Progress Report on Brian Research 2006

Home , Colin Blakemore, Marcus Raichle, Mary Bartlett Bunge

The 2006 Progress Report on ADVANCES IN NEUROIMAGING BRAIN RESEARCH

Disorders That Appear in Childhood Movement and Related Disorders Nervous System Injuries Neuroethics Neuroimmunology Pain

Psychiatric, Behavioral, and Addictive Disorders PROGRESS REPORT Sense and Body Function Stem Cells and Neurogenesis Thinking and Remembering

2006 The 2006 Progress Report on BRAIN RESEARCH

www.dana.org Introduction by Thomas R. Insel, M.D. and A Report on THE AGING BRAIN by Marilyn Albert, Ph.D., and Guy McKhann, M.D. AAPRESS DANA

The Dana Alliance for Brain Initiatives On the Cover: A Brain at Rest

Neuroimaging technologies have grown in sophistication and clarity. Now investigators can study questions such as the brain’s energy use in different states of action. A functional magnetic resonance imaging scan from 2005 shows that the brain exhibits highly organized behavior even when it is “at rest,” not focusing on any task. This activity likely reflects the brain’s ongoing operations, both conscious and nonconscious.

A downloadable version of the Progress Report on Brain Research is available online in PDF format at www.dana.org 2006

PROGRESS REPORT ON BRAIN RESEARCH

Introduction by Thomas R. Insel, M.D.

NEUROIMAGING Essay by Marcus Raichle, M.D.

A Report on THE AGING BRAIN by Marilyn Albert, Ph.D., and Guy McKhann, M.D.

The Dana Alliance for Brain Initiatives

Published by DANA PRESS Jane Nevins, Editor in Chief Dan Gordon, Editor THE DANA ALLIANCE FOR BRAIN INITIATIVES EXECUTIVE COMMITTEE

William Safire Chairman Eric R. Kandel, M.D. Vice Chairman James D. Watson, Ph.D. Vice Chairman Edward F. Rover President Marilyn S. Albert, Ph.D. Nancy C. Andreasen, M.D., Ph.D. Colin Blakemore, Ph.D., ScD, FRS Floyd E. Bloom, M.D. Dennis Choi, M.D., Ph.D. Leon N. Cooper, Ph.D. Joseph T. Coyle, M.D. Fred H. Gage, Ph.D. Zach W. Hall, Ph.D. Kay Redfield Jamison, Ph.D. Joseph B. Martin, M.D., Ph.D. Guy M. McKhann, M.D. Herbert Pardes, M.D. Steven M. Paul, M.D. Fred Plum, M.D. Carla Shatz, Ph.D. Barbara E. Gill Executive Director

The Progress Report on Brain Research is published annually in March by the Dana Alliance for Brain Initiatives, a nonprofit organization of more than 200 leading neuroscientists, including ten Nobel laureates. The Dana Alliance is committed to advancing public awareness about the progress and benefits of brain research and to disseminating information on the brain in an understandable and accessible fashion. Supported entirely by the Dana Foundation, the Dana Alliance does not fund research or make grants.

The Dana Alliance for Brain Initiatives 745 Fifth Avenue Suite 900 New York, NY 10151

ISSN: 1553-5398 ii CONTENTS

1 Introduction by Thomas R. Insel, M.D. 5 Neuroimaging by Marcus Raichle, M.D. 11 The Aging Brain by Marilyn Albert, Ph.D., and Guy McKhann, M.D.

Progress in Brain Research in 2005

17 Disorders That Appear in Childhood

25 Movement and Related Disorders 2006 Report

33 Nervous System Injuries

41 Neuroethics

49 Neuroimmunology

56 Pain

63 Psychiatric, Behavioral, and Addictive Disorders

72 Sense and Body Function

79 Stem Cells and Neurogenesis Contents

87 Thinking and Remembering

96 Notes

111 Dana Alliance Mission Statement, Goals, and Membership

126 Index

iii INTRODUCTION by Thomas R. Insel, M.D. Director, National Institute of Mental Health, National Institutes of Health

inston Churchill is usually considered the source of the Waphorism that we make a living from what we get and we make a life from what we give. Whoever is the source, the sentiment is as relevant to science as it is to individuals. In neuroscience, while much attention this year has been focused on “making a living,” the field

is clearly “making a life,” as we are giving more to society than 2006 Report ever. This Progress Report documents many of the areas where remarkable advances were reported in 2005. In truth, the report provides only a sampling. A comprehensive description of progress in neuroscience would need to be at least 10 times longer, even if limited to reports from 2005. What is apparent in every part of this Progress Report is that neuroscience is providing critical insights about the brain. In the best sense, this is science for public health. The need is certainly urgent. The more than 1,000 disorders of the nervous system result in more hospitalization than any other disease group, including heart disease and cancer. Stroke is one of the three greatest medical sources of mortality, depression causes the

greatest disability for adults under age 45, and suicides continue Introduction to outnumber homicides by almost two to one. The aging of our population makes Alzheimer’s and other neurodegenerative diseases an increasing public health priority. And, at the other end of the life span, the prevalence of autism spectrum disorders has now been estimated at 1 in 166 births, roughly a tenfold increase in the past decade. The good news is that we have extraordinary new tools and technologies with which to address these urgent public health challenges. The results from these advances are evident throughout this

1 report, but their development deserves recognition as a keystone of progress. The Human Genome Project, which was published with great fanfare in 2003 (on the 50th anniversary of the publication of the original double helix paper by James Watson and Francis Crick), provided a consensus map of human DNA, but it failed to describe variation. Because variation is the key to understanding individual vulnerability and resistance to disease as well as human diversity, a map of human DNA variation may be even more informative than the original consensus map. This year marks the completion of the “HapMap” project, the first comprehensive map of human haplotypes, which mark the millions of single points of variation in our genomes.1 With the HapMap and new chips for mapping variation, genetics has become markedly cheaper and faster just in the past year. The question of how individual variation in DNA sequence is associated with risk for disease can now be answered not only for single- gene diseases (such as Huntington’s disease), but also for complex genetic diseases. In the past year, scientists have used the power of this whole-genome approach to identify genomic variations that confer risk for Parkinson’s disease and age-related macular degeneration, changing our understanding of these disorders.2,3 In the next few months, we are hopeful that studies using the HapMap and new genomic technologies will provide similar insights for a range of nervous system disorders from autism to Alzheimer’s. Neuroimaging, discussed in detail by Marcus Raichle, also has given us a new perspective on the brain. Research in 2005 included remarkable advances in our ability to visualize individual cells, even in the living brain. In addition, both structural and functional studies of the whole brain have been enhanced to allow neuroscientists to identify pathways for information in the brain. With imaging we can map the remarkable plasticity in the human cortex,4 the circuits for processing faces and language,5 and even the evidence for information that is encoded without any conscious awareness.6 In ways that we may never have imagined, our brain anatomy appears to be determined by our genes, with differences in genetic sequence coding for very specific individual differences

2 Stem cell technology also provides a powerful tool for the researcher interested in how genetic variation or environmental factors alter the fate of a developing neuron. in brain structure and function.7 As one reads the several sec- tions in this report that describe various insights from neuroimaging, it is striking how the brain is organized in ways that we find counterintuitive. Indeed, the closer we get to mapping the circuitry for emotion or consciousness, for example, the more mysterious (and complex) these mental processes appear. Perhaps no area has held more surprises than stem cells. Although we might have expected neurons to be among the most complex adult cells to derive from stem cells, neurons have proved to be among the easiest cells to grow. As described in this report, in 2005 neuroscience made great strides identifying the developmental steps required to grow a neuron from the least 2006 Report developed precursor cell. The importance of this research for neurodegenerative diseases is obvious; stem cell biology has given birth to the entirely new field of regenerative medicine. Less appreciated but no less important, stem cell technology provides a powerful tool for the researcher interested in how genetic variation or environmental factors alter the fate of a developing neuron.8 For the first time, we can study both nature and nurture at the cellular level. The challenge in all of these areas—genomics, imaging, stem cell biology—is to translate the technological advances into improved public health and welfare. Each of these advances can be a powerful force for improving health care, but each can be used to perpetuate injustice. The emerging field of neuroethics Introduction has begun to grapple with the thorny questions of how we ensure that neuroimaging is not used for “mind reading” or that genomics is not used to preclude health insurance. While some of the concerns are based on a fantasy of what the technology can do (current neuroimaging has limited use for “mind reading,” and genomic assessment of disease risk is largely statistical), neuroscientists are increasingly thinking into the future to consider how the power of this science can be used for the greatest public good, as described in this report.

3 I began this essay by noting that scientists “make a life” by what they give. Since the beginning of 2005, neuroscientists have begun to join forces to try to give more. The Neuroscience Blueprint at the National Institutes of Health (NIH) is an excel- lent example.9 Analogous to the NIH Roadmap, which is designed to overcome obstacles to progress in medicine, the Neuroscience Blueprint is a multi-institute effort to address the big challenges in understanding the nervous system in health and disease. The Blueprint has already prompted new training programs on the neurobiology of disease, expanded collaborative efforts in neurogenomics and pediatric neuroimaging, and created a forum for all NIH institutes with an interest in neuroscience to work together. Projects in the next year include the development of transgenic mouse lines for neuroscience, training programs in neuroimaging, and the development of multi-institute core resources for scientists at universities. The 1990s were labeled the “Decade of the Brain.” The current decade may, in retrospect, appear to be the “Decade of Discovery,” with most of the major genes and proteins and pathways for brain function identified for the first time. This report, near the midpoint in this decade, attests to the excitement of this period in neuroscience research as we begin to map the intricacies of the body’s most complex organ. Increasingly, the discoveries from basic neuroscience are being translated into insights for public health, yielding new approaches to diseases as diverse as Alzheimer’s, autism, and drug addiction. For those with a nervous system disease, research is hope. There has never been a time to be more hopeful.

4 NEUROIMAGING by Marcus Raichle, M.D.

ridging the gap between descrip- tions of human behaviors and Bunderlying neural events has been a dream of both psychologists and neuroscientists for quite some time. William James, in his monumental, two-volume work The Principles of Psychology, written in 1890, clearly identifies the challenge: “A science of the mind must reduce … complexities (of behavior) to their elements. A science of the brain must point

out the functions of its elements. A science of the relations of 2006 Report mind and brain must show how the elementary ingredients of the former correspond to the elementary functions of the latter.”1 While it is clear that we have made progress ever since the time of James through studies in experimental animals and in patients with various diseases afflicting the brain, the opportunity to relate normal behavior to normal brain function in humans was largely nonexistent until the latter part of the 20th century. It was the introduction of modern brain imaging techniques in the 1970s that permitted us to monitor human brain function in a safe yet increasingly detailed and quantitative way. These breakthroughs created a revolution in medical diagnosis and cat- alyzed the development of other imaging techniques, particularly positron emission tomography (PET) and magnetic resonance Neuroimaging imaging (MRI). The introduction of PET and MRI presented researchers with an unprecedented opportunity to examine the neurobiological correlates of human behaviors. Researchers worldwide seized

One of the keys ... is to relate work in neuroimaging to that which parallels it in other areas of neuroscience.

5 this opportunity, first with PET and later with functional MRI, or fMRI (for a historical review see Raichle 2000).2 The result was the creation of a new scientific discipline known as cognitive neuroscience, and, more recently, social neuroscience, with combined agendas that now encompass virtually all aspects of human behavior in health and disease.3 Faculty positions for cognitive neuroscientists were unheard of in psychology departments in the late 1980s when the James S. McDonnell Foundation and the Pew Charitable Trusts initiated their program in cognitive neuroscience. They are now common, and young scientists with combined qualifications in imaging and behavior are eagerly sought. Equally remarkable has been the worldwide movement to establish research-imaging centers in which expensive imaging equipment (primarily MRI), along with teams of investigators, is devoted exclusively to research. This development breaks with a long-standing tradition in which research on humans and laboratory animals used clinical equipment, part-time, in a hospital setting, usually “after hours.” I know of no recent compilation of the budget for this agenda, but it is no doubt substantial. However, some researchers have questioned the ability of functional neuroimaging to provide analyses of brain function that are sufficiently refined to truly enlighten us about the relationship between behavior and brain function. One of the keys to evaluating such concerns is to relate work in neuroimaging to that which parallels it in other areas of neuroscience. Among the most important questions in this regard is how to relate neuroimaging measurements to the biology and neurophysiology of brain cells and the blood vessels that serve their needs. Importantly, there has been a burst of interest in the neurobiology of the signals generated by PET and fMRI. Subjects have included the neurophysiology of imaging signals,4,5 cell biology,6,7 and even the genetics of neuroimaging.8 An important aspect of this work has been the emergence of functional neuroimaging studies in nonhuman primates. These studies offer the opportunity not only to make direct comparisons between neurophysiology and brain imaging,9 but also to understand human brain organization from an evolutionary perspective.10

6 If we are not careful, functional brain imaging could be viewed as no more than a modern and extraordinarily expensive version of 19th-century phrenology.

Despite these developments, frequently stated or implied interpretations of functional imaging data suggest that, if we are not careful, functional brain imaging could be viewed as no more than a modern and extraordinarily expensive version of 19th-century phrenology, which associated certain mental faculties and character with parts of the skull.11 In this regard, it is worth noting that functional imaging researchers themselves have occasionally unwittingly perpetuated this notion. Data pre- sentations in journal articles, at meetings, and in lay publications have focused on specific areas of the brain, frequently without

presenting the entire data set for inspection. These areas are then 2006 Report discussed in terms of complex mental functions—just what the phrenologists did! It is Korbinian Brodmann, one of the pioneers in studying the organization of the human brain from both a micro- and macro- scopic point of view, whose perspective I find appealing even though it was written well in advance of the discovery of modern imaging technology (1909 to be exact). He said, “Indeed, recently theories have abounded which, like phrenology, attempt to localize complex mental activity such as memory, will, fantasy, intelligence or spatial qualities such as appreciation of shape and position to circumscribed cortical zones.” He went on to say, “These mental faculties are notions used to designate extraordinarily involved complexes of mental functions. … One cannot Neuroimaging think of their taking place in any other way than through an infi- nitely complex and involved interaction and cooperation of numerous elementary activities. … In each particular case [these] supposed elementary functional loci are active in differing numbers, in differing degrees and in differing combinations.” Without fail such activities, Brodmann continued, are a result “of the function of a large number of suborgans distrib- uted more or less widely over the cortical surface.”12

7 With this prescient admonition in mind, the task that lies before brain imaging researchers seems to be clear. First, identify the network of regions of the brain and their relationship to the performance of a well-designed task. This is a process that is well under way in the functional imaging community. It is com- plemented by a long history of neuropsychological studies focusing on brain lesions and behavior, and neurophysiological and neuroanatomical studies in laboratory animals, work that is increasingly being performed in conjunction with neuroimaging. Second, and definitely more challenging, researchers must identify the elementary operations performed within such a network and relate these operations to the task of interest. Very encouraging progress is clearly occurring, fueled by increasingly vigor- ous dialogue among scientists at all levels. Several issues are likely to be of increasing importance to our future understanding of human brain function and likely will receive increasing attention from the neuroimaging community. These include individual differences, development (brain maturation), and the activities of the “resting brain.”

Individual Differences

From the perspective of cognitive neuroscience and functional brain imaging, an early worry was that individual differences would be sufficiently great that attempts to average imaging data across individuals to improve their quality would be doomed to failure. These fears were quickly put to rest by the very first attempts to average functional imaging data across individuals. The results were stunning.13 The approach of averaging data across individuals has since dominated the field of cognitive neuroscience, and with great success. However, for all who have examined such data in detail (particularly high-quality fMRI data), the existence of individual differences begins to emerge with exciting prospects for an even deeper understanding of

We must remember also to consider brain function from a developmental perspective.

8 human behavior. Coupled with a long-standing interest in and techniques for the characterization of personality differences from psychology and psychiatry, we are poised to make major advances in this area.

