THE BRAIN FRONTIER

FROM:  NATIONAL SCIENCE FOUNDATION
Exploring the unknown frontier of the brain

James L. Olds, head of NSF's Directorate for Biological Sciences and the Shelley Krasnow University Professor of Molecular Neuroscience at George Mason University describes why and how NSF-funded researchers are working to understand the healthy brain
April 2, 2015

To a large degree, your brain is what makes you... you. It controls your thinking, problem solving and voluntary behaviors. At the same time, your brain helps regulate critical aspects of your physiology, such as your heart rate and breathing.

And yet your brain--a nonstop multitasking marvel--runs on only about 20 watts of energy, the same wattage as an energy-saving light bulb.

Still, for the most part, the brain remains an unknown frontier. Neuroscientists don't yet fully understand how information is processed by the brain of a worm that has several hundred neurons, let alone by the brain of a human that has 80 billion to 100 billion neurons. The chain of events in the brain that generates a thought, behavior or physiological response remains mysterious.

Why the big mystery? The brain is the most complex known biological structure in the universe. When researchers do figure out how it works, they will accomplish perhaps the greatest scientific achievement in recorded human history.

The search for a theory

Neuroscientists all over the world are working to develop an overarching theory of how a healthy brain works. Similar to the way the Big Bang theory offers one possible explanation for the cosmos and helps guide research on the origins of the universe, a theory of healthy brain function would offer a possible explanation of how the brain and the entire nervous system work and would help guide neuroscience research.

A theory of healthy brain function may also help to explain how injuries and diseases disrupt brain function and thereby help researchers identify new directions for research on traumatic brain injuries and brain diseases.

More knowledge about healthy brain function may also help inspire the development of smart technologies that mimic some of the human brain's unparalleled capabilities. If supercomputers--which can each annually consume millions of dollars' worth of electricity as well as huge amounts of cooling water--could match the brain's energy efficiency and processing power, their massive energy consumption would plummet, and science and innovation would leap forward.

Neuroscientists have made some progress toward understanding the brain. They have identified brain regions that regulate particular functions, including speech and motor function, and they can recognize structural and functional changes that occur in the brain throughout an animal's life span.

More recently, neuroscientists have developed game-changing tools for visualizing and analyzing parts of the brain in unprecedented detail. These tools provide the first detailed glimpses of the brain and are thrusting neuroscience forward, much as the first powerful telescopes provided the deep glimpses into the universe and thrust astronomy forward many years ago.

BRAIN Power

Building on these and other recent innovations, President Barack Obama launched the Brain Research through Advancing Innovative Neurotechnologies Initiative (BRAIN Initiative) in April 2013. Federally funded in 2015 at $200 million, the initiative is a public-private research effort to revolutionize researchers' understanding of the brain.

A co-leader of the initiative, the National Science Foundation (NSF) is working to reveal how a healthy brain works. Magnetic resonance imaging (MRI) technology, bionic limbs and laser eye surgery were all grounded in early NSF-funded fundamental research, and fundamental research on the healthy brain may lead to equally profound advances.

NSF will spend about $48.48 million on awards in 2015 supporting the BRAIN Initiative, part of approximately $106.44 million in awards we will provide for all "Understanding the Brain" research across a range of neuroscience and cognitive science topics. With that support, our research teams are tackling the mysteries of the brain from varied angles.

For example, NSF is funding collaborations among:

Computer scientists, cyberinfrastructure experts and biologists to create a cyberinfrastructure to store and manage the huge volumes of data--"Big Data”--generated by brain studies. (For some perspective, consider that if nanoscale images of one human brain were stored in a stack of 1 terabyte hard drives, the stack would reach to the moon, or beyond!)

Engineers, materials experts and physicists to develop new materials needed to invent new probes for monitoring and manipulating the brain.

Physicists, mathematicians and computer scientists to build models that can help reveal and predict the complex neural activities that drive thoughts and behavior.

Social and behavioral scientists and physicists to improve the resolution of functional magnetic resonance imaging of the brain to help explain how social and physical environments alter the brain.

Biologists, physicists, chemists and engineers to study the nervous systems of many species, from simple organisms to complex vertebrates.
In addition, NSF awarded $10.8 million in Early Concept Grants for Exploratory Research (EAGERs) to 36 teams--most of which are collaborative and multidisciplinary in nature--to support the development of new technologies that will help answer a critical question: How do circuits of neurons generate behaviors and enable learning and perception?

