Workshop Summary

INTRODUCTION1

The goals of medicine are to “wrest from nature the secrets which have perplexed philosophers of all ages….”

—Sir William Osler, 1849–1919


On June 25, 2008, more than 70 of the leading neuroscientists in the world gathered at the National Academy of Sciences building in Washington, DC, for a workshop hosted by the Institute of Medicine’s (IOM’s) Forum on Neuroscience and Nervous System Disorders titled, “From Molecules to Mind: Challenges for the 21st Century.” Their goals were significant: Each participant was asked to identify one or two “Grand Challenges” that could galvanize both the scientific community and the public around the possibilities for neuroscience in the 21st century.

This idea of identifying Grand Challenges has a strong history in science. For example, as Kathie Olsen, deputy director of the National Science Foundation, reminded the panelists, the physics community was united in 2003 by the publication of Connecting Quarks with the Cosmos. This National Research Council (NRC) committee report identified a handful of fundamental questions about the universe, such as “What powered the big bang?” and “What is dark matter?” (NRC, 2003). More

1

The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop.



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Workshop Summary INTRODUCTION 1 The goals of medicine are to “wrest from nature the secrets which have perplexed philosophers of all ages. . . .” —Sir William Osler, 1849–1919 On June 25, 2008, more than 70 of the leading neuroscientists in the world gathered at the National Academy of Sciences building in Wash- ington, DC, for a workshop hosted by the Institute of Medicine’s (IOM’s) Forum on Neuroscience and Nervous System Disorders titled, “From Molecules to Mind: Challenges for the 21st Century.” Their goals were significant: Each participant was asked to identify one or two “Grand Challenges” that could galvanize both the scientific community and the public around the possibilities for neuroscience in the 21st cen- tury. This idea of identifying Grand Challenges has a strong history in sci- ence. For example, as Kathie Olsen, deputy director of the National Sci- ence Foundation, reminded the panelists, the physics community was united in 2003 by the publication of Connecting Quarks with the Cos- mos. This National Research Council (NRC) committee report identified a handful of fundamental questions about the universe, such as “What powered the big bang?” and “What is dark matter?” (NRC, 2003). More 1 The planning committee’s role was limited to planning the workshop, and the workshop sum- mary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. 1

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2 FROM MOLECULES TO MINDS recently the National Academy of Engineering developed a set 14 Grand Challenges for engineering in the 21st century (NRC, 2008). 2 In each case, a common purpose—combined with new funding, new technologies, new ideas, and an influx of new scientists—drove re- searchers to tackle problems that seemed impossible just a few years ear- lier. Neuroscience has made phenomenal advances over the past 50 years and the pace of discovery continues to accelerate. Some of that progress has resulted from the simultaneous appearance of new technologies, like those of molecular biology, neuroimaging, and computer and information science. The progress of the past in combination with these new tools and techniques has positioned neuroscience on the cusp of even greater transformational progress in our understanding of the brain and how its activities result in mental activity. Recognizing that neuroscience is not, of course, really a single field is important. Rather, it is a multidisciplinary enterprise including diverse fields of biology, psychology, neurology, chemistry, mathematics, phys- ics, engineering, computer science, and more. If scientists within neuro- science and related disciplines could unite around a small set of goals, the opportunity for advancing our understanding of brain and mental function would be huge. Exploring that potential set of common goals, or Grand Challenges, was one of the major goals of the workshop. What Can We Achieve For a Grand Challenges exercise to work, it must ask questions that are both big and answerable. The questions must fire the soul and stir the spirit, but also be approachable in a scientifically rigorous manner, ex- plained Alan Leshner, chief executive officer of the American Associa- tion for the Advancement of Science and chair of the Forum on Neuroscience. For neuroscience, the first part is easy. Neuroscience is aimed at one of the most fundamental questions of all: How does our physical body 2 Connecting Quarks with the Cosmos: Eleven Science Questions for the New Century was au- thored by the NRC’s Committee on the Physics of the Universe. Grand Challenges for Engineering was authored by the NRC’s Committee on Grand Challenges for Engineering. Neither was a work- shop summary, but rather included specific findings and recommendations of the respective commit- tee.