Development

Cognitive neuroscience has focused largely on the adult human brain, examining how it functions normally and how it changes when damaged. We must remember also to consider brain function from a developmental perspective. The developmental psychology literature is very rich with details about developmental milestones associated with the maturation of the human brain. Missing, however, is a satisfactory understanding of the maturation process within systems of the human brain. Brain maturation at a systems level affects the development of attention, language, memory, personality, and the management of distress, to 2006 Report name a few. Information about this level of the maturation process would enrich not only our understanding of development itself, but also the end result of that development: the organization of the adult brain. The paucity of existing information reflects not only the challenge of safely and accurately accessing the needed information in humans. It is also a result of our general focus on the cellular and molecular level within developmental neurobiology to the relative exclusion of a more integrated systems approach. Data from the work of a small group of pioneering investigators employing neuroimaging techniques provide exciting glimpses of the future.14–16 Parallel studies in nonhuman primates, where changes down to a cellular level in the brain can be correlated with detailed analysis of complex Neuroimaging social behaviors, should be encouraged.

The Resting Brain

It will be critically important as we move forward to maintain a sense of proportion when it comes to viewing functional imaging signals. The human brain is an extremely costly organ in energy terms, while the activity changes observed in functional imaging studies are very small in terms of the overall cost. While this high

9 cost of ongoing brain function has been known for a long time,17 it only recently received the attention it deserves when we real- ized that most of this high cost is related to the primary function of the brain (perceiving and analyzing information and generating appropriate responses) rather than mere housekeeping (keep- ing cells and their environment properly maintained).18 This “cost analysis” approach to human brain function orients us to the view long espoused by Llinas and others:19 that the brain is largely concerned with creating and maintaining a mental state (both conscious and non-conscious) that represents the world in which we live and our position in it. In other words, the brain is not just an organ primarily responding reflexively to the world around us. As William James observed many years ago, “whilst part of what we perceive comes through our senses from the object before us, another part (and it may be the larger part) always comes … out of our own head.”20 Functional neuroimaging is clearly a work in progress, but one that is immensely interesting because it offers the potential of relating brain science to the full range of behaviors that define us as human beings in both health and disease. The challenge will be to understand how best to integrate the potential of brain imaging and its foundations in neurophysiology, cell biology, and genetics with the fascinating yet complex issues of interest to behavioral scientists and clinicians. The success of this integra- tion will benefit all of us.

10 THE AGING BRAIN by Marilyn Albert, Ph.D., and Guy McKhann, M.D.

s we age, some of us maintain our cognitive functions, such as mem- Aory or language, quite well, while others do not. Working with both humans and animals, scientists have revealed specific conditions associated with maintaining cognitive function. Their findings suggest types of intervention that could mini- mize or prevent cognitive decline at older ages. Effective measures could combine 2006 Report physical training, mentally stimulating activities, and psychosocial approaches.

Changes in Memory with Age

Does cognitive ability change as individuals get older, in the absence of disease? Researchers have focused on studying optimally healthy subjects across the age range, rather than subjects of just average health. The reason we study healthy subjects is that disease is more common with advancing age; thus, if we do not exclude individuals with common diseases, we are studying the interaction of age and disease, rather than aging per se. The Aging Brain There are changes in most aspects of cognition; we will focus here on changes in memory, in part because memory also can be studied in experimental animals. One common way to test memory is to ask someone to learn and recall new information. This “episodic memory” is often examined by asking someone to listen to a story and recall its details, both immediately and after a delay. When healthy individuals across the age range take a difficult memory test of this sort, we see significant changes in memory among those who are in their 50s and 60s, compared with

11 Recent careful studies of neuron loss in the brains of humans, monkeys, and rodents indicate very little diffuse loss of nerve cells with age, including parts of the brain, such as the hippocampus, that are vital for memory function.

people in their 30s. This difference is even greater in people over 70. Similar declines occur in other areas of cognitive function, such as language, but at differing ages. These changes in memory with age are readily demonstrated in middle-aged monkeys and rodents, providing further support for the findings. Not everyone experiences these changes with age. In fact, individuals vary greatly in how they change. Younger people have a relatively narrow range of variation from one another once we account for educational differences. Elderly adults show much greater variation: some maintain memory function similar to that of individuals many decades younger than themselves, while others show significant decline. Again, this change in vari- ability with advancing age is also seen in experimental animals.

Possible Causes

These observations about changes in memory with age raise the question of why some people experience a decline in memory and some do not. Researchers have suggested a variety of potential explanations for the decline. The first, a popular idea until recently, was that there was a loss of nerve cells with aging dif- fusely throughout the brain. However, recent careful studies of neuron loss in the brains of humans, monkeys, and rodents indicate very little diffuse loss of nerve cells with age, including parts of the brain, such as the hippocampus, that are vital for memory function. The loss of nerve cells in highly selective regions of the brain also has been suggested as a cause for memory decline. This loss does occur, particularly in collections of nerve cells deep within the brain, so-called subcortical nuclei. These nuclei, such as the nucleus basalis (which undergo as much as a 50 percent drop in

12 nerve cells), send projections to many other regions of the brain and influence the production of chemicals that are essential for learning and memory. A final possibility is that the mechanisms that nerve cells use in learning and memory change with age. This is best demonstrated in experimental animals in which performance in memory tasks can then be compared with changes in brain functions. For example, a decline in long-term potentiation, a neuronal mechanism thought to be critical for normal memory, is observed with age and correlates with poorer memory performance in rodents. Some older subjects, both humans and experimental animals, activate adaptive mechanisms that may allow them to compensate for age-related changes in function. Functional imaging, which indicates what parts of the brain are being used, has revealed that younger people use a few highly specific brain areas during a memory task. In contrast, older people with normal

brain function activate not only the same areas as younger peo- 2006 Report ple, but numerous additional areas. It is likely that older subjects with preserved memory function are exhibiting two traits: first, they are not demonstrating age- related declines in brain structure and function, and second, they are activating adaptive brain mechanisms for memory.

Genetics and Environmental Influences

We all know families in which numerous members live to old age with remarkable preservation of memory functions. This obser- vation leads to an obvious question: How much does genetics play a role in preservation of memory function? One of the standard ways of analyzing the effect of genetics is to compare the The Aging Brain behavior of identical twins reared together and separately. These studies suggest that genetics accounts for approximately 50 percent of variation in memory function. Thus, although genes are important, environmental factors must also be predictors of memory preservation. Numerous researchers examining subjects at repeated inter- vals have analyzed lifestyle aspects associated with maintaining memory and other aspects of cognitive function. Cumulatively, these studies involve up to 15,000 community-dwelling individ-

13 uals from many countries. Physical activity, mental activity, social engagement, and vascular risks repeatedly have emerged as important. Evidence suggests that these factors may be additive in their effects.

Brain Mechanisms

Epidemiological studies can identify the behavior of humans who preserve memory function. However, if we want to understand the underlying brain mechanisms, we must turn to experimental animals. People who maintain memory and other cognitive functions have higher levels of physical activity associated with daily living, as mentioned above. These activities include walking long dis- tances, climbing stairs, and lifting objects. Rodents can mimic this behavior by running on a wheel placed in their cages. These exercised animals show increased learning ability. At least three brain mechanisms have been associated with this increased learning and memory performance. The exercised rodents make more new nerve cells, specifically in the hippocampus, a part of the brain critical for normal memory. They also make increased amounts of substances required for the normal maintenance of nerve cells, so-called trophic factors, such as brain-derived neurotrophic factor, or BDNF. These trophic factors, too, seem to be specifically expressed in the hippocampus. Finally, the neurochemical mechanisms by which nerve cells in the hippocampus communicate with each other appear to be enhanced. Thus, physical activity not only improves the cardiovascular system, it also effects specific positive changes in parts of the brain involved in memory. Epidemiological studies have also indicated that those who preserve cognitive function have higher levels of mental activity—they are more likely to be involved in daily activities that are mentally stimulating, such as doing crossword puzzles, playing board games, reading books, and attending lectures. In rodents, it is possible to develop a mentally stimulating environment by exposing the animals to surroundings rich in objects to explore. Animals in such an environment show increased learning ability, similar to animals with greater physical activity. These animals

14 have more new neurons in the hippocampus and increased expression of trophic factors such as BDNF. Studies are now under way in rodents to see whether the effects of increased physical activity and mental stimulation are additive. Social stimulation also appears to be important in maintaining cognition. Variously termed social engagement, feelings of self- worth, or feelings of self-efficacy, these measures appear related to how connected people feel to others in their family and community and how much they think they can influence what happens to them. It has been difficult to develop a model to study these behaviors in experimental animals. However, one hypoth- esis is that the common element of these behaviors is the reduction of stress hormones in the brain, and studies show that excess stress and increases in levels of stress hormones lead to the loss of nerve cells in the hippocampus of experimental animals. Finally, what’s good for the heart also is good for the brain.

This understanding has emerged from research showing that 2006 Report controlling hypertension, recognizing and treating diabetes, low- ering cholesterol, controlling weight, and avoiding smoking are all associated with less disease of the blood vessels of both the heart and the brain. In people with uncontrolled vascular risk factors, cognitive function does suffer. Proper preventive measures can lessen these negative effects in the brain. These studies, in both humans and experimental animals, lay the groundwork for steps to reduce or avert cognitive decline in older people. Such steps likely would combine physical, mental, and psychosocial approaches. The implications of these findings have stimulated public interest, as exemplified by educational programs directed at older people: the AARP’s “Staying Sharp” program, the Alzheimer’s Association’s “Maintain Your Brain” The Aging Brain campaign, and the National Institutes of Health’s “Cognitive and Emotional Health Project.”

This essay is based on the Marilyn Albert’s Public Lecture at the Society for Neuroscience conference, November 12, 2005.

15 PROGRESS IN BRAIN RESEARCH IN 2005 DISORDERS THAT APPEAR IN CHILDHOOD 2006 Report

Challenging Assumptions about ADHD 18

Investigating the Brain Basis of Dyslexia 21

Seeking Early Signs of Autism 22 Disorders That Appear Disorders in Childhood

17 rain disorders that appear in childhood often spark contro- Bversy, with heated public debate about proper diagnosis and treatment. In 2005 researchers continued the effort to better understand the neurological basis of three such disorders: attention-deficit hyperactivity disorder, dyslexia, and autism.

Challenging Assumptions about ADHD

Attention-deficit hyperactivity disorder (ADHD) is the most commonly diagnosed psychiatric disorder in children, affecting an estimated 8 to 10 percent of schoolchildren,1 yet it is also one of the most controversial. Some people doubt that ADHD is a real disorder, chalking up any inattentiveness and hyperactivity in children to a lack of discipline or maturity. Others believe that the disorder is real but worry that children are being overmed- icated. Research reported in 2005 helped clarify some issues, but in other cases raised new ones. Two studies published in 2005 challenge the accepted wisdom about differences between boys and girls in ADHD. Although it is known that ADHD affects more boys than girls, the estimated prevalence rates vary depending on whether researchers are studying children being treated in clinics or analyzing a more general sampling of children who live in the community. One meta-analysis (a study that involves reviewing data from multiple separate but similar experiments), published in the Journal of the American Academy of Child and Adolescent Psychiatry, found that in clinics, the number of boys being treated is six to nine times greater than the number of girls, while in the community, only three times as many boys have the disorder.2 What accounts for the discrepancy? Until now, the prevailing view was that ADHD must manifest itself differently in boys and girls, causing different symptoms. In particular, boys with ADHD were believed to be more hyperactive and disruptive than girls, leading to problems in the classroom that prompted parents and teachers to seek referrals for treatment. But a study published in 2005 by Joseph Biederman and colleagues at Massachusetts General Hospital challenged the belief

18 that ADHD differs significantly in boys and girls. As reported in the June issue of the American Journal of Psychiatry,3 Biederman and his team studied a sample of children in the community. Using standard diagnostic techniques, they diagnosed ADHD in a subset of children living in the community who had never been referred for treatment of ADHD. Consistent with previous community studies, ADHD was about three times as prevalent in boys as in girls. But when Biederman and his colleagues delved deeper, they found no significant differences between the boys and girls in age of ADHD onset, symptoms, impairment, subtype (inattentive, hyperactive- impulsive, or combined), or the presence of other disorders along with ADHD. Why are so many more boys than girls being referred for treatment? Although the reasons are not clear, the cause could be referral bias, says Biederman. In his experience, boys with ADHD tend to be more outwardly disruptive than girls, especially when they 2006 Report are young, and this slight gender variation in the way disruptive behavior is expressed probably is what leads to referrals. Yet this also means girls with ADHD may not be diagnosed and treated as often as they should. If the study is replicated in other community populations, it could have important implications for the detection and management of ADHD in girls. Further support for the view that boy vs. girl differences in ADHD may be overrated is provided by a large study in twins and their siblings born singly, led by Florence Levy at the University of New South Wales in Australia.4 As reported in the April issue of the Journal of the American Academy of Child and Adolescent Psychiatry, the researchers found few differences between boys and girls in the occurrence of disorders frequent- That Appear Disorders in Childhood ly diagnosed along with ADHD, such as conduct disorder, oppo- sitional defiant disorder (characterized by persistent uncoopera- tiveness and hostility), and separation anxiety disorder. The one exception was that girls with ADHD were slightly more likely to

ADHD subtype and severity of ADHD symptoms, rather than gender, determined whether other disorders were present, and, if so, how severe they were.

19 be diagnosed with anxiety disorder. Otherwise, ADHD subtype and severity of ADHD symptoms, rather than gender, determined whether other disorders were present, and, if so, how severe they were. Other studies published in 2005 investigated the neurological basis of impulsivity and deficits in what are called “executive functions”—planning, organizing, and decision-making. These problems can affect school and work performance in ways that can limit an individual’s intellectual growth and professional achievement. Katya Rubia and colleagues at King’s College London used functional magnetic resonance imaging to identify

Gauging impulsivity Researchers at King’s College London found that boys with attention deficit hyperactivity disorder show less activity in the right inferior prefrontal cortex when they perform a task successfully, as indicated by these scans. patterns of brain activation in 16-year-old boys with ADHD who had never been treated with medication. As reported in the June issue of the American Journal of Psychiatry,5 the researchers conducted brain scans while asking the boys to perform a task that measured inhibition control (a way to gauge impulsivity). When compared with the control group without ADHD, boys with the disorder showed reduced activation in the right inferior prefrontal cortex when they successfully performed the task, and

20 Although questions remain about the brain basis of ADHD, the consensus about treatment remains the same.

reduced activation in the posterior cingulate and precuneus when they did not complete the task successfully. This pattern of brain activation not only differed from that seen in the control group, but also was nearly identical to the findings in a group of boys with ADHD who were medicated. This suggests that the problem is inherent to ADHD and not caused by medication. Although questions remain about the brain basis of ADHD, the consensus about treatment remains the same. In June 2005, the American Academy of Pediatrics issued a detailed review of the evidence behind its current treatment guidelines to help pediatricians see how different treatment options compare and choose one over the others.6 As reported in the academy’s jour- 2006 Report nal, Pediatrics, the medications studied in most detail were the stimulants methylphenidate (Ritalin), dextroamphetamine (Dexedrine), and pemoline, with some mention made of the tri- cyclic antidepressant desipramine (Norpramin) and the non- stimulant atomoxetine (Strattera). The report strongly endorses treatment with stimulant drugs to treat core symptoms and concludes that all stimulant drugs are equally effective. Tricyclics and atomoxetine, which are antidepressant medications, provide options for children who do not respond to stimulants. (It should be noted, however, that the FDA required late in 2005 that a black box warning be added to atomoxetine because it may increase suicidal thoughts in some children.) The authors endorse what has become the consensus That Appear Disorders in Childhood opinion about treatment, however: the best approach probably involves a combination of medication and behavioral therapy.