An EAGER team from the University of North Carolina School of Medicine is improving a new kind of microscope to simultaneously view individual neurons firing in two or more different regions of a brain at the same time. This microscope will enable researchers to see in detail, for the first time, how different areas of the brain team up to process information.

Taking an entirely different tack, researchers at the new $25 million NSF-funded Center for Brains, Minds & Machines at MIT are investigating human intelligence and the potential for creating intelligent machines. As researchers learn how to build those machines, they will likely also advance humanity's understanding of human intelligence.

Big innovations from basic research

If history is any guide, these and other fundamental brain-research projects will have important applications. For example, researchers around the world are currently studying diseases such as post-traumatic stress disorder, Parkinson's disease and schizophrenia with a powerful new tool called optogenetics.

Optogenetics, which was developed with partial funding from NSF, enables researchers to selectively turn on and off individual neurons in living animals by exposing them to light. The development of optogenetics was made possible, in part, by earlier NSF-funded research on light sensitivity in algae that was conducted purely out of curiosity about the survival strategies of algae and without any knowledge that it would eventually be pivotal to the seemingly far-flung field of brain research. (Optogenetics is explained in a short video, Biodiversity: A Boon for brain research.)

Viewers of the 2014 World Cup saw another important application of fundamental brain research: The first kick of the games was performed by a person with paraplegia wearing an exoskeleton. The development of this exoskeleton built upon NSF-funded research on how neurons are involved in motor learning--research that began nearly twenty years ago.

Across government and across the nation, hopes are high that additional, fundamental neuroscience research will lay the groundwork for continued advances that will help society take additional strides forward.

-- James L. Olds, National Science Foundation
-- Lily Whiteman,

NSF ON THE BRAIN AT REST

FROM:  NATIONAL SCIENCE FOUNDATION 

What happens to your brain when your mind is at rest?

Kavli Prize winner recognized as pioneer in research in the development and use of brain imaging techniques

For many years, the focus of brain mapping was to examine changes in the brain that occur when people are attentively engaged in an activity. No one spent much time thinking about what happens to the brain when people are doing very little.

But Marcus Raichle, a professor of radiology, neurology, neurobiology and biomedical engineering at Washington University in St. Louis, has done just that. In the 1990s, he and his colleagues made a pivotal discovery by revealing how a specific area of the brain responds to down time.

"A great deal of meaningful activity is occurring in the brain when a person is sitting back and doing nothing at all," says Raichle, who has been funded by the National Science Foundation (NSF) Division of Behavioral and Cognitive Sciences in the Directorate for Social, Behavioral and Economic Sciences. "It turns out that when your mind is at rest, dispersed brain areas are chattering away to one another."

The results of these discoveries now are integral to studies of brain function in health and disease worldwide. In fact, Raichle and his colleagues have found that these areas of rest in the brain--the ones that ultimately became the focus of their work--often are among the first affected by Alzheimer's disease, a finding that ultimately could help in early detection of this disorder and a much greater understanding of the nature of the disease itself.

For his pioneering research, Raichle this year was among those chosen to receive the prestigious Kavli Prize, awarded by The Norwegian Academy of Science and Letters. It consists of a cash award of $1 million, which he will share with two other Kavli recipients in the field of neuroscience.

His discovery was a near accident, actually what he calls "pure serendipity." Raichle, like others in the field at the time, was involved in brain imaging, looking for increases in brain activity associated with different tasks, for example language response.

In order to conduct such tests, scientists first needed to establish a baseline for comparison purposes which typically complements the task under study by including all aspects of the task, other than just the one of interest.

"For example, a control task for reading words aloud might be simply viewing them passively," he says.

In the Raichle laboratory, they routinely required subjects to look at a blank screen. When comparing this simple baseline to the task state, Raichle noticed something.

"We didn't specify that you clear your mind, we just asked subjects to rest quietly and don't fall asleep," he recalls. "I don't remember the day I bothered to look at what was happening in the brain when subjects moved from this simple resting state to engagement in an attention demanding task that might be more involved than simply increases in brain activity associated with the task.

"When I did so, I observed that while brain activity in some parts of the brain increased as expected, there were other areas that actually decreased their activity as if they had been more active in the 'resting state,"' he adds. "Because these decreases in brain activity were so dramatic and unexpected, I got into the habit of looking for them in all of our experiments. Their consistency both in terms of where they occurred and the frequency of their occurrence--that is, almost always--really got my attention. I wasn't sure what was going on at first but it was just too consistent to not be real."