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3 WORKSHOP SUMMARY give rise to a person who can think, love, learn, and dream? Hippocrates identified the brain as the seat of human experience in 400 B.C., and we have been trying to figure out how it works ever since. However, as was demonstrated throughout the workshop and as will be highlighted throughout this workshop summary, neuroscience has ad- vanced to the point where answering those questions in a rigorous man- ner is truly possible, commented Leshner. By the end of the workshop there was a sense of momentum and of new frontiers opening up, remarked Leshner. The brain is one of the most complicated and exquisite objects on earth. According to Colin Blakemore, a leading British neuroscientist from Oxford University and the former chief executive of the British Medical Research Council, “There are more neurons in the brain than there are stars in the galaxy.” Who among us has not wondered how it all works; how the lump of our physical brain gives rise to someone who can want, and love, and read poetry? About This Workshop The Neuroscience Challenges for the 21st Century workshop was hosted by the IOM’s Forum on Neuroscience and Nervous Systems Dis- orders, which is a convening activity at the IOM dedicated to furthering our understanding of the brain and nervous systems, disorders in their structure and function, and effective clinical prevention and treatment strategies. The Forum brings together experts from private-sector spon- sors of biomedical and clinical research, federal agencies sponsoring and regulating biomedical and clinical research, foundations, the academic community, and consumers to talk about issues of mutual interest and concern. The goals of a forum, and this workshop, are not to provide specific recommendations or arrive at consensus conclusions; rather, a forum seeks to highlight important issues and articulate the challenges facing a particular scientific field. Organized by an independently appointed planning committee, the workshop was organized so that representatives of all corners of the neuroscience world could provide updates on the latest advances in the field, and then discuss how they related to the con- cept of Grand Challenges. Throughout the day, participants learned how advances in imaging technology, computer science, molecular biology, biochemistry, and neuroscience in general had made it possible for us to

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4 FROM MOLECULES TO MINDS imagine understanding how the brain works at a fundamental level— something that was not possible just 2 or 3 years ago. 3 In addition, each participant was invited to present his/her impression of what one or two Grand Challenges would be for the neurosciences. As a result, through- out this document key insights are attributed to at least one participant. When multiple parties were involved in fashioning or honing a single idea or insight, the author has endeavored to attribute that idea or insight to the key parties involved. Leshner and Olsen concluded the workshop by synthesizing the day’s discussions into three overarching Grand Challenges that emerged during the workshop, which will be used to organize this workshop summary: • How does the brain work and produce mental activity? How does physical activity in the brain give rise to thought, emotion, and behavior? • How does the interplay of biology and experience shape our brains and make us who we are today? • How do we keep our brains healthy? How do we protect, re- store, or enhance the functioning of our brains as we age? In addition, this summary includes a synopsis of topics that emerged during the discussion that do not fall specifically under any one of the three Grand Challenge questions identified here, including some chal- lenges and technical limitations as well as ethical concerns. GRAND CHALLENGE: HOW DOES THE HUMAN BRAIN WORK AND PRODUCE MENTAL ACTIVITY? How does the brain work and produce mental activity? How does physical activity in the brain give rise to thought, emotion, and behavior? We envision our brains taking in data, running those data through some unknown processes, and then somehow telling us how to act, feel, or behave. “What are the algorithmic principles that the brain uses?” Blakemore asked. “Are there some which are nonalgorithmic? How can we approach the modeling of those principles?” In the deepest sense, we do not know how information is processed, stored, or recalled; how motor commands emerge and become effective; 3 To download presentations or listen to audio archives, please visit http://www.iom.edu/CMS/ 3740/35684/54555.aspx.

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5 WORKSHOP SUMMARY how we experience the sensory world; how we think or feel or empa- thize. This is because explanations ultimately must be integrated across levels of analysis, including: molecular, cellular, synaptic, circuit, sys- tems, computational, and psychological, and until now the field has not been mature enough to integrate information across all these disciplines. These are some of the most compelling questions in the world, said Olsen in the opening session of the workshop. Of course there is another reason—or rather, many millions of rea- sons—why we do not have a working theory of the brain. As Blakemore pointed out, there are more neurons in the brain than there are stars in the galaxy, and we form more than 1 million new connections among these neurons each day. Simply put, the scope of the challenge is awesome. Still, the feeling among many at the workshop was that there was hope in meeting this challenge. The reason? Major technological advances during the past few years are allowing neuroscientists to do the kind of research and tackle the kind of challenges they have always dreamed of, starting, according to many at the workshop, with drawing up the wiring diagram of the human brain. Mapping the Human Brain The idea of mapping the human brain is not new. The “father of neu- roscience,” Santiago Ramon y Cajal, argued at the turn of the 20th cen- tury that the brain was made up of neurons woven together in a highly specific way. We have been trying to map this exquisite network since then. In fact, scientists in other settings have called the wiring diagram a Grand Challenge of neuroscience in and of itself. It appears on the Grand Challenges of the Mind and Brain list for the National Science Founda- tion (NSF, 2006), on the Grand Challenges list of the National Academy of Engineering (NRC, 2008), and on the wish lists of at least a half- dozen major scientific fields, from genetics to computer science. If we are interested in how the mind works, then we definitely need to know the physical instantiation of brains and function, remarked Jeffrey Lichtman, professor of molecular and cellular biology, Harvard Univer- sity. This effort will require some mechanism to obtain the connectional maps that will integrate anatomy, neuronal activity, and function. Until those are available, the field will not be able to move forward to its full potential.