Investigating the Brain Basis of Dyslexia

Children with dyslexia usually have normal intelligence, but they have difficulty learning how to read. Exactly what brain abnormalities are responsible remains a matter of debate. Two studies published in 2005 may help provide answers.

21 Children with dyslexia also frequently are unable to correctly name objects such as those they see in pictures. Wondering if the same neurological abnormality might underlie both defects, researchers led by Eamon J. McCrory of the Institute of Psychiatry in London used positron emission tomography scans to map patterns of brain activation in children with dyslexia. As reported in the February issue of Brain, they found that children with dyslexia showed reduced activation in the left inferior occipitotemporal cortex while trying to read words or name pictures—suggesting that the underlying problem is a deficit in the processing of sounds.7 The research, if confirmed, has practical implications: identifying preschool-age children who have trouble naming pictures, and then providing remedial help from a speech and language specialist, might help improve later reading ability. Another study reported in 2005 provided a surprising new twist to the theory that dyslexia involves a problem in actually seeing words. Researchers led by Anne J. Sperling at the Georgetown University Medical Center reported in the July issue of Nature Neuroscience that the real problem may be an inability to discriminate visual cues from background signals called “noise.”8 The researchers asked children to look at a series of patterns, both flickering and static, on a computer screen and to say whether the patterns appeared on the left or right side. When the patterns alone appeared on the screen, children with dyslexia could identify them as often as other children. But when the researchers partly obscured the patterns by adding visual “noise” in the form of television-like “snow,” the children with dyslexia were less able than their peers to identify the patterns. The authors propose that the underlying problem in dyslexia may therefore involve an inability to screen out background “noise” and focus on important signals.

Seeking Early Signs of Autism

In 2005 scientists continued to provide evidence that the brain abnormalities that cause autism can be detected in the first months and years of life, even though this developmental disorder is usually not diagnosed until the child’s second or third year.

22 When does autism appear? Already at a first birthday party, children with early-onset autism show symptoms of the disorder, as was the case with the baby on the right. Babies with later-onset autism and babies developing normally, such as the one on the left, also were studied.

In the April/May 2005 issue of the International Journal of 2006 Report Neuroscience, Lonnie Zwaigenbaum and colleagues at McMaster University in Ontario report that some signs of autism are evident in babies as young as 6 months.9 Their pilot study involved 65 infant siblings of children with autism, recruited around age 6 months and followed until age 2 or older. (This pilot study has since mushroomed into what is now known as the High Risk Baby Autism Research Project, under way at 14 sites in Canada and the United States.) The researchers tested the babies at 6 and 12 months to measure behaviors and emotional reactions that sometimes become abnormal in autism. They identified characteristics, noticeable in children by their first birthday, that may predict a diagnosis of autism later. These include reduced capacity to shift visual atten- That Appear Disorders in Childhood tion when there were competing stimuli, other abnormalities in visual behaviors such as orienting to name, and exaggerated reactions to stress. Even at 6 months, babies later diagnosed with autism exhibit- ed certain telltale behaviors. For example, babies who were pas- sive and inactive at 6 months and who at 12 months became extremely irritable and tended to fixate on particular objects were more likely to be diagnosed with autism. The authors emphasize, however, that the results are based on a relatively

23 small sampling and are preliminary. Nor have any of the observed behaviors been correlated with measures of early brain development; trying to do so by methods such as brain scans poses technical and ethical challenges in infants. Even so, the study, if replicated, may provide a way to identify earlier in life some children with autism. Another study published in 2005 involved an analysis of home movies of children’s birthday parties that builds on a 1994 study now considered classic because it provided what is believed to be the first objective evidence that autistic regression exists. As reported in the August issue of the Archives of General Psychiatry, Geraldine Dawson at the University of Washington (who also authored the classic 1994 study) and her colleague Emily Werner viewed home birthday videos taken at the first and second birthdays of 56 children, 21 with early-onset autism, 15 with later-onset autism, and 20 who were developing normally.10 They found that the children with early-onset autism displayed symptoms of the disorder at the first birthday party, while those with later-onset autism displayed behaviors that were indistinguishable from the behaviors of the healthy babies. By the second birthday party, however, those babies who initially appeared healthy and were later diagnosed with autism had clearly regressed, supporting parents’ anecdotal reports. Research is now under way to better understand the cause and long-term prognosis of autistic regression.

24 MOVEMENT AND RELATED DISORDERS 2006 Report

Spotlight on Gene Mutations 26

Gumming Up the Works 28 Movement and Related Disorders

Continued Interest in GDNF 29

More Uses for Gene Therapy 30

Fine-Tuning Deep Brain Stimulation 30

Mice Yield New Clues in Huntington’s Disease 31

25 he most active research on movement disorders in 2005 Tcontinued to be in the area of genetics, and studies in the clinic and laboratory have revealed new treatments, refined current treatments, and led to new ways to deliver drugs to the brain. Researchers also studied the cellular and molecular changes associated with movement disorders to learn more about their causes.

Spotlight on Gene Mutations

In the past decade, technological breakthroughs in genetics have opened new doors to understanding human diseases. Parkinson’s disease is no exception. At least five genes have recently been identified in families with Parkinson’s. Although familial Parkinson’s makes up only a small proportion of cases, insights from studying these genes and their protein products have advanced scientists’ understanding of the disease process. For example, genetic studies helped uncover the causative role of the alpha-synuclein protein and the protective role of the parkin protein in Parkinson’s disease. Alpha-synuclein is a major component of Lewy bodies, protein deposits typically found in the neurons of Parkinson’s patients. Parkin is believed to protect against the disease by suppressing the action of the toxic alpha- synuclein or by causing the deposits to be degraded and eliminated by the cell. Two studies published in late 2004 associated mutations in the gene called LRRK2 (leucine-rich repeat kinase 2) with Parkinson’s disease.1,2 In 2005, a flurry of research, including three studies published in the Lancet and three published in Neurology,3–8 linked LRRK2 mutations with the disease in many families, and also in sporadic (nonfamilial) Parkinson’s.

Patients who have Parkinson’s and LRRK2 mutations exhibit disease that is clinically similar to typical Parkinson’s, with an age of onset ranging from 28 to 88.

26 In addition, the most common version of this mutation, G2019S, occurs in about 5 percent of familial Parkinson’s cases and 1 percent of sporadic cases. G2019S substitutes a single amino acid in a usually extremely stable part of the gene. Patients who have Parkinson’s and LRRK2 mutations exhibit disease that is clinically similar to typical Parkinson’s, with an age of onset ranging from 28 to 88. The pathology of LRRK2-associated Parkinson’s can vary, particularly with regard to the presence of Lewy bodies. As reported in the March issue of Annals of Neurology, positron emission tomography scans of patients with the G2019S mutation in LRRK2 show a pattern of decreased dopamine synthesis similar to that seen in patients with typical, nonfamilial Parkinson’s disease.9 The protein the LRRK2 gene makes was named dardarin, after the Basque word dardara, meaning “tremor.” The action of dardarin is unknown, but mutations in the gene might result in activation or inactivation of dardarin, or may change how it interacts with 2006 Report other proteins. Dardarin mutations might also increase susceptibility to Parkinson’s by promoting the formation of protein aggregates or making nerve cells more vulnerable to degeneration.10 Although no mutations were detected in thousands of unrelated, unaffected control subjects, some family members of patients with Parkinson’s had LRRK2 mutations but showed no sign of disease, and many patients with Parkinson’s had LRRK2 mutations but reported no family history of the disease. This indicates that other influences, either genetic or environmental, are probably involved in Parkinson’s development. Increasing age, already known to be a risk factor for the disease, may be one of those influences that favors the development of the disease when the LRRK2 mutation is present. The frequency with which Movement and Related Disorders the presence of the mutation is associated with disease increases with age. In a study published in the American Journal of Human Genetics, 17 percent of subjects with the mutation had Parkinson’s disease at age 50, while 85 percent of subjects with the mutation had symptoms at age 70.11 LRRK2 mutations may be the most common mutation associated with Parkinson’s disease. Some have proposed that genetic testing for LRRK2 mutations could be useful in the clinical setting because LRRK2 mutations may be present even without a

27 A buildup of alpha-synuclein in neurons is characteristic of Parkinson’s disease, but the normal job of alpha-synuclein is unknown and the connection between its aggregation and neurodegeneration is unclear.

family history of Parkinson’s. Such testing raises ethical issues, however, because no treatment prevents the disease and genetic testing provides no direct medical benefit.

Gumming Up the Works

A buildup of alpha-synuclein in neurons is characteristic of Parkinson’s disease, but the normal job of alpha-synuclein is unknown and the connection between its aggregation and neurodegeneration is unclear. In the June 17 issue of the Journal of Biological Chemistry, Chang-Wei Liu and colleagues describe how alpha-synuclein aggregation may occur in a cycle that is toxic to cells.12 In their experimental model of Parkinson’s, normal alpha-synuclein unfolds and is incompletely degraded. This leaves fragments of alpha-synuclein, which serve as “seeds” to initiate buildup of the full-length protein. The accumulation inhibits the cell’s protein-degradation system, compounding the accumulation with both more fragments and full-length protein. The cycle continues, eventually killing the cell. Deposits of alpha-synuclein also are found in the brains of patients with a disorder called multiple system atrophy, which can

A protein accumulates Cell death In Parkinson’s disease, a protein called alpha- synuclein may collect Toxic within neurons as part of Aggregates a cycle that eventually Incomplete kills the cells. degradation Protein degradation inhibited

A Vicious Cycle of Cytotoxicity

28 cause Parkinson’s-like symptoms, as well as dizziness, speech problems, and dementia. In this case, alpha-synuclein aggregates are predominantly found not in neurons but in oligodendrocytes, cells that make myelin, the insulating covering around the axons of neurons. In the March 24 issue of Neuron, Ikuru Yazawa and colleagues reported that they had produced the first mouse model for multiple system atrophy by overproducing alpha-synuclein in oligodendrocytes.13 This model should improve the understanding of the effects of alpha-synuclein aggregation on multiple system atrophy and may allow researchers to develop new treatments.

Continued Interest in GDNF

The search continues for new treatments for Parkinson’s disease. Levodopa, an amino acid that helps form dopamine, is currently the most effective treatment for the disease, but its effectiveness lessens over time and it can cause side effects such as dyskinesia 2006 Report (uncontrolled movements). Furthermore, levodopa treats only the symptoms of Parkinson’s; it has no effect on the degenerative process. Research in animal models has shown that a substance that nourishes neurons, called glial cell line–derived neurotrophic factor (GDNF), can protect or even restore the dopamine- producing neurons that are damaged in Parkinson’s disease. Unlike levodopa, GDNF cannot easily get through the tight mesh of blood vessels in the brain, called the blood-brain barrier, which is why, in recent clinical trials, the drug was delivered directly into the brain via catheter. The studies were terminated because of disappointing results, but interest in GDNF remains high. One reason for optimism is a report in Nature Medicine that regrowth of nerve cells was discovered in the postmortem exam Movement and Related Disorders of a man who had participated in a GDNF trial and later died of unrelated causes.14 This was the first time any reversal of damage in Parkinson’s disease had been demonstrated in humans. Another way to deliver GDNF where it is needed is to implant GDNF-producing cells into the brain. The carotid body is a small structure in the carotid artery that senses changes in blood gases and helps regulate breathing. Cells in the carotid body also produce dopamine and GDNF. Javier Villadiego and colleagues used a mouse model for Parkinson’s to demonstrate that recep-

29 tor cells within the carotid body—called glomus cells—produce large amounts of GDNF for a prolonged period after transplantation.15 They proposed that these glomus cells might be used to deliver GDNF to the brains of Parkinson’s patients. Gene therapy presents another possible treatment using GDNF. The gene for GDNF can be incorporated into a harm- less virus and injected into the brain, where the virus infects cells and causes them to produce GDNF. Andisheh Eslamboli and colleagues used this approach in a primate model for Parkinson’s disease and reported their findings in the January 26 issue of the Journal of Neuroscience.16 Dopamine-producing nerve cells were protected by the treatment, and the monkeys showed behaviors that indicated recovery of motor function.

More Uses for Gene Therapy

Because the side effects of levodopa may be caused by rising and falling levels of the drug between doses, gene therapy has been proposed as a treatment to be used along with or instead of levodopa to provide more continuous, consistent levels of dopamine to the brain. Thomas Carlsson and colleagues used gene therapy in a rat model of Parkinson’s, delivering the genes for two enzymes that work together to make dopamine.17 The treated rats showed reduction in both Parkinson’s-like behaviors and levodopa-induced movements. Experiments with genes can suggest new strategies for gene therapy, as Masanori Yamada and colleagues reported in the February issue of Human Gene Therapy.18 By introducing the gene for alpha-synuclein, they induced PD-like motor dysfunction in rats. If they delivered the gene for parkin at the same time, the dysfunction was lessened, presumably because parkin can suppress the action of, or eliminate, the alpha-synuclein deposits.

Fine-Tuning Deep Brain Stimulation

Deep brain stimulation (DBS) uses surgically implanted electrodes to relieve symptoms of Parkinson’s disease, essential tremor, and dystonia (abnormal muscle tone) by delivering pulses of electricity

30 Electrodes to the rescue Deep brain stimulation has been effective at relieving symptoms of movement disorders. Researchers are fine- tuning the technique, which involves placing electrodes in the brain that deliver electric pulses to specific brain regions.

to specific areas of the brain. In studies published in Archives of Neurology in 2005, researchers investigated ways to make deep brain stimulation more effective. One study included 41 patients who had unsatisfactory results after DBS.19 Outcomes were improved in more than half of the 2006 Report cases by replacing misplaced electrodes, reprogramming the device, or adjusting medications. Because DBS is being performed more frequently every year, the authors stressed the need for post-surgical follow-up and for more effective presurgical screening to determine which patients are likely to have successful outcomes. Another study in Archives of Neurology focused on the place- ment of DBS electrodes by comparing the two most common sites for DBS electrodes in PD, the globus pallidus interna (GPi) and the subthalamic nucleus (STN).20 Overall, both placements were equally effective, although STN stimulation was better than GPi stimulation at alleviating very slow movement (“bradykine- sia”). Cognitive and behavioral complications occurred only Movement and Related Disorders with STN stimulation. An accompanying editorial in the journal suggests that, although more research is needed, electrode place- ment in DBS may eventually be targeted to meet each individual patient’s needs.21

Mice Yield New Clues in Huntington’s Disease

No effective treatment exists for Huntington’s disease, which is caused by mutations that tack extra amino acids onto the end of

31 a protein called huntingtin. Mutant huntingtin seems to cause disease by collecting within nerve cells. The longer the chain of added amino acids, the earlier in life the disease begins. Mouse models for Huntington’s disease have been produced that express mutant huntingtin, and several labs have used these models to reveal the cellular and molecular events that lead to Huntington’s and to investigate potential treatments. Mutant huntingtin activates an important regulatory gene called p53, which, in turn, activates many other genes, ultimately resulting in cell death. Inactivation of the p53 gene in a mouse model for Huntington’s disease prevents the abnormal behaviors of the mice.22 Interestingly, p53 is inactivated in many cancers, and the lower incidence of cancer in patients with Huntington’s may have to do with the effects of high levels of p53. Mouse models also have revealed that mutant huntingtin may cause disease by impairing cell-to-cell interactions within the brain and altering normal calcium levels in neurons.23,24 Several drugs have been identified that can prevent cell death in the laboratory by correcting calcium levels. In the April 19 Proceedings of the National Academy of Sciences, Scott Q. Harper and colleagues reported the successful treatment of a mouse model for HD.25 They used a technique called RNA interference to inhibit production of mutant huntingtin, which resulted in near-normal behavior. Together, these findings provide hope that treatment for humans with Huntington’s disease may indeed be possible.

