when exposed to blue light. Because FingRs are proteins, the genes encoding them can be put into brain cells in living animals, causing the cells themselves to manufacture the probes.
The design of FingRs also includes a regulation system that cuts off the amount of FingR-GFP that is generated after 100 percent of the target protein is labeled, effectively eliminating background fluorescence — generating a sharper, clearer picture.
These probes can be put in the brains of living mice and then imaged through cranial windows using two-photon microscopy.
The new research could offer crucial insight for scientists responding to President Barack Obama’s Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative, which was announced in April.
Modeled after the Human Genome Project, the objective of the $100 million initiative is to fast-track research that maps out exactly how the brain works and “better understand how we think, learn and remember,” according to the BRAIN Initiative website.
The Present and Future of Neurogenomics
Support the BRAIN Initiative, but don’t overlook the neurogenomic diagnostics that are already driving breakthroughs in brain and rare neurological disorders.
On April 2nd, 2013, President Obama proposed a forward-thinking, $100 million research program designed to unlock the mysteries of the human brain. The BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative seeks to identify how brain cells and neural circuits interact in order to inform the development of future treatments for brain disorders, including Alzheimer’s disease, epilepsy, and traumatic brain injury.
This Initiative could favorably contribute to medical practice years from now. It should not, however, overshadow the potential of neurogenomic advances to improve the diagnosis, treatment and management of neurological disorders right now.
Most of my career has focused on neurogenomics. During the Human Genome Project era, I managed a clinical neurogenomics program at the National Institutes of Health to further understanding the genetic underpinnings of neurological disorders to help diagnose, treat, cure, and even prevent disease. Today, I oversee the development of neurodiagnostics for the neurology business of Quest Diagnostics, with an emphasis on rare neurological disorders, autism, and dementias.
Over the years, I’ve come to identify certain obstacles that prevent the translation of neurogenomic science into effective clinical management. These obstacles are surmountable, but they require a fundamental shift in how care is delivered to patients with neurological disorders.
Our current healthcare system groups healthcare professionals into two categories: generalists, such as primary care physicians and internists, and specialists, including neurologists. We assume that the former have the knowledge to reliably refer patients, when appropriate, to the latter. This may have been a fair assumption in the past, but in the age of genomic medicine, is it still valid?
In the case of neurogenomic disorders, such as genetic forms of epilepsy, neuromuscular disorders, dementia, and developmental disabilities overlapping clinical signs and symptoms often present a diagnostic challenge for neurologists, and even more so for generalists. A dearth of clinical information available on rare disorders, and the infrequency with which primary care physicians come in contact with effected patients, makes diagnosis even more difficult.
Dravet syndrome, for example, is a rare and catastrophic form of infantile epilepsy that is associated with a high incidence of developmental delays and even SUDEP (sudden unexplained death in epilepsy). Dravet is caused by a genetic defect in the SCN1A gene-affecting sodium channel. While not curable, the condition can be managed if diagnosed—but only if treating physicians are aware of the disorder, treatment options, and the detrimental effects of certain anticonvulsants.
Through advances in laboratory diagnostics, physicians are increasingly equipped to pinpoint the molecular causes of these diseases—some of which are amenable to treatment. But too often, the only clinicians who know about the tests and treatment options are specialists.
We must work more closely with medical societies and advocacy groups to educate primary care professionals and even patients in the value of, and tools for, diagnosing and treating neurological disorders.
Neurogenomic research is revealing that some rare disorders share similar molecular markers and mechanisms. By categorizing these rare disorders into clinical areas, we potentially reduce an otherwise lengthy diagnostic process for the patient and advance the development of new treatment options. Greater investment in new diagnostics that pinpoint molecular markers for disease will help remove the mystery that clouds the diagnosis of many disorders.
Too few clinicians, including neurologists, can keep on top of the rapid evolution of genomic science and diagnostics. As a result, patients are often referred from physician to physician, and administered test after test, in a protracted process to diagnose and treat. This wastes healthcare dollars. More importantly, it creates terrible anxiety and frustration for patients.
To alleviate this problem, medical societies need to do more to cultivate sub-specialists in neurogenomics—clinicians who have deep specialized expertise in specific neurological diseases, particularly rare disorders. With such experience, these experts can more efficiently and reliably diagnose the patient’s disorder.