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6 FROM MOLECULES TO MINDS The challenge is similar, in many ways, to mapping the human ge- nome: We might not know exactly what we will learn, but we have a strong belief that we will learn a lot, commented Leshner. So why has it not happened? Because neurons are very small and the human brain is exquisitely complex and hard to study. Eve Marder, professor of neuroscience at Brandeis University and president of the Society for Neuroscience, noted that scientists have been working on circuit analysis for nearly 40 years, primarily with smaller organisms, particularly invertebrates, because their simpler neurological systems are more amenable to study and analysis. The classic approach, in place since the 1960s, has been simple: De- fine behaviors, identify neurons involved in those behaviors, determine the connectivity between those neurons, and then excite individual neu- rons to understand their role in influencing behavior. This approach is called “circuit dynamics,” and it has been tremendously helpful to under- standing how these simple neurological systems work. But as you move from sponges and anemones to primates and hu- mans, each step of that analytical process becomes infinitely more chal- lenging. As Marder noted, the impediments, until today, to understanding lar- ger circuits and vertebrate brains include difficulty in identifying neu- rons, difficulty in perturbing individual classes of neurons in isolation, and difficulty in recording from enough of the neurons at the same time with enough spatial and temporal resolution. In other words, difficulty arose in every step of the circuit dynamics process. But the key words in Marder’s statement are “until today.” If you look at the three things Marder identified as stumbling blocks, major technological breakthroughs over the past few years have solved or are close to solving each one, starting with a new technique born from the lab of Lichtman: “the Brainbow.” Technological Advance: The Brainbow Mapping the brain is not easy. Neurons and the connections between them are so small and complex that tracing their path through the brain has been nearly impossible.

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7 WORKSHOP SUMMARY For more than a century, the best method available to researchers has been the “Golgi stain.” Developed in 1873 (and little improved on since), the Golgi method uses a stain of silver chromate salt to trace the path of individual neurons, right down to the axons and dendrites. The Golgi method works quite well, but comes with two major flaws that limit its use in studying complex connections among neurons in a single network. The first flaw is that the method stains everything the same color—grey—making it very difficult to study multiple neurons at once or to envision how different neurons link together. Second, it is dif- ficult to target specific cells to be stained, that is, neurons that are stained are done so in a largely random pattern. Over the years, researchers have improved on the Golgi stain. For example, geneticists found ways to “tag” different neurons with genes that naturally produce fluorescent colors, so that the neurons themselves could be made to glow red, blue, or yellow. This advance allowed re- searchers to study a handful of neurons at once. The neurosciences have now matured to the point where scientific knowledge and technological advances are converging to bring new ca- pabilities. For example, in 2007 Harvard University researcher Jean Li- vet, working out of Lichtman’s lab, published a paper showing how fluorescent-coding genes from jellyfish and coral could be combined to force different neurons to express hundreds of different colors (Livet et al., 2007). This Brainbow technique relies on three genes—coding for red, blue, and yellow—which are combined in different levels to produce all the different tones. A cell might have three red genes, two blue, and one yellow, for instance. The result? Researchers can, for the first time, identify and map hun- dreds of neurons at once, seeing how they wrap and interact with one another, tracing the map of the brain in greater detail than was possible just 1 or 2 years earlier. Technological Advance: Neuronal “Light Switch” Marder’s second impediment was the challenge of perturbing indi- vidual neurons. Even if you can see the connections between the actual cells, if you want to see how one neuron connects to and influences an- other, and most importantly what impact that has on behavior, you must be able to “excite” those neurons to find out. Over and over and over again.