32 NERVOUS SYSTEM INJURIES 2006 Report

Fixing Broken Cords 34

Inhibiting Progress 36

Harnessing Stem Cells for the Spine 37

Stroke 38

Brain Tumors 39 Nervous System Injuries

Steroids and Traumatic Brain Injury 39

Neural Prosthetics for Post-Injury Recovery 39

33 ervous system injuries comprise a diverse group of disor- Nders that include spinal cord injury (SCI) and traumatic brain injury (TBI) as well as stroke and brain cancer. SCI and TBI disproportionately affect the young, primarily because of motor vehicle accidents and violence, and stroke more commonly strikes older people, but brain tumors can develop at any age, with incidence peaking in children between the ages of 3 and 12 and in adults between 55 and 65. The common thread among these injuries is the debilitation that typically results, which is often severe and chronic. This is because the central nervous system has such limited capacity to repair itself after an injury—whether the trauma results from a blow to the head or spine, a lack of oxygen to the brain as in stroke, or the invasion of healthy brain tissue by malignant cells. As a result, much of the basic neuroscience research relevant to nervous system injuries focuses on regeneration—that is, finding ways to jump-start the innate repair mechanisms of the brain or spinal cord to achieve some level of functional recovery. In recent years, a growing proportion of this research has focused on spinal cord injury, and 2005 was no exception.

Fixing Broken Cords

To better understand the dynamics of nerve degeneration and regeneration following a spinal cord injury, Martin Kerschensteiner and colleagues at Harvard used fluorescent dyes and time-lapse imaging to track the death and regrowth of axons in a living mouse for several days post-injury. They found that axons had partially withered within 30 minutes of the injury, and within 6 to 24 hours, many of them attempted to spontaneously regenerate. This initially robust regrowth failed, however, as the axons seemed to lose their ability to navigate in the right direction.1 The sheer complexity of the challenge in healing a severed or crushed spinal cord has demanded innovative strategies to address the central problems in regeneration: first, overcoming the molecules in myelin (the insulating sheath surrounding nerve fibers) that inhibit regeneration, as well as the scar that forms after an injury and physically impedes the reconnection of axons; second,

34 Layers of protection Myelin, which surrounds nerve fibers called axons, plays a complex role after spinal cord injury. It must be restored to Axon axons that remain, yet it con- Myelin sheath tains molecules that discourage Dendrites axon regeneration.

restoring lost myelin from nerve fibers that remain; and third, inducing nerve fibers to grow across and beyond the injury to re- establish nerve connections. Continuing a trend begun in 2004, spinal cord injury researchers are increasingly relying on combined approaches to address multiple parts of the repair problem. One promising combination, reported in the Journal of

Neuroscience by an international team of researchers anchored 2006 Report by Damien Pearse at The Miami Project to Cure Paralysis, used an enzyme that counteracts inhibitory signals together with two types of nervous system cells to act as structural support and guide nerve fiber regrowth in the right direction.2 This three- pronged strategy achieved significant improvements in several measures of movement ability and motor coordination when tested in adult rats with completely severed spinal cords. Although preliminary, the results provide important direction for researchers developing combined treatment regimens for spinal cord injury in humans, according to the authors. A second experimental treatment combined stem cells with gene therapy to remyelinate nerve fibers in rats with spinal cord injuries, effectively improving the animals’ ability to walk, Nervous System Injuries according to work reported in the Journal of Neuroscience by Scott Whittemore and colleagues.3 The therapy teamed stem cells called glial-restricted precursor cells, which have “committed” to becoming central nervous system support cells, with gene therapy designed to mimic the effects of two types of nerve growth factors. The combination promoted the growth of myelin and enhanced nerve signal transmission along the resheathed nerve fibers, which corresponded with improved motor function. The

35 study provided the best demonstration to date that boosting myelin growth can lead to functional improvements, according to a statement from the National Institute of Neurological Disorders and Stroke, which funded the research. Another study, from the biotech firm Biogen Idec, combined an “old” drug with known anti-inflammatory action, methylprednisolone, with an experimental “Nogo blocker,” a drug that is being investigated for its ability to block inhibitory signals that restrict nerve growth (via a receptor called Nogo-66).4 Tested in rats with spinal cord injury, the combination had a more pro- nounced effect on recovery of movement and coordination and on axonal growth than either treatment alone, suggesting that each may work through different mechanisms.

Inhibiting Progress

Apart from trying to manipulate molecules that restrict or guide axons on their journey to regrow after an injury, deciphering these molecules continues to be a central emphasis of basic spinal cord research. Much of this work has focused on one or more of the three known myelin-based inhibitors, known as Nogo, MAG, and OMG, as scientists work on elucidating the molecular structures that underlie nerve growth inhibition. Several groups have reported separate findings that are gradual- ly revealing the intricacies of how this cellular machinery works. Separate teams of Nogo researchers have observed contradicto- ry effects of blocking or deleting the Nogo receptor in laboratory animals. A multisite team anchored by Marc Tessier-Lavigne, a Howard Hughes Medical Institute neuroscientist now at Genentech, reported in Proceedings of the National Academy of Sciences that genetically deleting the Nogo receptor from laboratory animals or cultured cells did not free nerves to regrow.5 Although this study contradicted other findings suggesting that Nogo is responsible for inhibition, it underscored that the receptor is probably not the simple on/off mechanism its name suggests.

New work suggests a fourth major player in nerve growth inhibition.

36 In fact, Steven Strittmatter’s group at Yale showed just how complex the Nogo receptor is. They reported in a Journal of Neuroscience article that different molecular pathways through the receptor exert different effects.6 Other clues in the Nogo molecular puzzle came from independent teams from Children’s Hospital Boston and from Biogen Idec. Reporting separately in Neuron, the teams discovered that a protein variously called TAJ or TROY is an important part of the Nogo receptor complex.7,8 Hunter College’s Mary Filbin and colleagues published a study, also in Neuron, in which they identified a pathway in the Nogo receptor that may be where the three known myelin-based inhibitors of axonal regeneration interact.9 New work suggests a fourth major player in nerve growth inhibition (in addition to Nogo, MAG, and OMG). A University of Texas–Southwestern team led by Luis Parada reported in

Proceedings of the National Academy of Sciences that a molecule 2006 Report known to play a role in guiding axon development in fetuses, ephrin-B3, remains active through life to inhibit nerve fiber outgrowth in myelin and that its inhibitory activity is equivalent to that of the other three families of inhibitors combined.10

Harnessing Stem Cells for the Spine

Slowly but surely, scientists are making progress in learning how best to harness stem cells, in all their variations, for the goal of spinal cord repair. In 2005, a number of researchers inched toward this goal, including two separate groups at the University of California at Irvine. Hans Keirstead and colleagues restored myelin in rats with Nervous System Injuries spinal cord injuries and improved their capacity to move around by transplanting glial support cells called oligodendrocytes, which they had successfully developed from human embryonic stem cells grown in culture dishes.11 In research reported in the Journal of Neuroscience, the team saw benefits when the cells were transplanted seven days after the injury, but not when the transplant took place 10 months after the surgery, suggesting an early therapeutic window of opportunity.

37 The second study, reported in Proceedings of the National Academy of Sciences by Brian Cummings and colleagues, used adult neural stem cells from humans to regenerate myelin and improve mobility in mice with spinal cord injuries.12 When the cells were transplanted nine days after an injury, they developed into oligodendrocytes that restored the insulating myelin sheath around nerve fibers, and the mice showed improved mobility.

Stroke

Long-awaited results from the large government-funded Women’s Health Study found that vitamin E does not protect women from stroke (or heart attack or cancer). The data, published in the Journal of the American Medical Association, add important new information to the ongoing debate about the health benefits of vitamin E supplementation, finding no support for recommending the antioxidant as preventative therapy for cardiovascular disease or cancer.13 On the diagnostic side, researchers from Johann Wolfgang Goethe University in Frankfurt, Germany, found that strokes affecting the right side of the brain are not recognized as frequently as those that strike the left side of the brain.14 Reporting in the Lancet, the team hypothesized that the more subtle symptoms characteristic of right-hemispheric strokes make them more difficult to identify, thus making an effective response a challenge.

Brain Tumors

The final report of the Glioma Outcomes Project, which studied patterns of care for adults with newly diagnosed gliomas, or glial cell tumors, found that doctors treating patients with these malignant brain tumors are not following published guidelines in a few key areas, including chemotherapy, which is apparently being underused.15 Of particular concern was the finding that 80 percent of patients with cancerous brain growths received anti-epileptic drugs to prevent seizures, for which people with brain tumors are at increased risk. However, these drugs seem to have little value for patients with no history of seizures, and they carry significant side effects. The study, published in the Journal of the American

38 Medical Association, provides benchmark data that will enable clinicians to better plan and assess treatment, the authors wrote. Researchers at the University of Alabama at Birmingham reported in the Journal of Neuroscience that a drug currently used to treat inflammatory disease can switch off a protective molecular defense mechanism used by gliomas. In preliminary animal studies, the drug, sulfasalazine, which is FDA-approved for inflammatory bowel disease and rheumatoid arthritis, dramatically reduced tumor size when administered by injection into a membrane that lines the walls of the abdomen.16 Meanwhile, a study in rats by Gail Clinton and colleagues at Oregon Health and Science University showed that herstatin, a protein that inhibits enzymes involved in tumor cell proliferation, blocks the growth of glioblastoma, a type of glioma that is particularly aggressive and deadly. The findings, published in Clinical Cancer Research, suggest an avenue of potential therapy 17 for another type of tumor that affects glial cells. 2006 Report

Steroids and Traumatic Brain Injury

Despite a 30-year history of use in traumatic brain injury, a group of powerful anti-inflammatory drugs called corticosteroids do not help head injuries, according to results published in the Lancet of a trial involving 10,000 adults with head injury.18 The authors reported that using these drugs following an acute injury actually increases the risk of death within two weeks and makes it more likely that the patient will die or be severely disabled within six months of treatment. In a statement released by the journal, lead author Phil Edwards of the London School of Hygiene and Tropical Medicine called for an urgent re-evaluation of the prac- Nervous System Injuries tice of treating head injuries with corticosteroids.

Neural Prosthetics for Post-Injury Recovery

Hundreds of thousands of Americans are paralyzed or have severely limited mobility from injuries or diseases of the nervous system. For many of them, so-called neural prosthetics may represent the only hope for regaining a measure of independence. The idea is to capture nerve signals with electrodes implanted in

39 the brain and translate the signals into movements on a prosthetic limb or a computer mouse, thereby enabling the person to use thought power alone to achieve a task such as grasping food or activating a computer-controlled light switch. A handful of specialized laboratories continue to advance the development of such “brain-machine interfaces.” Taking ownership Miguel Nicolelis and his team at Researcher Miguel Nicolelis Duke University found that monkeys poses with a monkey involved trained to use their brain signals to in research in which monkeys control a robotic arm are undergoing treated a robotic arm as their structural brain changes that treat the own—revealed by structural arm as if it were their own appendage. changes in their brains— The research, published in the Journal after they learned to control it of Neuroscience, has implications for with their brain signals. restoring function in paraplegics and others debilitated by neurological disorders.19 Meanwhile, Andrew Schwartz’s team at the University of Pittsburgh reported at the annual meeting of the American Association for the Advancement of Science that a monkey outfitted with a robotic prosthesis the size of a child’s arm learned to directly control the arm well enough to feed itself chunks of fruits and vegetables.20

40 NEUROETHICS 2006 Report

New Publications Add Perspective 42

Technological Advances Pose Tough Choices 43 Neuroethics Neuroethics

Bridging the Worlds of Science and Religion 45

Neuroethical Implications of the Schiavo Case 45

Ethical Challenges in Neuroimaging 47

41 he newly developing field of modern neuroethics encom- Tpasses both the ethics of neuroscience that has to with the conduct of research, especially in an age of ever-expanding methods and complexity, and the neuroscience of ethics, such as whether an ethical “center” exists in the brain or discoveries about the brain should com- pel changes in law. Neuroscientists first began grappling with the ethical, social, and public policy implications of neuroscience advances in 2002, by publishing papers in peer- reviewed journals and special journal volumes and by participating in the first formal conference on the subject, “Neuroethics: Mapping the Field.”1 The field has grown dramatically since then. The number of scientific papers published on the subject of neuroethics in 2005 was almost four times the number in 2002. Professional meetings on neuroethics proliferated as well, and the field is attracting thinkers from other branches of science, the law, and even religion. Several of these meetings and publications made important contributions to sharpening the issues and focus in this multi- faceted field in 2005.

New Publications Add Perspective

The first professional book and the first popular book on the subject of neuroethics were published in 2005, enabling readers to better engage in the issues that will ultimately call for their formal or informal attention. In October and November, concurrent with the annual meetings of the American Society for Bioethics and Humanities and the 35,000-member meeting of the Society for Neuroscience, Oxford University Press released the professional text, Neuroethics: Defining the Issues in Theory, Practice and Policy, edited by Judy Illes of Stanford University, laying out the state of the art in neuroethics today and the foundation of knowledge needed for future generations of neuroethics research. For the book, Illes, whose studies include the ethical implications of neuroimaging, commissioned 21 leading thinkers to contribute a chapter each on a specific aspect of neuroethics, such as moral

42 decision-making, creativity, neuroimaging, treatment of neurodegenerative diseases, the connection between genetics and brain science, social and political aspects of brain research, and the portrayal of the mind in popular culture. In April, the general public received its first wide-ranging opportunity to consider ethical implications of neuroscience with the publication of The Ethical Brain, by Michael S. Gazzaniga of Dartmouth College, a leader in the field of exploring how the mind emerges from the brain. In the book—to be republished by HarperCollins in May 2006—Gazzaniga explores neuroethical issues over the lifespan, from fetal development through old age; how neuroscience is redefining what is understood about memory and how these findings might affect the basis of the legal system; and finally, the insights neuroscience is providing into the nature of moral reasoning—and what implications these will have for the understanding of what

makes us human. 2006 Report

Technological Advances Pose Tough Choices

As the field of neuroethics has grown, so too have the number and type of issues under consideration. In light of that profusion, in May an invitation-only, two-day scholarly conference took on the task of focusing the discussion. “Hard Science, Hard Choices: Facts, Ethics and Policies Guiding Brain Science Today” convened at the Library of Congress in Washington, D.C.,2 sponsored by the Dana Foundation, the National Institute of Mental Health, Columbia University College of Physicians and Surgeons, and the Library of Congress. About

150 participants were on hand to discuss three key areas: neu- Neuroethics roimaging, neurotechnology, and psychopharmacology. Conference co-directors Gerald Fischbach, dean of the Columbia medical school, and Ruth Fischbach, director of

The half-day devoted to neuroimaging addressed the power of brain imaging technology, now being used to study behaviors as diverse as religious experience, moral decision-making, racism, lying, and investing money.

43 Columbia’s Center for Bioethics, chose these areas because the science within them is advancing so quickly—faster, arguably, than in any other area of neurobiology—and bringing the advent of ethical dilemmas closer than the work in more exotic areas. The half-day devoted to neuroimaging addressed the power of brain imaging technology, now being used to study behaviors as diverse as religious experience, moral decision-making, racism, lying, and investing money. Of greatest import, the participants agreed, are the risks of this research being misused or misunder- stood in ways both small and large. Possibilities range from attempts to manipulate consumer responses to the prospect that neuroimaging may lead people to recast the definitions that underlie common social principles, and not necessarily correctly or beneficially. The second conference subject, neurotechnology, dealt with ethical dilemmas already looming as a result of techniques now coming into clinical practice. For example, deep brain stimulation is already being used clinically for Parkinson’s disease and is under investigation for chronic pain and mood disorders, among other maladies. While deep brain stimulation raises some issues in common with older bioethics, such as access to care, informed consent, and insurance coverage, this technology affects an entire brain circuit, bringing the risk of unforeseen consequences. Such effects could be either neurological or behavioral; neuroscience has not yet learned the full workings of even one complete circuit in the brain. A different, equally potent concern, with not only deep brain stimulation but also other neurotechnologies such as neural prostheses, is the potential of desperate patients, overenthusias- tic investigators, and the media combining to speed the applications of such research too quickly and risk public backlash. The participants deemed psychopharmacology, the final conference subject, the hardest area in which to forge ethical agree- ment. While no one debates treating people who are truly ill, diagnoses of mental disorders usually come in shades of gray, not black and white. Moreover, drawing on previous work by Martha Farah, Alan Leshner, and others,3,4 participants agreed that one point of dispute can only grow more contentious: the use of drugs to enhance mental performance rather than to treat an underlying disease. This concept raises many metaphysical

44 questions, ranging from the nature of personal responsibility to the definition of the “self.”