These observations ultimately produced ground-breaking work that led to the concept of a default mode of brain function, including the discovery of a unique fronto-parietal network in the brain. It has come to be known as the default mode network, whose regions are more active when the brain is not actively engaged in a novel, attention-demanding task.

"Basically we described a core system of the brain never seen before," he says. "This core system within the brain's two great hemispheres increasingly appears to be playing a central role in how the brain organizes its ongoing activities"

The discovery of the brain's default mode caused Raichle and his colleagues to reconsider the idea that the brain uses more energy when engaged in an attention-demanding task. Measurements of brain metabolism with PET (positron emission tomography) and data culled from the literature led them to conclude that the brain is a very expensive organ, accounting for about 20 percent of the body's energy consumption in an adult human, yet accounting for only 2 percent of the body weight.

"The changes in activity associated with the performance of virtually any type of task add little to the overall cost of brain function," he continues. "This has initiated a paradigm shift in brain research that has moved increasingly to studies of the brain's intrinsic activity, that is, its default mode of functioning."

Raichle, whose work on the role of this intrinsic brain activity on facets of consciousness was supported by NSF, is also known for his research in developing and using imaging techniques, such as positron emission tomography, to identify specific areas of the brain involved in seeing, hearing, reading, memory and emotion.

In addition, his team studied chemical receptors in the brain, the physiology of major depression and anxiety, and has evaluated patients at risk for stroke. Currently, he is completing research studying what happens to the brain under anesthesia.

"The brain is capable of so many things, even when you are not conscious," Raichle says. "If you are unconscious, the organization of the brain is maintained, but it is not the same as being awake."

-- Marlene Cimons, National Science Foundation
Investigators
Marcus Raichle
Related Institutions/Organizations
Washington University School of Medicine

RESEARCHERS LOOK AT THE BRAIN

FROM:  NATIONAL SCIENCE FOUNDATION 

Engineers ask the brain to say, "Cheese!"

How do we take an accurate picture of the world’s most complex biological structure?

Creating new brain imaging techniques is one of today's greatest engineering challenges.

The incentive for a good picture is big: looking at the brain helps us to understand how we move, how we think and how we learn. Recent advances in imaging enable us to see what the brain is doing more precisely across space and time and in more realistic conditions.

The newest advance in optical imaging brings researchers even closer to illuminating the whole brain and nervous system.

Researchers at the Massachusetts Institute of Technology and the University of Vienna achieved simultaneous functional imaging of all the neurons of the transparent roundworm C. elegans. This technique is the first that can generate 3-D movies of entire brains at the millisecond timescale.

The significance of this achievement becomes clear in light of the many engineering complexities associated with brain imaging techniques.

An imaging wish list

When 33 brain researchers put their minds together at a workshop funded by the National Science Foundation in August 2013, they identified three of the biggest challenges in mapping the human brain for better understanding, diagnosis and treatment.

Challenge one: High spatiotemporal resolution neuroimaging. Existing brain imaging technologies offer different advantages and disadvantages with respect to resolution. A method such as functional MRI that offers excellent spatial resolution (to several millimeters) can provide snapshots of brain activity in the order of seconds. Other methods, such as electroencephalography (EEG), provide precise information about brain activity over time (to the millisecond) but yield fuzzy information about the location.

The ability to conduct functional imaging of the brain, with high resolution in both space and time, would enable researchers to tease out some of the brain's most intricate workings. For example, each half of the thalamus--the brain's go-to structure for relaying sensory and motor information and a potential target for deep brain stimulation--has 13 functional areas in a package the size of a walnut.

With better spatial resolution, researchers would have an easier time determining which areas of the brain are involved in specific activities. This could ultimately help them identify more precise targets for stimulation, maximizing therapeutic benefits while minimizing unnecessary side effects.

In addition, researchers wish to combine data from different imaging techniques to study and model the brain at different levels, from molecules to cellular networks to the whole brain.

Challenge two: Perturbation-based neuroimaging. Much that we know about the brain relies on studies of dysfunction, when a problem such as a tumor or stroke affects a specific part of the brain and a correlating change in brain function can be observed.

But researchers also rely on techniques that temporarily ramp up, or turn off, brain activity in certain regions. What if the effects of such modifications on brain function could then be captured with neuroimaging techniques?