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8 FROM MOLECULES TO MINDS The classical method uses electrodes to stimulate neurons, but it is neither precise nor particularly sophisticated. Neurons are so small and make so many connections—an individual neuron can make well over 100 separate connections with other neurons—that it is extremely diffi- cult to precisely activate a single neuron, let alone a specific neuronal connection, in an in-vitro model system, and even more so in an in-vivo vertebrate nervous system. In 2005, however, researchers in Stanford University and the Max Planck Institute of Biophysics Germany developed a neuronal “light switch” that allows them to turn individual neurons or neuronal connec- tions on or off by exposing them to light (Boyden et al., 2005). The sci- ence behind the study is impressive. Researchers discovered a protein from green algae that switches the electrical state of a cell when exposed to blue light. By inserting this gene into rat neurons, researchers were able to gain control over those neurons and consequently their connec- tions, turning them on and off with the flip of a switch. As an added bo- nus, researchers attached this protein to a gene that glows when exposed to green light, allowing them to both identify and control individual neu- rons. Therefore, under green light researchers can view the neurons that make the protein, and by switching the light beam to blue, they can ex- cite a neuron and investigate its effects. The applications and implications of this new technique are many. From a research perspective, being able to turn individual neurons on and off allows advanced study of the function of individual neurons in the brain. From a clinical perspective, the ability to modulate neurons using something as simple and noninvasive as light opens up opportunities for extremely targeted therapies for diseases such as Parkinson’s, depression, and more. Technological Challenge: Spatial and Temporal Resolution Marder’s third challenge—the difficulty in recording from enough of the neurons at the same time with enough spatial and temporal resolu- tion—remains a major challenge for the field. Both imaging and elec- trode recording capabilities have come a long way in recent years, but multiple researchers expressed the need for more.

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9 WORKSHOP SUMMARY Multichannel Microelectrode Recording Arrays The development of multichannel microelectrode recording arrays al- lows researchers to accurately measure the activity of multiple neurons at a single time. Advances in photonics, electronic circuitry, and engineer- ing have made it possible for these arrays to be shrunken substantially, dramatically increasing the number of neurons that can be monitored directly through the skin. Moreover, researchers believe the devices can now be implanted in the brain, or else where in the nervous system, sug- gesting we could measure the output of neurons on an individual level over long periods of time (Kelly et al., 2007). If we are going to get a real map of the functional wiring diagram of the human, we need to be able to do it noninvasively and on a wide- spread basis. “Brain functions are encoded in a distributed network in the brain,” said Bin He, professor of biomedical engineering, electrical engineering, and neuroscience, University of Minnesota, so it is important to image brain connectivity and network dynamics not only beyond localized cir- cuits, but throughout the entire network. Functional Magnetic Resonance Imaging Functional Magnetic Resonance Imaging (fMRI) allows researchers to noninvasively measure blood flow and blood oxygenation in the brain. Because blood flow and oxygenation are closely linked with brain activ- ity, researchers can see which areas of the brain are active when volun- teers (or research animals) are performing an assigned task. A circuit map that does not correlate back to activity is not extremely valuable. fMRI is one technique used to integrate anatomy back to func- tion, allowing this correlation. Unfortunately, fMRI readings are not per- fect. Spatial resolution has only recently advanced to the millimeter level, and unfortunately the measurements are not in real time. There is a delay of about a second between brain activity and associated changes in blood flow and oxygenation that can be detected by the fMRI. However, researchers need to be able to measure activity in a real-time, millisec- ond-by-millisecond basis and on a much smaller spatial scale. As a re- sult, they are now working on ways to combine fMRI readings with instantaneous feedback loops such as electroencephalography (EEG) and magnetoencephalography (MEG).

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10 FROM MOLECULES TO MINDS “Can we develop a technique which can noninvasively image the neural activity at millimeter spatial resolution and millisecond temporal resolution?” asked He, in a comment echoed by others at the workshop. But even this is resolution is course relative to the size of a neuron—a cubic millimeter of brain cortex contains 104 to 105 neurons. Computer Science and Learning Algorithms Even with all these advances in collecting data, the challenges of mapping the brain remain enormous. The human genome project would not have been possible until the turn of the 21st century, as the genetics field simply did not have the automated techniques or the computer power to tackle the project. The amount of data involved in mapping the structure of the brain is likely to be an order of magnitude greater than was required for mapping the genome, and will require enormous com- puting capacity. This is where computer science comes in. One example of using computational methods to link neural activity to psychological states was provided by Tom Mitchell, chair of the Ma- chine Learning Department at Carnegie Mellon University, who de- scribed how, through the use of machine learning methods, a person’s neural activity and reactions to words or pictures can be decoded via fMRI. Such computer algorithms, which have been adopted by research- ers studying brain-wide neural representations, provide a direct link be- tween the biology of neural activity and abstract mental states such as thinking about an object. In addition, the work of Sebastian Seung’s lab at the Massachusetts Institute of Technology was highlighted. Seung and colleagues have been able to develop a machine-learning algorithm that can help trace the path of individual neurons through the brain (Jain et al., 2006). In Seung’s program, a machine “watches” as humans go through and map individual neurons. It then examines how the human researchers did this work and develops parameters to follow the same pattern, therefore potentially providing a tool that would dramatically decrease the number of person hours required to some of the work. To localize proteins and other chemicals efficiently and construct the neurochemical microcircuitry of the brain will require the equivalent of the automated sequencers that drove, with increasing rapidity, the se- quencing of the human genome, said Joseph Coyle, professor of psychia- try and neuroscience at Harvard Medical School.