Bridging the Worlds of Science and Religion

Neuroscientists have long and informally been aware that advances in neuroscience raise philosophical questions tradition- ally in the purview of religious studies. In another milestone for neuroethics, organizers of a conference in April undertook to bridge the two worlds with a dialogue among neuroethicists and representatives of diverse religious communities. “Our Brains and Us: Neuroethics, Responsibility and the Self,” held in Cambridge, Massachusetts, was sponsored by the American Academy for the Advancement of Science, the Massachusetts Institute of Technology, and the Boston Theological Institute. In this scholarly meeting, the focus was the philosophical

implications of medical and surgical advances in neuroscience 2006 Report that can alter the brain and behavior, raising fundamental questions about the nature of free will, moral choice, and the self. Topics ranged from the propriety of neural enhancement via pharmacological and technological means to recent studies that begin to outline the neuroanatomical basis of moral reasoning. The goal of the conference was not to arrive at conclusions but rather to foster discussion among participants approaching these issues from different intellectual traditions. The theologians gained a deeper understanding of the kinds of advances in neuroscience that are evoking questions of an ethical nature, while the neuroscientists had an opportunity to reflect upon some of the deeper implications of their laboratory work. Neuroethics Neuroethics Neuroethical Implications of the Schiavo Case

As reflected in numerous scientific articles and commentaries in 2005, the highly politicized and publicized case of Theresa Marie (Terri) Schiavo demonstrated what happens when dialogue between people of opposing viewpoints breaks down. Schiavo, who entered a persistent vegetative state after suffering severe brain damage in 1990, was the subject of years of anguished liti- gation and political controversy, until her husband won the legal

45 As many as 15,000 Americans are in a persistent vegetative state, a condition in which someone shows no signs of conscious behavior, while another 100,000 are in a minimally conscious state, exhibiting intermittent periods of consciousness.

right to remove her feeding tube and she died on March 31, 2005. Her case embodied the legal, medical, and ethical issues created by brain treatment advances that have extended survival and redefined death. Yet, although it fostered vast public concern about those important issues, it resolved none of them. In an editorial in the May Journal of Clinical Investigation, Joy Hirsch of Columbia University wrote that the Schiavo case raised awareness of the similar plight faced by other families and patients.5 As many as 15,000 Americans are in a persistent vegetative state, a condition in which someone shows no signs of conscious behavior, while another 100,000 are in a minimally conscious state,6 exhibiting intermittent periods of consciousness. In a functional magnetic resonance imaging study published in Neurology, Hirsch and colleagues sought to compare brain activation in patients in a minimally conscious state with activation in healthy controls.7 Their findings suggest that certain brain circuits in minimally conscious patients are able to handle information much as those in healthy patients do. The same cannot be said for patients in a persistent vegetative state. However, further research lies ahead to ascertain whether brain activation represents some kind of awareness and whether any form of recognition exists that brain scans cannot detect. Moreover, although scientists have reached a working consensus on how to define and diagnose the minimally conscious state,8 they are not yet ready to provide what is considered the “gold standard” in medicine: evidence-based guidelines for diagnosis, prognosis, and management that would provide a roadmap for physicians. Similar concerns about the unsettled issues were raised by Joseph J. Fins of the Weill Medical College of Cornell University in the March–April issue of the Hastings Center Report.9 Fins noted the chilling example of Terry Wallis, who suddenly began to talk in 2003, nearly 20 years after suffering a severe brain

46 injury. Fins believes that Wallis progressed from a vegetative state to a minimally conscious state within months of his injury, then remained incorrectly diagnosed for years. But the larger issue, Fins argues, is that severe brain injuries force professionals and lay people alike to confront the nature of consciousness and overly simplistic notions of recovery. After severe brain injury, recovery often takes years, even decades, and may significantly alter the life not only of the injured individual but of the family.

Ethical Challenges in Neuroimaging

As indicated by its selection as one of the topics for the conference at the Library of Congress, deciding how to handle multiple challenges created by neuroimaging is not merely a theoretical problem but a rapidly evolving necessity. These issues were discussed

at several scientific meetings and in a number of journal articles. 2006 Report On January 6 and 7, 2005, the National Institutes of Health and Stanford University co-sponsored a conference entitled “Detection and Disclosure of Incidental Findings in Neuroimaging Research.” The 50 participants included ethicists, radiologists, neurologists, and other relevant professionals, who sought to develop consensus recommendations about what to do when brain scans reveal variations from expected brain architecture, or brain tumors or other sorts of brain pathology. Such incidents are surprisingly common: researchers have found variations in the expected brain form or structure in as many as 20 percent of study participants, and clinically significant abnormalities in anywhere from 2 to 8 percent.10

Working to shape recommendations that would be adopted Neuroethics by laboratories, institutional review boards, journals, and research sponsors, the conferees reached consensus on many questions. Others remained unresolved, and their work continues.11,12 Their work also spawned special sessions on incidental findings in the brain at the National Institutes of Health, research funding devoted to incidental findings in body imaging and genetics, and similar interest abroad. Meanwhile, the American Journal of Bioethics devoted most of its March–April 2005 issue to the subject of neuroimaging.

47 In one article, Judy Illes and Eric Racine of Stanford University noted that neuroimaging raises some of the same concerns as genetics, including the ability to predict disease and risks to privacy.13 Yet neuroimaging, far more than a genetic profile, provides a window into aspects of personality previously thought to be unquantifiable—including such things as values, morality, and social attitudes. And just as geneticists worry that genetic testing might lead to discrimination, neuroethicists worry that employers, judges, and educators might use brain scans to screen potential employees, convict suspects of crimes, or choose which students to admit. Such uses would be questionable, the authors point out, because no “norm” yet exists (or may ever exist) with which one person’s brain can be compared. Brain scans published in journals are not “pictures” in any traditional sense; they are computer composites averaging and consolidating findings from many individuals. What’s more, the field has not yet arrived at stan- dards for how to produce particular images. In short, Illes and Racine argue, it is important not to read too much into neuroimaging scans for use outside the laboratory just yet. Another prospective use for brain imaging, one that is particularly controversial, is thought to be lie detection. Paul Root Wolpe, Kenneth Foster, and Daniel Langleben, all of the University of Pennsylvania, argue in the same issue of the American Journal of Bioethics that it is premature to see brain imaging as promising a sort of mental polygraph, even though significant money is being invested in such technology for use in criminal and terrorist investigations.14 Because significant questions exist about the reliability of this technology, the authors warn that premature commercialization could undermine and squelch research aimed at improving it and even lead to the misuse of brain scans in criminal cases. They urge that research continue while at the same time scientific, legal, and civil forums begin examining the ethical problems before they arise.

48 NEUROIMMUNOLOGY 2006 Report

Novel Approaches to Treating MS 50

Immunotherapy for Neurological Disorders 52

Viruses Implicated 55 Neuroimmunology Neuroimmunology

49 he young field of neuroimmunology continued to experi- Tence rapid growth in 2005, with more research published and a wider variety of disorders in the spotlight. Recent studies shed more light on the interactions between the nervous system and various components of the immune system. Several new, promising approaches have been proposed regarding the treatment of multiple sclerosis, an autoimmune disease, and a number of studies have indicated that immunotherapy could be used to treat some non-autoimmune neurological disorders, such as Alzheimer’s and Parkinson’s disease. Neuroimmunologists also have uncovered new evidence indicating that certain viruses might play a role in the development of some neurological disorders.

Novel Approaches to Treating MS

Multiple sclerosis (MS) is a chronic, progressive neurological disorder that occurs when a person’s immune system attacks parts of the central nervous system (CNS), resulting in the gradual destruction of myelin, the fatty substance that insulates nerve cells. The treatment of MS has been hindered by side effects from therapies that target all immune cells and thus result in infections. But a research team led by Peter Calabresi of Johns Hopkins Hospital in Baltimore identified in Proceedings of the National Academy of Sciences a specific potassium channel called Kv1.3, which is plentiful on immune system T cells that attack the protective myelin around neurons.1 Targeting this molecule could lead to the development of new MS drugs that have considerably fewer side effects than the ones currently being used. Calabresi and colleagues had previously shown that Kv1.3 expression is increased on some T cells found in the blood of

Stem cells can protect the central nervous system from chronic damage caused by diseases such as multiple sclerosis, brain tumors, and spinal cord injuries by acting as potent, natural drugs capable of blocking inflammation.

50 patients with multiple sclerosis. In the 2005 study, they analyzed brain tissue from patients with MS after the patients had died. The researchers found that these cells get inside the brains of MS patients and may contribute to the development of the disease. These results indicate that drugs that inhibit Kv1.3 could be a more specific therapy than drugs that generally suppress the immune system. Targeting another kind of immune cell, the perivascular dendritic cell, inside the CNS may also lead to successful new therapies for MS, according to a study in the March issue of Nature Medicine by Burkhard Becher and colleagues at the University of Zürich, Switzerland.2 Perivascular dendritic cells are located near blood vessels inside the brain. Becher’s team found that these cells act as crucial “antigen-presenting cells,” signaling certain components of the immune system to recognize and destroy myelin cells.

In the past, most experts blamed microglia for initiating this 2006 Report signal. However, the findings of Becher and colleagues show that the antigen-presenting cells are dendritic cells, a completely different cell type, and are located at a different site than previously believed. The scientists are trying to develop new medications to combat MS based on this new information. Another promising new approach to treating MS involves the use of stem cells. In 2003, a research team led by Gianvito Martino of San Rafael Hospital in Milan, Italy, reported that neural stem cells transplanted into the brains of mice with an MS-like disease migrated to the inflamed areas of the brain and differentiated into mature brain cells, actively repairing the damaged myelin.3 In a more recent study, these scientists showed that stem cells can protect the central nervous system from chronic Neuroimmunology damage caused by diseases such as multiple sclerosis, brain tumors, and spinal cord injuries by acting as a potent, natural drug capable of blocking inflammation.4 The study, performed in mice affected by a relapsing-remit- ting form of multiple sclerosis, showed that adult neural stem cells can replace bloodborne inflammatory cells while sparing healthy nearby cells. One of the most innovative aspects of the study was the demonstration that, once within the inflamed CNS, a significant proportion of stem cells did not mature into

51 neural tissue. According to the scientists, transplanted adult neural stem cells that do not mature and are not integrated into the host tissue are capable of escaping from and surviving the inflammation. Moreover, these undifferentiated cells can lower the risk of tumors, which are a common problem associated with stem cell transplantation. Another group of researchers investigated the use in MS treatment of stem cells obtained from patients’ own bone marrow.5 In a study published in the Journal of Experimental Medicine, the researchers found that such “hematopoietic stem cell transplantation” (HSCT) can be used to suppress active multiple sclerosis by decreasing the number of T cells that attack the nerve cells’ protective myelin sheath. By studying the patients’ white blood cells and analyzing the molecular properties of their T cells before and after transplantation, the scientists were able to show that the transplanted stem cells matured and the patients’ post-therapy immune systems were almost completely reconstituted by the new cells. These data show that HSCT exerts a beneficial long-term effect in MS, not simply by temporarily suppressing or modulating the immune system (as con- ventional treatments do), but by actually “rebooting” the immune system and greatly reducing the risk of new autoimmune attacks.

Immunotherapy for Neurological Disorders

Modifying the immune system appears to be helpful in treating other neurological disorders as well. For example, Richard Hartman of Loma Linda University and colleagues investigated the potential use of such immunotherapy for Alzheimer’s disease (AD) and published their findings in the Journal of Neuroscience.6 One of their goals was to determine whether PDAPP mice—a mouse model of Alzheimer’s disease—develop age-related learning deficits similar to those observed in human Alzheimer’s patients. As this type of mouse ages, plaques composed of the beta-amyloid protein form in their brains. These plaques are comparable to those found in the brains of humans with AD. The investigators found that these mice also developed age-related deficits in spatial learning, a type of learning that is profoundly affected in Alzheimer’s disease.

52 Pursuing a protein In mice with plaques composed of beta-amyloid protein, such as the plaque shown here, researchers were able to reduce buildup and improve a type of learning by treating the mice with a beta- amyloid antibody.

The researchers also wanted to determine if the plaques and behavioral deficits could be reduced even after a significant buildup of plaques had taken place. Older PDAPP mice were treated for several weeks with an antibody to beta-amyloid. As a result, plaque levels were reduced by about 50 percent, and spatial learning performance improved significantly.

According to the investigators, these data confirm that the 2006 Report buildup of beta-amyloid plaques in the brain is responsible for the learning and memory deficits associated with Alzheimer’s disease. The findings also suggest that targeting this protein using immunotherapeutic techniques may be a viable and effective treatment option for use in humans. Because previous studies suggested that immunization might be a potential therapy for Alzheimer’s disease, a research team led by Eliezer Masliah of the University of California, San Diego, hypothesized that immunization might also have therapeutic effects in Parkinson’s disease. Parkinson’s is characterized by the loss of dopamine-producing neurons in a certain area of the brain, and recent research indicates that an abnormal accumulation of a protein called alpha-synuclein is at least partly respon- Neuroimmunology Neuroimmunology sible for the loss of these neurons. The researchers used human alpha-synuclein to vaccinate mice bred to model Parkinson’s disease. Reporting in Neuron, they found that the vaccination resulted in a reduction of alpha- synuclein in and around the affected neurons and that it limited the amount of neurodegeneration in these animals. These results suggest that vaccination is effective in reducing the accumulation of alpha-synuclein in neurons and that this approach might have a potential role in the treatment of Parkinson’s.7

53 In another paper, published in the February issue of the Annals of Neurology, investigators at Johns Hopkins University and the Kennedy Krieger Institute at Baltimore, led by Carlos A. Pardo, investigated the potential involvement of neuroimmune action and glia (cells that support neurons) in the development of autism.8 Autism is a neurodevelopmental disorder characterized by significant impairments in social, behavioral, and com- municative functions. By studying brain tissues obtained at autopsy from patients with autism and individuals without the disorder, these researchers demonstrated a marked increase in immune and glial responses, characterized by the activation of microglia and astroglia in the brains of patients. According to the researchers, these increased responses are likely part of neuroinflammatory reactions associated with the central nervous system’s innate immune system. It remains unclear how and when microglia and astroglia become activated in the brains of patients with autism. Glial responses in autism may be part of intrinsic, or primary, reactions that result from disturbances in glial function or neuronal- glial interactions during brain development. They may also be secondary, resulting from unknown disturbances (such as infections or toxins) in prenatal or postnatal CNS development. Nevertheless, the findings of this study highlight the existence of neuroimmunological processes in autism and provide a setting for new research approaches to the diagnosis and treatment of this debilitating neurological disorder.

Autism and the immune system Slides A and C, from patients with autism, show an increase in neuron-supporting cells called glia. This increase is likely a sign of a neuroimmunological response to the disorder.