While the BRAIN Initiative may yield clinically valuable insights in the future, scientists and physicians can do a great deal now with current technologies to translate genomic knowledge into effective diagnosis, management and, in some cases, treatment. With greater genomics education and collaboration, we can help improve the quality of life for patients with neurological disorders—and that, ultimately, is the most meaningful measurement of success.
(Source: the-scientist.com)
Mapping The Brain Onto The Mind
BRAIN initiative aims to improve tools for studying neurons to answer questions about human thought and behavior
The images appearing on the computer screen were almost too detailed and fast-moving to take in, Misha B. Ahrens remembers. He and colleague Philipp J. Keller were recording the activity of about 80,000 neurons in a live zebrafish brain, the first time something on this scale had been done. Cross-sectional pictures of the young fish’s head flew by, dotted with splotches of light.
The Howard Hughes Medical Institute (HHMI) neuroscientists were using a zebrafish larva with a fluorescent protein inserted in its neurons, and the protein was lighting up every time the cells fired. Their custom-built microscope imaged and recorded the resulting lightning storm in the fish’s brain in real time.
Ahrens commemorated the milestone experiment—which took place nearly seven months ago in a lab at the institute’s Janelia Farm Research Campus outside Washington, D.C.—by filming it with his iPhone. “It was mind-blowing to see the entire brain flash past our eyes,” he remembers.
Keller sat in awe at the computer, repeatedly pulling up and admiring slices of data the high-speed apparatus was collecting. The translucent zebrafish, immobilized in a glass tube filled with gel and nestled among the microscope’s optics, was completely unaware that its neural processing was causing such a stir.
Up until that point, scientists had been able to record simultaneous activity from only about 2 to 3% of the 100,000 neurons in a young zebrafish’s head, Keller says. He and Ahrens managed to capture 80%—a giant leap for fishkind.
On March 18, the duo reported their brain-imaging feat online at Nature Methods. Just 15 days later, President Barack Obama announced a large-scale neuroscience initiative to study the dynamics of brain circuits (C&EN, April 8, page 9).
Unlike the Human Connectome Project—a federal program that strives to uncover a static map of the brain’s circuits—this new initiative aims to uncover those circuits’ activity and interplay. BRAIN (Brain Research through Advancing Innovative Neurotechnologies), as the project is called, will get $100 million in federal support if Obama’s request is granted (see page 25), and it will get a similar amount from private foundations such as HHMI in 2014.
“It was a coincidence,” Keller says of the timing of the proposal. He and Ahrens weren’t involved in developing BRAIN, but their goal—to record all the activity from all the neurons in a simple organism’s brain at once—falls directly in line with the initiative.
Eighty-thousand neurons is a lot. But it’s nothing compared with the 85 billion nerve cells that humans have in their brains, or even the 75 million that mice have. To make the leap to measuring large swaths of the brain circuits of rodents or even humans, BRAIN researchers will need to develop new methods of measuring neuronal activity. They are already working on molecular tags to more accurately indicate nerve cell firing in real time. And scientists are developing miniaturized probes to monitor brain cells without disturbing the organ itself, as well as faster techniques for analyzing the flood of data generated by such a huge number of neurons.
Some imaging methods that monitor multitudes of neurons, like that of Ahrens and Keller, already exist. As do techniques for probing scads of nerve cells with tiny electrodes. BRAIN will likely build on these technologies, experts say. But it will also shoot to build “dream” technologies such as implantable nanomaterials that transmit the activity of individual neurons from inside the head.
At the moment, however, no one knows the exact scope of BRAIN. The National Institutes of Health has already appointed a team of neuroscientists to draw up a blueprint for what should be a multiyear initiative. Other federal agencies involved—the National Science Foundation and the Defense Advanced Research Projects Agency—have yet to announce their strategies.
“Neuroscience is getting to the point where researchers cannot take the next big step to understand neural circuits armed with traditional technology,” says Rafael Yuste, a neuron-imaging expert at Columbia University.
And taking that step, he argues, is vital to understanding human thought. “We have a suspicion that the brain is an emerging system,” Yuste says. In other words, how the brain produces memories or actions involves the interactions of all its neurons, rather than just one or even 1,000. It’s like watching television, Yuste adds. “You need to see all the pixels, or at least most of them, to figure out what’s playing.”
Along with five other scientists, Yuste made the original pitch for a public-private project to map the brain’s dynamics in a 2012 article in Neuron. The group argued that not only could this approach help reveal how the human mind works, but it might also offer some insight into what happens when the brain malfunctions. Knowing how the brain’s circuits are supposed to function, Yuste says, could help pinpoint what’s going wrong in conditions such as schizophrenia, which likely involve faulty circuitry.