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11 WORKSHOP SUMMARY There is no way that a human mind or a collection of human minds could effectively and efficiently sift through the tremendous amount of data. Rather, it is going to require automated procedures running on computers that have proved themselves in one domain being applied to this domain, added Read Montague, professor of neuroscience at the Human Neuroimaging Lab, Baylor College of Medicine. Lichtman stressed that this is big science. No single laboratory can do this. Rather it can only be done through a multilaboratory, national, even an international effort. All of these advances have researchers like Lichtman and Marder very excited. “I would say, today, 2008, 2009, we are right at a historical cusp, be- cause we have revolutionary opportunities for circuit analysis in the next decade,” said Marder. “Is this a possibility?” asked Lichtman, who used the word “connec- tome” to refer to the wiring diagram of the brain. “Can we get connec- tomes? I would argue that we can. Finally, there are the necessary techniques to do this.” The Importance of Neural Networks The connectome, of course, is just one step, a way of breaking the brain down into understandable pieces. New research shows that the brain is significantly more than the sum of its parts, and that a network- level view is critical to understanding how it functions. When information comes in from the outside world—say, when you look at the Mona Lisa—the sensory input is transformed in the brain into a series of electrical spikes. It is not that one or two neurons fire; entire regions of the brain (and perhaps the entire brain itself) light up, with a complexity of pathways that tells us a simple circuit map cannot fully account for activity in the brain. William Bialek, a professor at the Joseph Henry Laboratories of Physics and the Lewis-Sigler Institute of Integrative Genomics, Prince- ton University, described this series of spikes at the workshop as “the language in which the nervous system does its business.” “Although much of the history of neuroscience is about understand- ing the responses of individual neurons,” said Bialek, “in fact, almost all of our experiences are based on the activity of many, many neurons.”

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20 FROM MOLECULES TO MINDS Not only is the scale of the problem enormous, but it is growing as the population ages, and neither the public nor the scientific community is content to wait on basic discovery before we start investigating cures. “Society [has a] hunger for interventions long before we have a deep, fundamental knowledge” of how the neurological system works, said Hyman. For many aging people, the question of how and why their brains age is much deeper than small forgetfulness; it goes down right to the core of personality. “People are obviously interested in how ‘me’ is developed,” said Marcelle Morrison-Bogorad, director of the Division of Neurosci- ence at the National Institute on Aging. “But they are also very interested in how ‘me’ is retained and how to retain ‘me’ in the presence of aging- related changes which take ‘me’ away.” Theories do exist. Many have noted a rise in inflammatory markers in the aging brain, and guessed about ischemic effects that build up over time. There are signs of decreases of protein transcription and protein expression in the brain, signal-transduction alterations that likely lead to the morphological changes that are observed, including decreased num- bers of neurons and connections between neurons Some believe that a lifetime of toxic exposures play a role, although we have not yet con- ducted the kind of epidemiological studies that would provide this infor- mation. Starting at Square One For many neurological disorders, we are really at square one in un- derstanding how a particular disease works, and what avenues we should explore for treatment, let alone having a better understanding of what life style adjustments could be made to avoid or minimize the onset of aging- related complications. Many participants, including Greenberg and Ste- ven Dekosky, chair of the Department of Neurology at the University of Pittsburgh, expressed a desire for a better core understanding of the physical morphology of neurological disease, as well as the physical morphology of aging. The ability to diagnose presymptomatic disease by either looking for biomarkers or, better yet, studying the genetic makeup, genetic expression, and neurological makeup of individual patients would be one good proxy for gaining an understanding of how diseases arise. This kind of research was not possible a few years ago, before the