Being able to observe what happens when certain parts of the brain are activated could help researchers determine brain areas' functions and provide critical guidance for brain therapies.

Challenge three: Neuroimaging in naturalistic environments. Researchers aim to create new noninvasive methods for imaging the brain while a person interacts with his or her surroundings. This ability will become more valuable as new technologies that interface with the brain are developed.

For example, a patient undergoing brain therapy at home may choose to send information to his or her physician remotely rather than go to an office for frequent check-ups. The engineering challenges of this scenario include the creation of low-cost, wearable technologies to monitor the brain as well as the technical capability to differentiate between signs of trouble and normal fluctuations in brain activity during daily routines.

Other challenges the brain researchers identified are neuroimaging in patients with implanted brain devices; integrating imaging data from multiple techniques; and developing models, theories and infrastructures for better understanding and analyzing brain data. In addition, the research community must ensure that students are prepared to use and create new imaging techniques and data.

The workshop chair, Bin He of the University of Minnesota-Twin Cities, said, "Noninvasive human brain mapping has been a holy grail in science. Accomplishing the three grand challenges would change the future of brain science and our ability to treat numerous brain disorders that cost the nation over $500 billion each year."

The full workshop report was published in IEEE Transactions on Biomedical Engineering.

An imaging breakthrough

Engineers, in collaboration with neuroscientists, computer scientists and other researchers, are already at work devising creative ways to address these challenges.

The workshop findings place the new technique developed by the MIT and University of Vienna researchers into greater context. Their work had to overcome several of the challenges outlined.

The team captured neural activity in three dimensions at single-cell resolution by using a novel strategy not before applied to neurons--light-field microscopy, using a novel algorithm to reverse distortion, a process known as deconvolution.

The technique of light-field microscopy involves the shining of light at a 3-D sample, and capturing the locations of fluorophores in a still image, using a special set of lenses. The fluorophores in this case are modified proteins that attach to neuron and fluoresce when the neurons activate. However, this microscopy method requires a trade-off between the sample size and the spatial resolution possible, and thus it has not been before used for live biological imaging.

The advantage presented by light-field microscopy, here used in an optimized form, is that the technique may quickly capture the neuronal activity of whole animals, not simply still images, while providing high enough spatial resolution to make functional biological imaging possible.

"This elegant technique should have a large impact on the use of functional biological imaging for understanding brain cognitive function," said Leon Esterowitz, program director in NSF's Engineering Directorate, which provided partial funding for the research.

The researchers, led by Edward Boyden of MIT and Alipasha Vaziri of the University of Vienna, reported their results in this week's issue of the journal Nature Methods.

"Looking at the activity of just one neuron in the brain doesn't tell you how that information is being computed; for that, you need to know what upstream neurons are doing. And to understand what the activity of a given neuron means, you have to be able to see what downstream neurons are doing," said Boyden, an associate professor of biological engineering and brain and cognitive sciences at MIT and one of the leaders of the research team.

"In short, if you want to understand how information is being integrated from sensation all the way to action, you have to see the entire brain."

-- Cecile J. Gonzalez,
Investigators
Edward Boyden
Bin He
Related Institutions/Organizations
Massachusetts Institute of Technology
University of Minnesota-Twin Cities

CUTTING EDGE STUDIES OF BRAINS

FROM:  NATIONAL SCIENCE FOUNDATION 

NSF-funded researchers describe their cutting-edge brain research
Why and how are researchers studying the brains of mice, octopuses, zebra fish, frogs, lizards and cichlid fish?

Our understanding of the brain is still downright rudimentary compared to our understanding of other organs. To revolutionize brain science, President Obama in April 2013 announced the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, which is co-led by the National Science Foundation (NSF).

But even before BRAIN was created, NSF had a long history of funding innovative basic research focused on the brain. NSF's research approaches integrate information, methods and models at scales ranging from the molecular level to the behavioral level; they also draw from multiple scientific, engineering and computational disciplines.

In addition, some NSF-funded scientists are examining how changes in brain structure and activity correlate with different external environments and behavioral changes. These factors, along with genetic analyses, are--in many cases--easier to study in relatively simple organisms than in humans. Also, by identifying features that are similar and different across species, and by studying organisms throughout their lifespans, scientists are advancing their understanding of how nervous systems work.

Featured here are video interviews with selected NSF-funded brain researchers about their cutting-edge, multidisciplinary research on mice, octopuses, zebrafish, frogs, lizards and cichlids. These interviews were recorded at the NSF Workshop on Phylogenetic Principles of Brain Structure and Function at the Howard Hughes Medical Institute's Janelia Farm Research Campus in Ashburn, Va., in October 2013.