BRAIN proponents also say areas outside of science and medicine could profit from the initiative. If successful, they claim, BRAIN could yield economic benefits similar to the Human Genome Project, a program launched in 1990 to sequence all the base pairs in a person’s DNA. “Every dollar we spent to map the human genome has returned $140 to our economy,” President Obama noted when he announced BRAIN.
As was the case for the Human Genome Project, BRAIN has been criticized by many scientists. In an already-tight fiscal climate, some researchers have voiced worries that paying for the initiative will mean losing their own funds. And others have expressed reservations that the project is going after too many neurons to yield interpretable, useful results.
But no one seems to dispute that better tools to record activity from nerve cells is a worthwhile goal. “There’s definitely room to grow in many of the techniques we use to record brain activity,” says Mark J. Schnitzer, a neuroscientist at Stanford University. So far, he says, progress has been made mainly by individual labs doing their own thing. But to get to the next level more rapidly, a coordinated effort like BRAIN—centers and labs of neuroscientists, chemists, and researchers in other disciplines working together—might be the ticket.
Until recently, the number of neurons being recorded simultaneously in experiments was doubling every seven years, according to a 2011 review in Nature Neuroscience. But the Janelia team blew this trend out of the water with its high-speed camera and microscope, which rapidly illuminates and images slices of the brain.
The Janelia experiment worked primarily because zebrafish larvae are transparent to light and can be easily immobilized without negative consequences to their brain activity. But moving to mice, which have more neurons and a light-impenetrable skull, will require some more serious innovation, Keller adds.
Some researchers have designed implantable prisms and fiber-optic probes to direct light into the depths of the mouse brain. But those optical tricks are still limited to measuring a few hundred neurons at once. Plus, the mouse has to be tethered to the fibers or prevented from moving altogether.
Stanford’s Schnitzer has overcome the mobility issue with a miniaturized microscope that he and his team designed to fit onto a mouse’s head. Standing three-quarters of an inch tall, the lightweight device, which contains its own light source and camera, gets implanted into the rodent’s brain, enabling researchers to track the freely moving animal’s nerve cell activity.
Early this year, Schnitzer’s group used the setup to follow the dynamics of roughly 1,000 neurons in a mouse’s brain for more than a month (Nat. Neurosci., DOI: 10.1038/nn.3329). The team learned that neurons in one part of the mouse’s brain fired in similar patterns whenever the mouse returned to a familiar spot in its enclosure.
Still, such optical techniques are invasive. “The most elegant experiment would be done from the outside, without mechanical disturbance to the brain,” Columbia’s Yuste says. He’d like to see BRAIN help develop new light sources that can penetrate farther into brain tissue than a few millimeters.
Also on Yuste’s neuron-imaging wish list is a better way to indicate cell firing. As in the Janelia experiment and Schnitzer’s microscope study, the imaging of neuronal activity is typically carried out with calcium indicators. These are molecules that move to the insides of neurons or are proteins engineered to reside there, both designed to fluoresce when they bind to calcium ions.
As a nerve cell fires, its ion channels open, allowing calcium ions to trickle inside and trigger the indicators.
However, “calcium imaging is flawed,” Yuste says. “It’s an indirect method of tracking neuronal firing.” The indicators can’t tell scientists whether a nerve cell fired a little or a lot, he argues. And they don’t track the cells’ electrical activity in real time because calcium diffusion and binding are comparatively slow.
So Yuste and others are working to develop dyes or nanomaterials, called voltage indicators, that bind within a neuron’s membrane and optically signal the cell’s electrical status. Progress is slow-going, however, because a cell’s membrane can hold only so many indicators on its surface and the resulting signal is low.
Another way neuroscientists are more directly measuring nerve cells’ electrical activity is with miniaturized electrodes and nanowires. These probes measure, at submillisecond speeds, the electrical current emitted by a neuron when it fires.
“But anytime you plunge anything into the brain, you have to worry about tissue damage,” says Sotiris Masmanidis, a neurobiologist at the University of California, Los Angeles. “The concern is, how much are you perturbing the system you’re studying?”
To minimize tissue disturbance, Masmanidis and others are lithographically fabricating arrays of microelectrodes that can record nerve cells’ electrical signals from 50 to 100 µm away. So far, the UCLA researcher says, electrode arrays are capable of measuring, at most, 100 to 1,000 neurons at a time.