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21 WORKSHOP SUMMARY advent of high-throughput genetic sequencing and high-resolution neuro- imaging, but it is becoming increasingly possible every day. The Complicated Role of Genetics A popular presumption is that many diseases are driven by a single genetic mutation, and that a magic switch in the body is either on or off—and as a result, you either have a disorder such as autism or Parkin- son’s or you do not. Increasingly, however, research suggests that these are disorders of complex genetics, where multiple genes and varying levels of expression are combined to create the impact of the disease. Understanding the eti- ology of a disorder is further compounded by the influence of the envi- ronment on genetic expression. Greenberg explained research showing how parts of the genome are involved in the process of synapse devel- opment, synaptic pruning, and the balance between exciting and inhibit- ing individual synapses. Another emerging idea is that it is not just a genetic mutation that knocks out function, but subtle mutations that affect the level of expres- sion of the genes and greatly impact disease and normal function. Per- haps this may give us some insight into the processes that lead to “graded” neurological spectrum disorders, such as autism spectrum dis- orders. As Takahashi highlighted, the use of applications made through advances in genetic tools will allow for a much more integrated under- standing of our behaviors. Consequently, an improved understanding of the role of genetics and the environment will almost certainly improve our understanding of how best to protect, restore, or enhance the function of our brains and nervous systems. The Trouble with Current Treatments Without a core understanding of how the brain works, the current generation of neurological treatments and preventions is imprecise. In diseases like depression, our best current therapies are to expose the en- tire brain with a neuromodulator like serotonin, producing only a partial therapeutic response along with unwanted side effects. As Montague ob- served during the workshop, “We wiggle the knobs down here at the mo-

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22 FROM MOLECULES TO MINDS lecular end in a way . . . and we get some sort of behavioral endpoint out there. . . . In between there is nothing.” With depression there is not even a real scientific definition of the fo- cus of the disease—“mood”—and no accurate way to measure how it changes, nor is there a core understanding of how serotonin impacts the brain as a whole to alter mood, explained Coyle. Similarly, Montague described how there is very limited understand- ing of the widespread “placebo effect,” both in neurological diseases and in other physical diseases. What is the physical morphology of the pla- cebo effect, and how does the body use that to treat and cure itself? The impact is not small; huge efforts are undertaken to account for it in clini- cal trials. While it appears that the neurotransmitter dopamine has a role in the process, we still do not know how the total process works. Marder also highlighted deep brain stimulation (DBS), in which elec- trodes are implanted into the brain to treat Parkinson’s disease, depres- sion, and other maladies. Although the process of DBS is based on some understanding of what areas of the brain are impacted by disease, there is no depth to our understanding of the physical process by which DBS works. DBS is a perfect example of where a fundamental understanding of the structure and function of the brain could drive tremendous bene- fits. New neuroimaging techniques and new neuronal mapping tech- niques make it easy to imagine mapping out the structure and functional map of the brain in such a way that we could precisely target an interven- tion like DBS to create a desired treatment effect, for example as has been done to treat individuals suffering from Parkinson’s disease. However, as Volkow described, at the end of the day the brain not only gives rise to some disorders of the nervous system, but it is also where emergent behaviors originate. Consequently, the brain is very likely to be driving the likelihood of optimizing health, through deter- mining our behaviors, which then affects our lifestyles and our health. INSPIRING THE NEXT GENERATION OF SCIENTISTS As the previous pages explain, much of the discussion at the work- shop focused on the ways that advances in neuroscience can help us treat disease, handle aging, and otherwise improve the health and functioning of the brain. This is the core charge of neuroscientists, and drives many of the Grand Challenges identified during the workshop.

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23 WORKSHOP SUMMARY However, who among us is not fascinated by the brain? Who does not want to know how it works, why it fails, how we learn, and how our current personalities develop? These are some of the most fundamentally interesting questions in the world. The fact that these questions can now be approached in a rigorous way, Leshner hoped, would capture the attention of the public, particu- larly budding scientists of all ages. Ultimately, answering these questions will take more than just focus and money (although both of those will be important); it will take smarts and effort, two resources that can only be tapped by capturing the imagination of our youth. Thomas Insel, director of the National Institute of Mental Health, identified this inspiration as a potential Grand Challenge for the field. “I think it would be a fantastic Grand Challenge to have neuroscience taught at every high school in America, that we make this as appealing as astrology might be to the American public—or football,” said Insel. “It is something that could . . . [ensure] that this field will move even faster and further than it has in the last 10 years, if that is possible.” CHALLENGES AND TECHNICAL LIMITATIONS Many barriers that have impeded researchers from addressing the questions highlighted in the Grand Challenges workshop have disap- peared over recent years, remarked Leshner. Advances in imaging tech- nology, new techniques such as those similar to the Brainbow, and neuronal “light switches” have laid the groundwork for researchers to explore the brain as never before. However, many of the advances that have been made over the last decade have also been a direct result of ba- sic unrestricted discovery research. For example, the increased use and power of the internet and computer programming, sequencing the human genome, and the discovery of small non-coding RNA, are all examples of the value of basic discovery research that have had major impact on how we view and understand our brains and nervous systems. It is very likely that future unexpected discoveries and advances in other areas of physics, biochemistry, computer science, and molecular biology will continue to have a significant impact on the future progress that will be made in the neurosciences. But the path from where we are today to where we want to go is not easy. Both conceptual and technical impediments must be solved. This document does not intend to capture each and every one of those chal-