54 Viruses Implicated

A study led by Yoshihisa Yamano of the National Institute of Neurological Disorders and Stroke (NINDS) and published in the May issue of the Journal of Clinical Investigation suggests for the first time that a virus-encoded protein induces dysfunction of a critically important component of the human immune system.9 This component, called a regulatory T cell, is important in maintaining the immune system’s ability to recognize a person’s own tissue, and, therefore, prevent autoimmune diseases. Loss of function of regulatory T cells has been reported in several autoimmune disorders, such as type-1 diabetes, rheumatoid arthritis, and multiple sclerosis. Although it has been demonstrated in rodents that removing or interfering with regulatory T cells leads to the spontaneous development of autoimmune diseases, how these cells might lose their ability to restrain immune attack in human disease is 2006 Report unknown. The study by Yamano and colleagues revealed that patients with an uncommon virus-associated chronic, progressive neurological disease (known as “HTLV-I-associated myelopathy/tropical spastic paraparesis”) have dysfunctional regulatory T cells, and this may contribute to the development of inflammation inside the CNS. These findings could help explain why certain viral infections are often associated with autoimmune diseases. Peter G. Kennedy and Margaret L. Opsahl at the University of Glasgow, Scotland, reported in Brain the possible involvement of viruses in the development of multiple sclerosis.10 Using both novel and traditional methods, these scientists were able to confirm previous reports finding increased human herpes virus HHV- Neuroimmunology 6 around the myelin damage in multiple sclerosis.

55 PAIN

A Drug Combination to Treat Neuropathic Pain 57

Suppressing Pain Outside the Brain 58

Treating Severe Pain 59

Genetic Basis for Pain Perception 60

Pain Research Database to Identify Underfunded Areas 61

56 lood pressure, pulse, respira- tion, and temperature are the Bvital signs that help doctors measure a person’s physical condition. Many doctors now consider pain to be equally important. While there is no objective test for measuring it, an individual’s perception of pain can indicate his or her state of health and well-being. In 2005, pain researchers continued their quest to determine the mechanisms of pain and to develop more effective ways to treat it. Two studies found that certain drug combinations are effective treatment regimens for pain resulting from injury to peripheral nerves and for severe pain. Another investigation found that activating certain cells in the body eliminates pain by releasing substances that affect how some neurons respond to noxious stimuli. Scientists also discovered a genetic basis for variations in pain perception and the development of a common muscu- loskeletal pain condition. And, while nearly 45 percent of 2006 Report Americans will seek treatment for pain at some point in their lives, a team of researchers found that only 1 percent of grants funded by the National Institutes of Health had pain as a primary focus.

A Drug Combination to Treat Neuropathic Pain

Neuropathic pain is pain that arises from nerve disease or damage and is a common complication of diabetes, cancer, human immunodeficiency virus, herpes zoster (shingles), and neurodegenerative diseases. The burning, searing nature of neuropathic pain can have a profound impact on quality of life. The drugs to Pain treat neuropathic pain, however, are not totally effective and have dose-limiting side effects. In an effort to find more effective ways to treat neuropathic pain, researchers at Queen’s University in Canada discovered that combining two drugs commonly used to treat painful diabetic neuropathy and acute nerve pain resulting from herpes can significantly reduce pain more than either drug given individually. In the March 31 issue of the New England Journal of Medicine,1 Ian Gilron and colleagues reported that treating

57 Researchers have found that drugs that mimic the action of natural pain-relief processes in the body are promising candidates for the treatment of acute, inflammatory, and neuropathic pain. patients with a combination of gabapentin and morphine reduced their neuropathic pain more than treatment with either drug as a single agent. Gabapentin, which quells the acute radi- ating spasms of neuralgia, is a first-line treatment for painful neuropathy. Morphine is a powerful narcotic used to treat other kinds of moderate and severe pain. Forty-one of 57 patients—35 with diabetic neuropathy, 22 with postherpetic neuralgia—completed the trial. Using a pain scale from 0 to 10 (the higher the number, the more severe the pain), the patients reported a mean daily pain score of 5.72 before treatment and, at the highest tolerated dose, 4.49 with placebo, 4.15 with gabapentin, 3.70 with morphine, and 3.06 with the gabapentin-morphine combination. In addition, the highest tolerated doses of gabapentin and morphine were considerably lower when given in combination than when either was used as a single agent, suggesting an additive interaction between the drugs. The researchers also discovered that the gabapentin-morphine combination resulted in fewer adverse effects (such as constipation, sedation, and dry mouth) than either drug caused individually. Gilron and his team say that, in view of the potential benefits of drug-combination therapies such as this one, trials are needed that will study other combinations of pain fighters and compare them to the use of drugs as single agents for the treatment of neuropathic pain.

Suppressing Pain Outside the Brain

Researchers have found that drugs that mimic the action of natural pain-relief processes in the body are promising candidates for the treatment of acute, inflammatory, and neuropathic pain. Reporting in the February 22 issue of the Proceedings of the National Academy of Sciences,2 the University of Arizona

58 researchers wrote that they developed a drug that activates the “CB2” receptor—one of a frequently studied group called “cannabinoid” receptors because they respond to the active ingredient of marijuana, or cannabis. Activation of the CB2 receptor, the researchers reported, stimulates the release of a substance that acts on the neurons that send signals from senso- ry receptors—skin, eyes, ears, nose, and tongue—to the central nervous system to eliminate pain. More important, the researchers say, is that drugs targeting CB2 cannabinoid receptors do not act widely in the central nervous system, primarily because CB2 receptors are not found there. Because multiple nervous system effects limit many current pain therapies, the narrow range of action is an important feature of this class of drugs.

Treating Severe Pain 2006 Report Researchers at Memorial Sloan-Kettering Cancer Center identified more effective therapies for moderate and severe pain by combining nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, with more powerful painkilling drugs. Used alone, NSAIDs have limited effect in managing moderate-to-severe pain conditions. In a study published in the March 2 issue of Brain Research,3 the researchers sought to evaluate the effectiveness of certain combinations of NSAIDs and narcotics in a model of moderate- to-severe pain. By applying heat to the tails of mice to elicit a response to painful stimuli, the researchers found that certain NSAIDs greatly increase the pain-relieving effect of two widely prescribed narcotic drugs, hydrocodone and oxycodone, while Pain other combinations have little utility in combating moderate-to- severe pain. For example, ibuprofen increases pain relief from hydrocodone and oxycodone, but another NSAID does not boost hydrocodone’s effect, and ibuprofen does not increase the pain relief of the narcotics fentanyl and morphine. NSAIDs suppress the activity of a specific enzyme, cyclo-oxygenase. Two forms of the enzyme—Cox-1 and Cox-2—are known to promote inflammation. The researchers say that more studies are needed to determine how potential combinations of

59 NSAIDs and narcotics interact with Cox-1 and Cox-2 to inhibit inflammation and pain responses. The researchers say that testing different combinations in the clinical setting may help identify better pain-control therapies.

Genetic Basis for Pain Perception

Significant numbers of people develop chronic pain conditions characterized by increased sensitivity to pain. Seeking why some people and not others become especially pain-sensitive, scientists at the University of North Carolina have found that subtle variations in genes can make people less sensitive to painful stimuli and protect them from developing a common, debilitating pain condition called chronic temporomandibular joint disorder (TMJ). The researchers, led by Luda Diatchenko of UNC’s Comprehensive Center for Inflammatory Disorders, examined 202 healthy women ages 18 to 34 over five years to determine their relationship between pain sensitivity and the development of TMJ, which is characterized by such symptoms as headache, earache, and jaw and facial pain. Focusing on the genetics of an enzyme called catecholamine- O-methyltransferase (COMT), which controls certain chemicals related to stress response, the researchers conducted molecular biology, cell culture, and animal behavior experiments to demonstrate how COMT and pain sensitivity are related. (Researchers also are studying COMT in relation to schizophrenia; see page 64.) The findings, reported in the January issue of Human Molecular Genetics,4 showed that individuals with lower levels of COMT were more sensitive to pain and more likely to develop temporomandibular joint disorder. Slight differences in the gene that produces the COMT enzyme, they found, can predict the

An estimated 50 million Americans suffer from persistent pain and nearly 45 percent of the U.S. population seeks medical care for pain at some point in their lifetime.

60 Slight genetic differences, significant effects People with lower levels of a certain enzyme were more sensitive to pain and more likely to develop a debilitating pain disorder. 2006 Report risk of developing TMJ, which affects nearly 10 percent of the U.S. population. The UNC researchers believe their findings may also apply to other chronic pain conditions, including fibromyalgia, irritable bowel syndrome, and certain chronic sen- sory disorders. Diatchenko and her colleagues say their findings have ramifi- cations for the development of genetic markers of pain conditions, as well as strategies for treating pain. Based on their findings, they are now investigating new drug therapies for TMJ and related disorders. Pain Pain

Pain Research Database to Identify Underfunded Areas

An estimated 50 million Americans suffer from persistent pain and nearly 45 percent of the U.S. population seeks medical care for pain at some point in their lifetime. In the May issue of the Journal of Pain,5 with this prevalence of pain in mind, researchers from the University of Utah issued the first-ever classification of pain-research spending by the National Institutes of Health

61 (NIH). They found that in 2003, the year for which they com- piled and analyzed data, the NIH funded 518 pain-related grants. Although these grants totaled $170 million, they account- ed for only 1 percent of all NIH funding in 2003. The researchers classified pain grants as either primary or secondary. Primary grants involved research with a main focus on advancing knowledge about pain, reducing pain symptoms, or treating pain, while secondary grants involved studies of pain as a symptom of a specific disease but contributed little to the understanding of pain. Using these findings, the researchers developed the Pain and Related Conditions Database (PRCD) to identify underfunded areas of pain research. This interactive database, the researchers say, provides objective and verifiable information about NIH funding patterns for pain research. The University of Utah researchers say their findings will aid federal and state policymakers, professional pain organizations, researchers and clinicians, as well as those responsible for future pain research. An accompanying editorial argues that, in addition to helping to determine whether clinical conditions associated with pain are being overlooked by scientists and funding agencies, the PRCD’s strength is its ability to classify research projects by a study’s level of focus on pain. The current NIH research database (called CRISP, for Computer Retrieval of Information of Scientific Projects) does not provide this level of detail.

62 PSYCHIATRIC, BEHAVIORAL, AND ADDICTIVE DISORDERS 2006 Report

Schizophrenia 64

Depression 66

Addictive Disorders 68 Psychiatric, Behavioral, and Addictive Disorders Future Directions 71

63 common theme in mental health research in 2005 was the Arole of genes in mental disorders and the interaction of these genes with environmental factors such as drug use. Schizophrenia research emphasized genes that control metabolism of the neurotransmitter dopamine; depression studies focused on genes that control metabolism of the neurotransmitter serotonin; and several advances in research into addictive disorders centered on genes that control the neurotransmitter receptors that interact with addictive substances.

Schizophrenia

In schizophrenia research, scientists have focused in recent years on different alleles, or common genetic variants, of the gene for an enzyme called catecholamine-O-methyltransferase (COMT), which breaks down dopamine. (Researchers also are studying COMT in relation to pain; see page 60.) In some people, a specific sequence of the COMT gene encodes one kind of amino acid, while in others it encodes another. This change in just one amino acid affects COMT enzyme activity. In individuals carrying two alleles for the form called Met, the enzyme is least active; in those carrying two alleles for the form called Val, it is the most active; and in individuals carrying one of each allele, COMT’s activity is somewhere in between. Some, but not all, studies have linked possession of two Val alleles to an increased risk for schizophrenia. The theory, in part, is that the increased COMT activity in Val/Val individuals increases the degradation of dopamine released from neurons projecting to the front part of the brain, the prefrontal cortex. This causes deficits in prefrontal cortex function such as impaired memory and attention, which are characteristic of schizophrenia. In a study published in Biological Psychiatry, Terrie Moffitt and colleagues determined that among individuals who started using cannabis regularly before age 15, Val/Val individuals had an increased risk of a temporary disorder resembling schizophrenia in adulthood, and, to a lesser extent, so did Val/Met

64 Results of the study add to the growing evidence linking the Val allele to psychosis but possibly only if a person is exposed to environmental influences, such as cannabis use. individuals. In contrast, Met/Met individuals did not show an increased risk. People who began using cannabis as adults did not have an increased risk of the disorder, no matter what COMT alleles they carried, which indicated that the gene- cannabis interaction was limited to a sensitive period of brain development in adolescence. Results of the study add to the growing evidence linking the Val allele to psychosis but possibly only if a person is exposed to environmental influences, such as cannabis use.1 In a related study published in Nature Neuroscience, Andreas

Meyer-Lindenberg and his collaborators used a brain imaging 2006 Report technique called positron emission tomography to provide evidence that dopamine “tunes” neuronal activity in the prefrontal cortex (PFC) during mental tasks. In other words, the amount of dopamine release determines how much neural firing occurs in connection with an actual task versus the firing occurring when the brain is at rest. While performing a memory task, people who were COMT Met carriers showed a positive correlation between dopamine synthesis in the midbrain and blood flow in the prefrontal cortex (blood flow is an indirect measure of neural activity). This finding is consistent with the idea that dopamine tunes PFC activity. In contrast, COMT Val carriers showed an inverse correlation between dopamine synthesis and PFC blood flow during the Psychiatric, Behavioral, and Addictive Disorders

“Tuning” neurons A positron emission tomography scan highlights areas where dopamine “tunes” neuronal activity in the prefrontal cortex during mental tasks. Dopamine levels in carriers of certain gene sequences may indicate a role for those sequences in schizophrenia risk.

65 same task. While both Met and Val carriers performed the memory task adequately, the results suggest that Val carriers may not achieve sufficient dopamine levels in the PFC to get it done most efficiently. This may suggest how Val plays a role in the increased risk for schizophrenia among people who have this form of the gene, the researchers suggest.2

Depression

Numerous family studies have shown an increased risk for major depressive disorder in the first-degree relatives of patients with depression, compared with controls. These studies indicate a role for genes in the transmission of major depression. Now, Myrna Weissman and colleagues have published in the Archives of General Psychiatry results from the first long-term, three-generation study of the disorder. They found that among grandchildren who had both grand- parents and parents with depression, nearly 60 percent had at least one psychiatric disorder, such as anxiety disorder or disruptive disorder. The grandchildren with a parent, but not a grandparent, with depression were at no greater risk for any psychiatric diagnosis, compared with grandchildren whose parents were not depressed.3 One gene that appears to be involved in depression is the gene encoding the protein that transports serotonin back into the neuron to be released again the next time the neuron fires. Long ago, research implicated dysfunction in serotonin neurotransmission as having a key role in depression. The serotonin transporter gene has two common alleles that are named “long” and “short,” depending on the length of one region of the gene. The short allele, designated “s,” is associated with reduced availability of the serotonin transporter. Exactly why the s allele predisposes individuals to depression is not known. Studies in late 2004 by Rene Hen and colleagues showed that fewer serotonin transporters or inhibition of the transporter during early development produced adult mice with anxiety-like symptoms. This suggested that serotonin transporter availability and hence serotonin levels affect the development of the brain’s emotional circuitry.4,5 Because the s allele reduces

66 Anterior Cognitive behavior therapy cingulate cortex Studies in 2005 revealed new information involving the amygdala, anterior cingulate cortex, and posterior subcallosal cortex Prefrontal cortex in depression; and about the prefrontal cortex, which plays a role in schizophrenia and addiction. Posterior subcallosal cortex Amygdala

serotonin transporter availability, perhaps the s allele affects the development of emotional circuitry. In 2005, Daniel Weinberger and colleagues provided evidence

for this theory in results published in Nature Neuroscience indi- 2006 Report cating a predisposition toward inadequate control of negative emotions in individuals carrying the s allele.6 The researchers found that in humans with the s allele, a circuit involved in dampening negative emotions is working poorly. The researchers first found that in healthy subjects with the s allele but no lifetime psychiatric diagnosis or treatment, threatening visual stimuli caused an exaggerated response in the amygdala, a collection of nerve cells located on both sides of the brain in front of the ears. Amygdala hyperactivity is associated with increased anxiety-related temperamental traits, which, in turn, are related to increased depression risk. The scientists then determined that this exaggerated amygdala response was apparently caused by reduced inhibition coming from a specific part of a region called the anterior cingulate cor- Psychiatric, Behavioral, and Addictive Disorders tex (ACC), which is located along the midline of the brain. This particular place in the ACC—called the rostral subgenual portion, or “rACC”—is densely packed by neurons that are the target of serotonergic neurons from a lower region of the brain. Previous studies have shown reduced rACC activity in depression and sadness. Writing in Neuron, Marc Caron and colleagues have identified another allele that appears to predispose individuals to depression. This one directs the production of a slightly altered version