Partha Mitra of Cold Spring Harbor Laboratory is currently focused on the Mouse Brain Architecture Project (MAP), which is aimed at creating 3-D maps of the mouse brain at various scales. (The mouse brain is 1/1000 of the volume of the human brain.) MAP is also dedicated to relating brain circuits (groups of neurons) to behavior.

One way that Mitra is contributing to MAP is by mapping the projection patterns of groups of similarly organized neurons across regions of the mouse brain. He is thereby helping to identify how neurons are connected and communicate across regions of the brain.

In addition, Mitra is applying his background in theoretical physics to his studies of the mouse brain. He is doing so by working to identify ways to apply to brain research methods in statistical physics that are used to analyze the macroscopic behavior of large, distributed networks.

Specifically, these methods have been used by engineers to analyze technologically important networks--such as power grids and coordinated formations of vehicles--and to help design such networks with wanted properties. If these methods can be applied to brain research, they may enable researchers to identify and prioritize important aspects of brain networks for study--helping to distinguish microscopic details that play important roles in overall behaviors from those that do not.

Once the map of the mouse brain is completed and analyzed, it will be the first-of-its-kind map of a whole vertebrate brain. MAP's future goals include mapping connectivity patterns in the marmoset monkey brain and ultimately in the human brain.

Information and images from MAP are publically available on MAP's website.

Clifton Ragsdale of the University of Chicago is researching the nervous system of the octopus, which is a successful predator partly because it has excellent eyesight--the best of any invertebrate. The octopus's excellent eyesight enables it to visually zero in and focus on prey.

What's more, each of the octopus's eight agile, boneless arms has about 44 million nerve cells (or almost 10 percent of all of its neurons). These arm neurons are connected to the animal's brain.

When an octopus spots a tasty-looking fish, the information it collects about this prey travels from the animal's eye to its brain. This information then travels through its arm neurons to help these soft-bodied contortionists determine how to snatch the prey.

Conversely, tactile information, such as the feel of a crab's rough shell, travels back through the octopus's arm neurons to its brain's learning and memory centers to help these clever animals improve their hunting skills.

Ragsdale is currently pioneering the use of modern molecular techniques to study how the octopus's unique nervous system processes visual information, and if its processing system significantly differs from those of vertebrates.

Melina Hale of the University of Chicago is studying neuronal circuits in zebrafish that generate startle responses. (Yes, the kinds of startle responses that are produced by sudden sounds or movements.)

Because little is known about how circuits operate in any organism and because startle responses are controlled by relatively simple circuits, an improved understanding of the circuitry of the zebrafish's startle responses is expected to help lay the groundwork for research on more complicated circuits.

The zebrafish--a small common aquarium fish--serves as an excellent fish for laboratory studies because molecular tools are available for experimenting with its neurons. The zebrafish can also be easily maintained and reproduces and develops rapidly. Also, young zebrafish are transparent and so their nervous systems are easily observable.

Walter Wilczynski of Georgia State University is researching how non-mammals signal one another in mating competitions, and how these signals influence the behavior of individual males and females. According to Wilczynski's research, an individual's behavioral responses to such signals and whether it loses or wins a mating competition may modify its brain in ways that may influence its future behavior.

Wilczynski's research is important because a) competition for reproduction is fundamental to all of biology; and b) Wilczynski uses model organisms whose social interactions are, in many ways, simplified versions of human social interactions. These model organisms include frogs, which communicate through vocal calls, and lizards, which communicate through visual displays.

Hans Hofmann of the University of Texas, Austin, is researching the influences of environment and genetics on the brains and behavior of cichlid fish. Cichlids provide excellent model organisms for such studies because thousands of species of cichlids have evolved; many of these species are genetically similar but behaviorally and socially different from one another. Hofmann is using the diversity of cichlid species to help identify which genes regulate various behaviors and evaluate how different social environments affect brain function and behavior.

Mammals and cichlids share many of the same genetic mechanisms that are sensitive to social environments and help govern mating systems (such as monogamous vs. non-monogamous systems) and parental care systems (such as those that involve fatherly caretaking vs. those that don't). Therefore, research on the effect of social environments on cichlid brains, genetics and behavior may ultimately help advance our understanding of differing human mating and parental care systems.