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24 FROM MOLECULES TO MINDS lenges—the science is too intricate and involved—but rather to highlight a few high-level topics raised by multiple workshop participants. Integrating Neuroscience and Working Toward a Common Goal “Grand Challenges” are designed to unite a scientific field around a few common problems. This is not easy. The nature of science is that researchers are often focused on micro-fine topics and must promote the importance of their particular corner of expertise to secure funding and attention for their fields. The result can be scientific fiefdoms and intel- lectual turf wars, emboldened by the need for financial support. The problem is more acute in neuroscience than in other fields. As mentioned earlier, one of neuroscience’s great strengths is also its great- est weakness: It is not a single “science” at all, but an interdisciplinary field drawing on biology, chemistry, computer science, genetics, and others. “It is a very large continuum . . . from molecular to behavioral neuro- science, with extraordinary opportunities,” said Story Landis, director of the National Institute of Neurological Disorders and Stroke at the Na- tional Institutes of Health (NIH). “We need to figure out how to portray the excitement across that continuum in a way that not only the public and our funders, but, most important, the neuroscience community as a whole, can embrace.” Working with Psychological Concepts and Defining Behavior A further challenge highlighted by some at the workshop was to free neuroscience from its roots in psychology and psychiatry. “We have ei- ther enjoyed or suffered under the concepts that psychology has brought to us for the last, let’s say, 100 years,” said Montague. A further challenge highlighted by some at the workshop was the need to reconcile understanding of psychological phenomenon at the be- havioral and cognitive levels with understanding at the molecular and cellular levels. Montague decried the disconnection between much of cognitive neuroscience and molecular neuroscience. Terms like percep- tion, awareness, consciousness and disease states like depression, anxi- ety, mood, do not easily translate into their underlying molecular

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25 WORKSHOP SUMMARY mechanism. Therefore, we need to find a common language that allows both ends of the neuroscience spectrum to communicate. This likely will require an agreement on a common unit of analysis, which is the most reduced unit for the cognitive and most complex for the molecular neu- roscience approaches. Montague, Hyman, and others argued for the need for more concrete and quantitative definitions of behavior-understanding behavior derived from an agnostic approach to the problem, rather than one driven by our preconceived ideas about how the brain functions.” New Technological Requirements Despite tremendous advances in the past few years, many workshop participants highlighted the need for additional technical advances to drive the field forward. Although the workshop did not focus too closely on specific technological needs, one technology stood out: an imaging device or series of devices that can offer both ultra-fine spatial imaging resolution and ultra-fine time resolution. Techniques are needed that can produce both high resolution in space and high resolution in time, said Blakemore. Magnetic resonance imag- ing (MRI) and positron emission tomography (PET) provide fairly good resolution in space, but they are slow techniques. Electrical recording from the brain with an EEG or MEG can give us high temporal resolu- tion, but poor spatial resolution. Finding ways of combining these char- acteristics of different techniques, or new kinds of methodology, which can provide improved spatial and temporal resolution in both is going to be very important for the future. Professor He agreed, emphasizing that the tool must be noninvasive to study the human brain. He added that the field needed a new way to image connectivity in the brain and that such a tool would have major clinical appeal as well. “[Y]ou can help with the surgical planning on epilepsy patients,” said He. “You can help treat a lot of neurological dis- ease by rationally designing a neuromodulation or neurostimulation paradigm if you know the pattern. You just block that pattern and you can treat the patient even without surgery.”

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26 FROM MOLECULES TO MINDS ETHICAL CONSIDERATIONS The brain is an object of great fascination and power. It is the seat of humanity, the source of everything we are and everything we want to be. Understanding how the brain works—really understanding, on a core physiological level—would have tremendous benefits for society. But it would also raise significant moral, ethical, and practical considerations, which neuroscience must address carefully as it moves forward. “I think it is useful to realize that neuroscientists do operate in a kind of interestingly sensitive area,” said Moreno. “As the old saying goes, just because you are not paranoid doesn’t mean somebody is not follow- ing you.” As Moreno explained, people become nervous when they hear ques- tions such as “How does the brain work?” and how to intervene in the brain. “The idea that scientists can have what I call technologically me- diated access [to the brain]—can use devices or drugs, fancy machines that most of us do not really understand . . . I think is of great concern to many people and is something that, going forward, the community needs to think about,” said Moreno. A comparison was made to the Human Genome Project, which at- tracted a great deal of concern from both the public and professional ethicists because it edged so closely to the foundations of life. Ulti- mately, extensive education and careful restrictions convinced people that the genome project was a safe idea, but only because its backers ad- dressed the topic directly and in a public manner. Understanding “how the brain works” raises similar issues, and must be discussed, examined, and considered in the same light. Clinical Concerns Moreno raised a number of additional areas where ethics should im- pact the work of researchers. For instance, in clinical trials, it is possible that neurological interventions could change people’s sense of them- selves. How can these kinds of changes be measured, monitored, and understood, not only as they happen, but in the process of obtaining in- formed consent and in the investigative process itself? In a similar vein, Moreno pointed out, as we develop a better understanding of the pre- symptomatic risk factors for certain diseases, the issue of how to notify research subjects of their likelihood of developing neurological disease