Determining what types of nerve cells an arrayed microelectrode is measuring, however, is not exactly straightforward, given that it blindly measures any neuron in its vicinity, Masmanidis says. To figure it out, scientists have to take extra steps and monitor the cells’ reaction to drugs or other modulators.
But what good is measuring the dynamics of a slew of nerve cells without having any idea why they’re firing? BRAIN supporters think one way of getting an answer to which environmental cues or perceptions trigger certain neuronal activity patterns is a technique called optogenetics.
Hailed by Nature Methods as the “method of the year” in 2010, optogenetics enables scientists to activate particular nerve cells in the brains of animals with light. The researchers first engineer light-activated proteins into a mouse’s neurons and then trigger the macromolecules via fiber-optic arrays implanted in the rodent’s brain.
Once researchers have measured a firing pattern from an animal’s nerve cells, they can later play it back to see what happens, says Edward S. Boyden, an optogenetics pioneer and neurobiologist at Massachusetts Institute of Technology. “Once we ‘dial’ an activity pattern into the brain,” he says, “if we see that it’s enough to drive some behavior, that could be quite powerful for understanding which parts of the brain drive specific functions.”
Researchers have already been optogenetically stimulating clusters of a few hundred cells in mice, investigating the rodents’ decision-making abilities and aggressive tendencies.
But a brain is more than just electrical activity, says Anne M. Andrews, a psychiatry professor at UCLA. It also uses at least 100 types of neurotransmitters that are involved in triggering neuronal activity at cell junctions, or synapses. “If we want to understand how information is encoded in neuronal signaling, we have to study chemical neurotransmission at the level of synapses,” Andrews says.
And what better way to do that than with nanotechnology? asks Paul S. Weiss, a chemist and nanoscience expert, also at UCLA. After all, the junctions between neurons are just 10 nm wide, he adds.
Andrews and Weiss are hoping BRAIN will support the development of nanoscale sensors to measure the chemical activity at synapses. And they’re already in talks with UCLA’s Masmanidis to functionalize channels on his microelectrodes with molecules that could sense neurotransmitters.
No matter what BRAIN ends up encompassing, one thing is clear: Advances in the numbers of neurons monitored will necessitate improvements in data analysis and storage.
Take, for instance, the experiment done at Janelia. That single session of recording from a zebrafish brain generated 1 terabyte of data. “So you can fit two or three experiments on a computer hard drive,” Ahrens says. “It’s not a bottleneck yet, but when we start creating faster microscopes, computational power might become a problem.”
He and Keller also have just scratched the surface when it comes to analyzing the data they obtained from their initial experiments. As they reported in their Nature Methods paper, the pair found a circuit in the fish’s hindbrain functionally coupled to a specific part of its spinal cord. But determining what that means and what the rest of the brain is doing will require more study and help from computational neuroscientists.
BRAIN Initiative Launched to Unlock Mysteries of Human Mind
Today at the White House, President Barak Obama unveiled the “BRAIN” Initiative — a bold new research effort to revolutionize our understanding of the human mind and uncover new ways to treat, prevent, and cure brain disorders like Alzheimer’s, schizophrenia, autism, epilepsy, and traumatic brain injury.
The NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is part of a new Presidential focus aimed at revolutionizing our understanding of the human brain. By accelerating the development and application of innovative technologies, researchers will be able to produce a revolutionary new dynamic picture of the brain that, for the first time, shows how individual cells and complex neural circuits interact in both time and space. Long desired by researchers seeking new ways to treat, cure, and even prevent brain disorders, this picture will fill major gaps in our current knowledge and provide unprecedented opportunities for exploring exactly how the brain enables the human body to record, process, utilize, store, and retrieve vast quantities of information, all at the speed of thought.
Why is the NIH BRAIN Initiative needed?
With nearly 100 billion neurons and 100 trillion connections, the human brain remains one of the greatest mysteries in science and one of the greatest challenges in medicine. Neurological and psychiatric disorders, such as Alzheimer’s disease, Parkinson’s disease, autism, epilepsy, schizophrenia, depression, and traumatic brain injury, exact a tremendous toll on individuals, families, and society. Despite the many advances in neuroscience in recent years, the underlying causes of most of neurological and psychiatric conditions remain largely unknown, due to the vast complexity of the human brain. If we are ever to develop effective ways of helping people suffering from these devastating conditions, researchers will first need a more complete arsenal of tools and information for understanding how the brain functions both in health and disease.