67 of the enzyme tryptophan hydroxylase-2, which is involved in making serotonin. Despite differing from the normal enzyme by only one amino acid, the mutant form produces 80 percent less serotonin in laboratory experiments. The researchers identified this mutation in 9 of 87 patients with major depression, compared with 3 of 219 control subjects. The three control subjects with the mutation were not diagnosed with major depression, but they did display clinical symptoms, including generalized anxiety and mild depression. These findings suggest that a defi- ciency in the fabrication of brain serotonin may be an important risk factor for major depression.7 Although raising serotonin levels through the use of antidepressants is the mainstay of depression treatment, many patients fail to respond to these drugs. Up to 20 percent of patients with depression fail to respond to antidepressants or the other treatments, such as psychotherapy and electroconvulsive therapy. A preliminary study by Helen Mayberg and colleagues, published in Neuron, suggests that these unresponsive patients may respond to electrical stimulation of a brain region called the posterior subcallosal cortex (PSC), located deep along the midline of the brain behind the rACC. In contrast to the rACC’s reduced activity during depression, the PSC is overactive during depression and stays overactive in patients who fail to respond to traditional treatments. The researchers implanted electrodes in the neural pathways from the PSC on both sides of the brain in six patients with treatment-resistant depression. The delivery of high-frequency electrical stimulation to these regions reduced activity in the PSC. During stimulation, all patients spontaneously reported positive effects on mood, such as “sudden calmness,” “disappearance of the void,” and increased interest. In four of the six patients, continuous stimulation for six months led to long-term improvements in mood that continued after the stimulation ended.8

Addictive Disorders

As with schizophrenia and depression, genes may play a role in the development of addictive disorders. One gene that researchers are focusing on makes the mu-opioid receptor (MOR), which

68 responds to natural chemicals in the body that are similar to opiate drugs such as morphine and heroin. Opiate drugs bind to this receptor, which is how they exert their sedative effects. One allele of the MOR—designated 118G—is of interest partly because receptors produced by this allele bind the natural chemical beta-endorphin three times more strongly than receptors produced by the normal allele. Gavin Bart and his collaborators found an association between the 118G allele and alcohol dependence in a Swedish population. Why 118G contributes to alcoholism risk is unknown, the researchers wrote in Neuropsychopharmacology, but may involve altered responsivity to stress.9 Naltrexone, an MOR blocker, provides more evidence that the MOR is involved in alcoholism. Naltrexone is effective against alcoholism, though many alcohol-dependent individuals fail to adhere to the treatment regimen, which involves taking naltrexone orally, daily. To improve adherence, scientists devel- 2006 Report oped a formula that releases naltrexone for one month following a single intramuscular injection. James Garbutt and colleagues conducted a large clinical trial of the monthly formula with alcohol-dependent patients, using two doses over a 6-month period combined with a low-intensity psychosocial intervention. Results published in the Journal of the American Medical Association showed that long-acting naltrexone reduced heavy drinking, more so with the high dose than the low dose. For reasons that are unclear, men responded to the

10 Behavioral, and Addictive Disorders treatment much better than did women. , Another receptor that appears to play a major role in drug and alcohol abuse, as well as other addictive behaviors, is the cannabinoid CB1 receptor. This neurotransmitter receptor nor- Psychiatric mally binds a chemical produced in the body that is similar to THC, the active ingredient in marijuana. A paper by Taco De Vries and Anton Schoffelmeer in the August Trends in Pharmacological Sciences reviews evidence that the cannabinoid CB1 receptor is important not in the rewarding properties of drugs but in the classical, or Pavlovian, conditioning that occurs during the addiction process.11 This process involves the formation of memories for cues associated with drug intake. For example, if an addict revisits a

69 neighborhood where he used to take cocaine, just seeing the neighborhood triggers memories of taking the drug, which triggers craving for the drug. Medications, such as rimonabant, that block the cannabinoid CB1 receptor appear to be able to block that craving. However, they cannot block stress-induced craving, which occurs when the craving develops in response to a stressor, such as losing a job. This finding indicates that drug addiction will most likely have to be treated with multiple medications. Progress also is being made in uncovering the neural circuits involved in addiction. One circuit that has received considerable attention is that between the prefrontal cortex (PFC) and the nucleus accumbens (NA), which is located in the midbrain. Nerve fibers from the PFC to the NA release the neurotransmitter glutamate, which is important in learning and memory. In turn, pathways from the NA to the PFC release dopamine, which, as mentioned before, helps the PFC focus attention. Peter Kalivas, Nora Volkow, and James Seamans published in Neuron a comprehensive theory of addiction that involves alterations at both ends of this circuit.12 According to this theory, at the PFC, changes in neuronal chemicals involved in internal cell signaling cause increased signaling by dopamine D1 receptors relative to signaling by other dopamine receptors. This causes the addict to become motivat- ed only by drug-associated cues and not by other reinforcers, such as sexually evocative cues for which a different dopamine receptor is important. At the end of the pathway from the PFC to the NA, changes in the neurons’ operations and in the surrounding support cells (the glia) result in a larger release of glutamate. This causes the addict to become more compulsive about taking drugs. The authors propose various targets along this circuit where medications could break the vicious cycle and restore normal functioning.

The authors propose various targets along this circuit where medications could break the vicious cycle and restore normal functioning.

70 Future Directions

In January 2005 the Josiah Macy Jr. Foundation convened 30 individuals from the fields of psychiatry, neurology, and neuroscience to determine how to promote and advance interdisciplinary training of future health care professionals in neurology and psychiatry. The conference was called “The Convergence of Neuroscience, Behavioral Science, Neurology and Psychiatry,” and was chaired by Joseph B. Martin, M.D., Ph.D., dean of the faculty of Harvard Medical School. Recommendations included surveying graduates in these fields to determine their career trajectories; establishing a national repository of teaching materials in basic and clinical neuroscience; developing strategies to maintain student interest in the fields; and providing neurobiology Ph.D. candidates with experience in clinical disease to guide their future research interests. Perhaps the most important discussion focused on the educa- 2006 Report tional enterprise and the importance of an interdisciplinary approach in medical school education and in residency training. Behavioral, and Addictive Disorders , Psychiatric

71 SENSE AND BODY FUNCTION

Sleep, Appetite, and Obesity 73

A Bigger Role for Orexin 74

Research Advances in Age-Related Macular Degeneration 76

Understanding the Sensitive Nature of Smell 77

72 iological mysteries that have con- founded scientists for decades Bseem to be unraveling at lightning speed, thanks in large part to new technologies that allow researchers to examine the inner workings of the body in ways never before possible. Such scrutiny is revealing complex cellular relationships that govern everything from appetite to sleep to smell. Several important studies reported in 2005 have provided some of the missing pieces to such mysteries as how the brain senses odors and how sleep patterns are linked with appetite and behavior. Elsewhere, some of the same inventiveness that is leading to long-sought-after answers in other disorders is contributing to the development of procedures and technologies to aid patients with macular degeneration.

Sleep, Appetite, and Obesity 2006 Report

Scientists long have suspected that biological pathways that control sleep and those that control appetite are somehow connected. A report published in Science in May 2005 by researchers at Northwestern University strengthened that idea. Joseph Bass, Fred Turek and colleagues studied mice with a mutation in the “clock” gene, which helps control the body’s circadian rhythms of sleeping, waking, and eating.1 When fed normal and high-fat diets, these mice gained much more body fat than mice with normal clock genes. The off-balance internal clock also affected how much the mice slept, when they ate, and how those additional calories were stored. Finally, the mutant mice had elevated levels of cholesterol, triglycerides, and blood sugar as well as reduced insulin—all of which put Sense and Body Function mice and humans at risk for obesity, heart disease, and diabetes. The study suggests that irregular eating patterns may have been related to changes in levels of leptin and ghrelin, chemical messengers that play important, opposing roles in appetite regulation. The findings are bolstered by studies in humans published at the very end of 2004, which also demonstrated the importance of the hormones on the sleep-appetite cycle. Emmanuel Mignot and colleagues at Stanford University and the University of Wisconsin, Madison, asked more than 1,000

73 volunteers to spend a night in the sleep lab and have their blood analyzed in the morning. As reported in the December 2004 issue of Public Library of Science Medicine, participants who slept less than 8 hours had a higher body mass index than those who slept 8 hours or more. The shorter-sleeping subjects also had elevated levels of ghrelin (which signals feelings of hunger) and reduced levels of leptin (which contributes to the feeling of fullness).2 Reporting in the December 2004 Annals of Internal Medicine, Eve Van Cauter and colleagues at the University of Chicago found that healthy young men whose sleep was curtailed showed elevated ghrelin, reduced leptin, and increased hunger and appetite.3 Taken together with the 2005 mouse research, and with a 2004 report that sleep restriction in healthy young men increases levels of a protein whose presence is a risk factor for heart attack,4 these findings suggest strongly that disruptions in eating and sleeping patterns may play a role in obesity and its attendant health risks. A clearer understanding of these patterns is essential, especially in the United States, where people tend to sleep too little, high-calorie food is readily available, and rates of obesity and diabetes are rising rapidly.

A Bigger Role for Orexin

Studies in the past few years have identified several key chemical components involved in sleep, such as orexin (hypocretin), a neurotransmitter produced in the hypothalamus that stimulates wakefulness. A lack of orexin can cause narcolepsy in humans. In 2005, several research teams identified other roles for orexin. One study, led by Glenda Harris and Gary Aston-Jones at the University of Pennsylvania School of Medicine, found that orexin influences how the brain perceives pleasure and controls reward- seeking behaviors.5 Scientists knew that regions of the hypothalamus were involved in reward and motivation, but just which neurotransmitters play a role was unknown. By stimulating orexin

Orexin seemed to reawaken drug-seeking behavior in rats in which this behavior had been methodically eliminated.

74 neurons in rats, the researchers found a link between high orexin activity and drug- and food-seeking behavior. The team also discovered that orexin seemed to reawaken drug-seeking behavior in rats in which this behavior had been methodically eliminated. What’s more, when the scientists injected those rats with an anti-orexin chemical, the animals’ drug- seeking behavior vanished. The work, published in Nature in September 2005, could have important implications for the study of addictive behaviors such as drug abuse and compulsive eating. Two teams, one led by Barbara Jones at McGill University in Montreal and one headed by Jerry Siegel of the University of California, Los Angeles, reported in 2005 that orexin neurons begin to fire just before animals emerge from rapid-eye-movement sleep.6,7 The twin findings, published in the Journal of Neuroscience and Neuron, respectively, suggest that orexin neurons fire primarily during wakefulness, and that they fire fastest in association with motor responses, particularly exploration. 2006 Report Thus the activity of orexin neurons seems more closely related to Sense and Body Function

The perception of pleasure High activity of a neurotransmitter called orexin, indicated by the dotted oval, corresponds with an increase in drug- and food-seeking behavior. Orexin in the lateral hypothalamus (LH) is activated by stimuli related to reward, such as food. Once orexin is activated, it affects other regions of the brain: the ventral tegmental area (VTA), nucleus accumbens (NAc), and amygdala (Amy). Stimuli unrelated to reward, such as stress, activate orexin in a different part of the brain, with different effects.

75 the movement itself than to the underlying state of waking or sleeping—a finding consistent with the very low levels of locomotor activity of orexin-deficient mice. Finally, a study in the online edition of the Journal of Physiology by Yoshimasa Koyama and colleagues at Asahikawa Medical College in Japan shows that orexin neurons carry messages to the midbrain that play an important role in regulating motor function and locomotion during both wakefulness and sleep.8

Research Advances in Age-Related Macular Degeneration

Studies published in 2005 could offer hope to those who suffer from age-related macular degeneration (AMD). This condition affects the macula, the region of the retina responsible for detailed vision, thus compromising visual abilities such as reading. The retina converts light into nerve signals it then sends to the brain. With age, the cells in the macula can be damaged, leading to permanent vision loss. More than 15 million Americans have AMD, which is the most common form of legal blindness in the United States. In the early 1990s, Robert Machemer at Duke University pio- neered a surgical procedure called macular translocation to repair damage from AMD, a technique that fellow Duke researchers Cynthia Toth and Sharon Freedman have spent a decade perfecting for use in patients who have almost no vision remaining and for whom other treatments have been ineffective.

Help for the eyes Cynthia Toth and her team of researchers at Duke University have perfected a procedure that can restore considerable vision— and, thus, quality of life—to patients with age-related macular degeneration.

76 In 2005, the pair led a team that found that the procedure can restore substantial vision in some patients.9,10 The technique, now known as macular translocation with 360- degree peripheral retinectomy, or MT360, is a two-step procedure in which surgeons first restore function by rotating the retina and moving the degenerating macula to a spot in the eye free from scar tissue and abnormal blood vessels. Because this surgery causes the patient’s vision to appear tilted, a second step taken later corrects the tilt by rotating the eye. Toth and Freedman reported in the journal Ophthalmology that before surgery, patients with severe vision loss reported a very low quality of life. When those patients were interviewed again one year after surgery, both their vision and quality of life had greatly improved. In other work, three independent research groups reporting in Science identified a gene involved in macular degeneration. The gene codes for an immune system protein called complement factor H. Scientists have long suspected that the immune 2006 Report system is somehow involved in the onset of AMD. Now, scientists have a molecular target for new drugs to treat the disorder. Teams from Vanderbilt University Medical Center, Duke University Medical Center, the University of Texas Southwestern Medical Center, and the Boston University School of Medicine identified the gene for complement factor H.11,12 Meanwhile, a group at the Yale University School of Medicine led by Josephine Hoh found that a variant of the complement factor H gene cannot produce the factor H protein, which is supposed to regulate the body’s response to abnormal cells.13 Hoh’s team used blood samples from the National Eye Institute’s Age-Related Eye Disease Study, analyzing DNA from 96 unrelated patients with advanced AMD and 50 people with normal vision. The discov- Sense and Body Function ery of the gene and its variant could help researchers develop treatments for the disorder.

Understanding the Sensitive Nature of Smell

The sense of smell can warn an animal of nearby predators and give humans a hint about what’s for dinner. But just how does the brain distinguish between smells? Two studies in 2005 offer insight into this question.

77 A molecule called an ion transporter, known to play a role in digestion, hearing, balance, and fertility, also is important in helping the brain sense odors.

Lawrence Katz at Duke University Medical Center led a team that identified neurons in the mouse brain that trigger a response to certain odors.14 Specifically, the team found that mice use a chemical in urine to distinguish between male and female mice. The neurons the researchers isolated are located in the brain’s main olfactory system, contradicting a long-held belief that nonhuman mammals process such smells in the accessory olfactory system, which humans lack. Katz’s research, published in Nature, suggests that higher regions of the brain, in both humans and other animals, may be involved in analyzing smells. Meanwhile, advances by a team at the Johns Hopkins School of Medicine could lead to a better understanding of how the brain knows the difference between the sweet aroma of a fresh- ly baked apple pie and the pungent odor of low tide.15 Jonathan Bradley and colleagues reported in Neuron that a molecule called an ion transporter, known to play a role in digestion, hearing, balance, and fertility, also is important in helping the brain sense odors. Cells responsible for the sense of smell require charged chloride atoms, or ions, to communicate odor information to the brain. Scientists knew that a transporter called NKCC1 regulated the amount of chloride in other cells in the body. Bradley’s team found that NKCC1 also helps to shuttle chloride in and out of odor-sensing cells, which allows signals carrying information about odor to travel from the cells to the brain. The next step will be to figure out just how chloride is involved in the processing of smells in the brain.