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27 WORKSHOP SUMMARY becomes a major concern. This is already a live challenge in diseases such as the debilitating and deadly Huntington’s disease, which can be diagnosed in a presymptomatic state, but is invariably fatal. Expanding capabilities to identify disease on a presymptomatic basis would expand the potential treatment options of these challenges exponentially. Fostering a Dialog Throughout the discussion, ethical and morals concerns were raised. The ongoing discussion of learning disabilities, for instance, and the po- tential to intervene and mediate disorders medically, caused concern among many on the question of streamlining and mainstreaming in edu- cation and the cost to society of losing diversity within the population. Similarly, discussions of transhumanism—supercharging the brain— made some hesitant, while others saw it as a means to help the elderly regain function. The overarching point was that neuroscience stands on the cusp of huge advances, and those huge achievements raise major issues that the field has never considered before. “The time is really now to start thinking about what that means and how we want to . . . self-regulate and engage in better professional forethought as to how the impact of what we are doing inside our labora- tories is actually reaching beyond the borders of our community,” said Insel. The community was acutely aware that if they do not self-regulate their efforts and engage the public in a focused dialogue on the issue of neuroscience, politicians and other nonscientists will do it for them. CONCLUSION The purpose of a forum at the National Academies is not to come to consensus or make specific recommendations to the public. It is, rather, to foster an open discussion among leading experts in the field; to gather some of the best and brightest around a common topic and see what emerges. To that end, Leshner proclaimed the workshop a tremendous success. The opportunity to step back and discuss the big issues surrounding neu- roscience pulled researchers out of their particular areas of focus and

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28 FROM MOLECULES TO MINDS forced them to take a 30,000-foot view of the space. They made it clear that the neurosciences have advanced tremendously over the past 50 years. The progress of the past in combination with new tools and tech- niques has positioned neuroscience on the cusp of even greater transfor- mational progress in our understanding of the brain and how its activities result in mental activity. On the Cusp Neuroscience is on the cusp of exciting breakthroughs that take ad- vantage of the convergence of scientific knowledge and technologies, like Brainbows, neuronal light switches, and computer learning tech- nologies have made it possible to answer questions such as the follow- ing: • How does the brain work and produce mental activity? How does physical activity in the brain give rise to thought, emotion, and behavior? • How does the interplay of biology and experience shape our brains and make us who we are? • How do we keep our brains healthy? How do we protect, restore, or enhance the functioning of our brains as we age? As highlighted during the last panel discussion with Coetzee, Marder, Hyman, Insel, Leshner, Volkow, and Ting Kai Li, director of the Na- tional Institute on Alcohol Abuse and Alcoholism, if there was any de- bate about the feasibility of answering these questions, there was no debate on this: Doing so would have tremendous benefits to society, eas- ing the suffering of those with disease, helping people age gracefully, and even improving our understanding of issues like learning disabilities and more. It is a classic investment problem—taking money away from the current need to invest in a brighter future, commented Coetzee. How- ever, the advantages gained from understanding the mechanisms of brain function, plasticity, and other topics would lead to step-wise improve- ments in therapies—improvements that cannot happen any other way. The challenges will be great, said Landis. Integrating the various fields of neuroscience toward a common goal will be tough, and the field still requires new technological advances and ideas to achieve its goals. It will be a step-wise process, with the benefits taking years or even dec-

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29 WORKSHOP SUMMARY ades to realize. But with the right injection of new funding and resources, there was a feeling that the potential payoff balanced this load. “Both NIH and NSF believe that the field [of neuroscience] is now poised on a threshold of major transformational advances,” said Olsen. “I do not think it is an exaggeration to say that . . . in the next decade and beyond ‘neuro’ will become the new ‘nano’ in terms of experimental capabilities that are beyond anything we could previously imagine, and discoveries that fire the imagination, achieve great practical advances, and grow the economy.” Added Olsen: “I think the potential benefits are too enormous to let this opportunity pass.” I would say, today, 2008, 2009, we are right at a historical cusp. . . . —Eve Marder

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