Why is now the right time for the NIH BRAIN Initiative?
In the last decade alone, scientists have made a number of landmark discoveries that now create the opportunity to unlock the mysteries of the brain. We have witnessed the sequencing of the human genome, the development of new tools for mapping neuronal connections, the increasing resolution of imaging technologies, and the explosion of nanoscience. These discoveries have yielded unprecedented opportunities for integration across scientific fields. For instance, by combining advanced genetic and optical techniques, scientists can now use pulses of light in animal models to determine how specific cell activities within the brain affect behavior. What’s more, through the integration of neuroscience and physics, researchers can now use high-resolution imaging technologies to observe how the brain is structurally and functionally connected in living humans.
While these technological innovations have contributed substantially to our expanding knowledge of the brain, significant breakthroughs in how we treat neurological and psychiatric disease will require a new generation of tools to enable researchers to record signals from brain cells in much greater numbers and at even faster speeds. This cannot currently be achieved, but great promise for developing such technologies lies at the intersections of nanoscience, imaging, engineering, informatics, and other rapidly emerging fields of science.
How will the NIH BRAIN Initiative work?
Given the ambitious scope of this pioneering endeavor, it is vital that planning for the NIH BRAIN Initiative be informed by a wide range of expertise and experience. Therefore, NIH is establishing a high level working group of the Advisory Committee to the NIH Director (ACD) to help shape this new initiative. This working group, co-chaired by Dr. Cornelia “Cori” Bargmann (The Rockefeller University) and Dr. William Newsome (Stanford University), is being asked to articulate the scientific goals of the BRAIN initiative and develop a multi-year scientific plan for achieving these goals, including timetables, milestones, and cost estimates.
As part of this planning process, input will be sought broadly from the scientific community, patient advocates, and the general public. The working group will be asked to produce an interim report by fall 2013 that will contain specific recommendations on high priority investments for Fiscal Year (FY) 2014. The final report will be delivered to the NIH Director in June 2014.
How will the NIH BRAIN Initiative be supported?
In total, NIH intends to allocate $40 million in FY14. Given the cross-cutting nature of this project, the NIH Blueprint for Neuroscience Research — an initiative spanning 14 NIH Institutes and Centers — will be the leading NIH contributor to its implementation in FY14. Of course, a goal this audacious will require ideas from the best scientists and engineers across many diverse disciplines and sectors. Therefore, NIH is working in close collaboration with other government agencies, including the Defense Advanced Research Projects Agency (DARPA) and the National Science Foundation (NSF). Strong interest has also been expressed by several private foundations, including the Howard Hughes Medical Institute, the Allen Institute for Brain Science, and The Kavli Foundation, and the Salk Institute for Biological Studies. Private industries have also expressed a high level of interest in participation in this groundbreaking initiative.
Obama proposes $100m to map the human brain
President Barack Obama on Tuesday asked Congress to spend $100 million next year on a new project to map the human brain in hopes of eventually finding cures for disorders like Alzheimer’s, epilepsy and traumatic injuries.
Obama said the so-called BRAIN Initiative could create jobs and eventually lead to answers to ailments including Parkinson’s and autism and help reverse the effect of a stroke. The president told scientists gathered in the White House’s East Room that the research has the potential to improve the lives of billions of people worldwide.
‘‘As humans we can identify galaxies light-years away,’’ Obama said. ‘‘We can study particles smaller than an atom, but we still haven’t unlocked the mystery of the three pounds of matter that sits between our ears.’’
BRAIN stands for Brain Research through Advancing Innovative Neurotechnologies. The idea, which Obama first proposed in his State of the Union address, would require the development of new technology that can record the electrical activity of individual cells and complex neural circuits in the brain ‘‘at the speed of thought,’’ the White House said.
Obama wants the initial $100 million investment to support research at the National Institutes of Health, the Defense Advanced Research Projects Agency and the National Science Foundation. He also wants private companies, universities and philanthropists to partner with the federal agencies in support of the research. And he wants a study of the ethical, legal and societal implications of the research.
The goals of the work are unclear at this point. A working group at NIH, co-chaired by Cornelia ‘‘Cori’’ Bargmann of The Rockefeller University and William Newsome of Stanford University, would work on defining the goals and develop a multi-year plan to achieve them that included cost estimates.