78 STEM CELLS AND NEUROGENESIS 2006 Report

Developmental Benchmarks for Stem Cells 80

Nuclear Fallout Dates Stem Cells 80

Junk DNA Distinguishes Individual Brains 81

Dopamine Nixes Neurogenesis 82

Neurogenesis Helps Fight Brain Tumor 83 Stem Cells and Neurogenesis Stem Cells and Neurogenesis Gene Helps Stem Cells “Graduate” 83

Embryonic Stem Cells Go Native 84

Neurogenesis Is a Coping Technique after Stroke 85

New Neurons Vital to Some Kinds of Memory 86

79 eurogenesis refers to the birth of new brain cells; not until Nthe late 1990s did scientists prove that this process occurs in the human adult brain. Since then, and particularly in 2005, scientists have gained greater understanding of how a newborn neuron, or neural stem cell, can grow and develop into a cell that performs a specific task in the brain. Throughout the year, neurogenesis also revealed itself to be part of the healthy brain’s ongoing activities—as well as a process that can be harnessed for therapeutic purposes.

Developmental Benchmarks for Stem Cells

The adult brain contains many cells that look like young neurons maturing: they produce proteins, unique to various stages of development, that can be seen with specialized stains. But for stem cells to be useful in treating brain disorders they must function as neurons, stepping in for those that die off or are injured. In the June 15 issue of Brain, Morten Moe and colleagues at the Karolinska Institute in Sweden show that neural stem cells go through characteristic steps as they develop into mature, functional neurons. Working with tissue from the brains of patients who had undergone surgery to correct epilepsy, the researchers cultured neural stem cells and studied them with both staining and electrophysiological techniques. Over four weeks, the cells began to show the membrane properties and firing abilities of neurons; they developed several kinds of ion channels (through which neurons exchange electrical impulses), and, finally, synapses for two of the brain’s chief neurotransmitters. The finding is among the first to outline the changes in “behavior,” not just appearance, of adult human neural stem cells as they differentiate and mature.1

Nuclear Fallout Dates Stem Cells

Although neurogenesis has been demonstrated in several parts of the adult brain, such as the hippocampus, evidence for its occurrence in the cortex is inconclusive. The obvious solution would be to determine the age of cells—something not possible until Jonas

80 Elements called retrotransposons, which make up about 15 percent of the human genome and were long thought to be genetic junk, not only change the destiny of neural stem cells but may help make each brain unique.

Frisen and colleagues at the Medical Nobel Institute in Stockholm looked to the seemingly unrelated field of archaeology. Carbon-14, or 14C, dating accurately tells the age of antiquities, but because carbon decays over thousands of years, it is less useful for dating more recent objects. However, a burst of 14C entered the Earth’s atmosphere with the testing of nuclear weapons in the 1950s, declining in measurable increments as it worked its way into the cells of plants and animals, including humans. In their study published in Cell, the researchers found that levels of 14C in cortical tissue obtained at autopsy from people born before 1950 were identical to those in the pre-nuclear-test 2006 Report atmosphere—meaning the cells were the same age as the individual. But in newly born blood cells, 14C concentrations matched those in the atmosphere today. The finding is credible evidence that neurogenesis does not occur in the cortex because none of the neurons in this area were younger than the individual. It also provides an elegant method for verifying the age of a cell.2

Junk DNA Distinguishes Individual Brains

When harnessing the power of stem cells, a central question is whether they truly can develop into any type of cell. In the June issue of Nature, Fred Gage and colleagues at the Salk Institute in California show that elements called retrotransposons, which Stem Cells and Neurogenesis make up about 15 percent of the human genome and were long thought to be genetic junk, not only change the destiny of neural stem cells but may help make each brain unique. The investigators introduced a line of human retrotransposons into cultured neural stem cells in rats. The bits of DNA embedded themselves into several genes expressed by neurons and changed the way the cells’ genes were expressed, often redi- recting the cell’s path of development—turning the cell into a neuron rather than a “support” cell such as an astrocyte or oligo-

81 Change of fate A cell, center, has become a neuron thanks to genetic elements called retrotransposons. These elements can change the way a stem cell develops, incorporating new traits and guaranteeing that no two brains are alike. Nuclei of other cells appear in the background. dendrocyte, for example. The finding suggests that retrotransposons help stem cells not only differentiate into mature cells but also bring in new traits, ensuring that no two brains—even those of identical twins—develop in exactly the same way.3

Dopamine Nixes Neurogenesis

Many studies show that antidepressants increase the rate of neurogenesis in the brain, suggesting that the absence of neurogenesis may be a factor in psychiatric disorders. Similar studies using antipsychotic drugs, however, have yielded conflicting results. In a study in the June 15 issue of the Journal of Neuroscience, the drug haloperidol offers clues to the effects of the neurotransmitter dopamine in the normal brain and in cases of schizophrenia (the symptoms of which arise in part from the excessive actions of dopamine). Tod Kippin and colleagues at the University of Toronto showed that one role of dopamine may be to inhibit neurogenesis when necessary. The team found that haloperidol, which blocks dopamine receptors, increases the numbers of neural stem cells, and consequently new neurons, in the adult rat brain. Turning to the culture dish, the researchers demonstrated that dopamine inhibits stem cell proliferation, that neural stem cells contain dopamine receptors, and that by binding “pre-emptively” to dopamine receptors, haloperidol can interfere with dopamine’s inhibitory effect. In the animals, the increase in neural stem cells was dramatic in the striatum, a nexus of dopamine activity. Because striatal volume is reduced in people with schizophrenia and restored with haloperidol treatment, the new study offers a novel explanation for the antipsychotic drug’s effects. It also

82 shows that inhibition of neurogenesis, at the right time and place, may be an integral part of brain health.4

Neurogenesis Helps Fight Brain Tumor

A provocative study in the March issue of the Journal of Neuroscience shows that the brain may employ neurogenesis to fight cancer. Using mice whose neural stem cells were “labeled” with green fluorescent protein, Helmut Kettenmann and colleagues at the Max Delbruck Center for Molecular Medicine, Berlin, infected the animals with glioblastoma cells. As the tumor developed, stem cells originating deep in the brain made their way to the site and densely clustered around the tumor. The cells also followed cancer cells that were spreading to nearby tissue. When tested in culture, stem cells constrained the growth of the cancer cells and induced apoptosis, or programmed cell death— indicating that in the mice, the stem cells were fighting the cancer 2006 Report and not just replacing damaged tissue. Though older mice showed less of this spontaneous cancer-fighting ability, when injected with neural stem cells they had the same survival time as younger animals. Because glioblastoma is rare in young people and peaks in those over age 55, the findings suggest that in the young brain, neurogenesis is a powerful defense against this type of cancer—a defense that might be exploited as a treatment.5

Gene Helps Stem Cells “Graduate”

To harness the therapeutic power of stem cells, scientists must understand how these precursors mature not only into neurons but into cells that do a particular job. In the July 27 issue of the Stem Cells and Neurogenesis Journal of Neuroscience, Arturo Alvarez-Buylla and colleagues identified a gene called pax6 that may play a key role in the development of dopamine-producing cells. Working with normal, adult mice, the investigators transplanted stem cells lacking a working copy of the pax6 gene into the animals’ olfactory bulbs, an area rich in dopamine activity. The mutant stem cells colonized the olfactory bulb but failed to become either dopamine-producing cells or so-called superficial granule cells (which make an enzyme crucial to dopamine production).

83 The results indicate that pax6 is a gene that allows stem cells to specialize into dopamine-producing cells—important information for scientists seeking to treat diseases involving these cells, such as Parkinson’s disease.6 Another study, in the June issue of Nature Neuroscience, confirms the importance of pax6 in generating dopamine-producing cells and identifies a specific neural “niche,” called the rostral migratory stream, in which the cells originate.7 Taken together, the studies help to explain both extrinsic and intrinsic mechanisms controlling neuronal identity in adult neurogenesis.

Embryonic Stem Cells Go Native

Stem cells derived from embryos pose an ethical dilemma, but evidence suggests that they are more versatile than those in the adult brain. Although embryonic stem cells in culture can be nudged along a particular path of development—to step in for cells that are dying, for example—the process by which transplanted cells incorporate themselves into a brain is not understood in detail. In the May issue of Nature Biotechnology, Viviane Tabar and colleagues at Memorial Sloan-Kettering Cancer Center show that human embryonic stem cells, when grafted into the brains of young adult rats, migrated and differentiated along with the cells residing at the site of the graft—taking up positions in the same places and contributing to further neurogenesis. Because past studies hint that transplanted stem cells “fuse” with existing cells, rather than changing their own developmental destinies, the authors looked for signs of fusion—a double nucleus or extra chromosomes, for example—and found none. The authors conclude that transplanted embryonic stem cells can respond appropriately to cues from their new environment and that their offspring can replenish dying or injured neurons.8 Meanwhile, two studies offer approaches that could address the ethical concerns surrounding embryonic stem cells. In order to propagate such cells, the embryo that produces them must be destroyed. Reporting in the October 16 online issue of Nature, Robert Lanza of Advanced Cell Technology in Worcester, Massachusetts, and colleagues modified a technique already used

84 in assisted-reproduction clinics, in which a single cell is removed from the eight-cell stage of development (before the “blastocyst” that will implant in the uterus has formed) and checked for genetic defects. Lanza’s variation, demonstrated in mice, uses this single cell to develop a line of embryonic stem cells without compromising the blastocyst’s ability to develop into an embryo.9 In the same issue of Nature, Alexander Meissner and Rudolf Jaenisch drew from previous research that showed a gene called Cdx2 to be crucial in forming the interface through which the embryo implants in the uterus. The investigators developed mouse blastocysts with altered Cdx2, which were unable to implant. The method produced an entity that could not become a viable embryo but could give rise to embryonic stem cell lines, possibly heading off concerns that a potential life is destroyed. 10

Neurogenesis Is a Coping Technique after Stroke 2006 Report Stimulating neurogenesis may be a therapeutic approach not only for neurodegenerative disease and depression but for more direct forms of brain impairment as well. Some studies show that experimentally induced stroke increases the rate of neurogenesis in young adult rats. In the August issue of the journal Stroke, researchers at University Hospital in Lund, Sweden, examined whether the same increase takes place in older brains. They found similar rates of post-stroke neurogenesis in the brains of both young and old rats, indicating that this mechanism for self- repair also operates in the aged brain.11 A report in the June issue of the same journal shows that following a stroke, in rats at least, neurogenesis can be stimulated in a surprisingly straightforward way: by providing an enriched envi- Stem Cells and Neurogenesis ronment. After undergoing a procedure to mimic a stroke, adult rats were given an injection of a chemical that fastens onto dividing cells. The rats were then housed in either “enriched” environments

Five weeks after the stroke, the rats given an enriched environment showed an increase in neural stem cells and neurogenesis—a finding of great significance in understanding and treating brain damage.

85 stocked with toys, tunnels, and exercise equipment, or standard cages with food, water, and bedding only. Five weeks after the stroke, the rats given an enriched environment showed an increase in neural stem cells and neurogenesis—a finding of great significance in understanding and treating brain damage.12

New Neurons Vital to Some Kinds of Memory

Neurogenesis in the memory center called the hippocampus has been linked to learning and memory, but the details remain largely unknown. Research suggests that newly generated neurons have properties uniquely suited to the formation of new memories, and neurons “born” during a memory task are dedi- cated to that activity. Martin Wojtowicz and colleagues at the University of Lethbridge, Alberta, Canada, used low-dose irradiation to stifle neurogenesis in the hippocampus of adult rats; they trained the rats in a water maze four weeks later, when no new neurons would be present. The rats returned to the maze one, two, and four weeks after training to test their memory retention. The irradiated rats learned the maze as easily as their untreated coun- terparts and performed as well after one week, but after two and four weeks their performance became significantly worse. These results, published in the January issue of the journal Neuroscience, show that new neurons that are 4 to 28 days old at the time of training are required for long-term spatial memory. Treated rats easily remembered a maze test in which they could use visual cues, and irradiation either just before or just after training had no effect. The finding argues strongly that neurogenesis plays a role in the formation and consolidation of long- term, hippocampus-dependent, spatial memories.13

86 THINKING AND REMEMBERING 2006 Report

Familiar Alzheimer’s Culprit, New Location 88

The Impact of Diet on Dementia 89

New Approaches to Treating Alzheimer’s Disease 90 Thinking and Remembering

The Role of Emotion in Memory 92

Identifying the Sites of Memory Recall in the Brain 93

87 n a year when researchers found significant new insights into how Iwe form and retrieve memories and clinical researchers started testing novel approaches to slow dementia, the most important study came from studies on a mouse model of Alzheimer’s disease (AD).

Familiar Alzheimer’s Culprit, New Location

One of the biggest challenges facing scientists researching Alzheimer’s disease is to determine whether the plaques and tangles that form in the brains of patients are a cause of the disease or a by-product of it. Frank LaFerla and colleagues at the University of California at Irvine have found what is likely to be an important clue. Previously they developed a mouse model of AD in which the animals develop plaques and tangles throughout the brain and suffer memory and learning problems that resemble the deficits seen in humans. In 2005 they reported in Neuron that the mice start to show behavioral problems at 4 months of age, before the plaques and tangles begin to appear.1 When they looked closely at the brains of 4-month-old mice, however, they saw that the building block of plaques, the beta- amyloid protein, was accumulating inside the neurons. Furthermore, when they treated these mice with antibodies against beta-amyloid, the deposits within neurons cleared and the animals’ performance improved on memory and learning tasks.

Plaques and tangles: cause or effect? Studies of the plaques and tangles that form in Alzheimer’s disease indicate that the beta-amyloid protein first accumulates inside neurons; their appearance outside neurons occurs later. A plaque, upper left, appears darker in this image of tissue from the hippocampus, and tangles appear as smaller black spots.

88 These data suggest that the accumulation of beta-amyloid is the underlying problem in AD. Unexpectedly, though, it is not the plaques external to the neurons that cause the problems, but early deposits within the cells. The team hypothesizes that having too much beta-amyloid protein inside the neurons prevents signals required for learning and memory function from passing normally through the cell. Plaques and tangles, it seems, arise later in the pathology and likely exacerbate the memory and learning problems that already have begun.

The Impact of Diet on Dementia

Announcements that some food or vitamin helps stave off dementia are common. In 2005, researchers made discoveries that back one such claim and deflate another. In a study published in Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association, Maria Corrada and colleagues at 2006 Report the University of California at Irvine found that high folic acid intake reduced the risk of developing Alzheimer’s disease.2 Participating in the Baltimore Longitudinal Study of Aging were 579 volunteers over the age of 60 who were free of dementia. They completed a diary of food intake for a typical week shortly after they enrolled in the study. The researchers analyzed each participant’s diet and calculated their intake of B vitamins, including folate, B6, and B12, and antioxidants, including vitamins E and C and carotenoids. After a median follow-up time of nine years, 57 participants had developed AD. When the researchers compared dietary intake data with the list of who developed AD, they found that individuals who consumed at least the recommended daily Thinking and Remembering allowance of folate were significantly less likely to develop the disease. No association was seen with the other nutrients. How folate protects neural function is not yet clear. The researchers did note that taking folate supplements appeared to be an effective way to obtain adequate amounts of the nutrient. Meanwhile, Thomas Rea and colleagues at the University of Washington in Seattle used information from the large Cardiovascular Health Study to evaluate the impact of statin use on AD risk.3 Statins are drugs used to lower the level of damaging

89 cholesterol. Previous epidemiological studies suggested that statins might lower the risk of developing dementia, but the data were not conclusive. Writing in the Archives of Neurology, Rea’s team reported no reduction of risk with statin use when they examined the pattern of prior statin use and dementia in 2,798 individuals who participated in the Cardiovascular Health Cognition sub-study. All participants were over the age of 65 and free of dementia when they enrolled. The higher average age of the participants in this study, relative to earlier ones, may have played a role in the outcome. The researchers hypothesized that statin use that starts at an earlier age may be beneficial.

New Approaches to Treating Alzheimer’s Disease

In the past several years scientists have been testing various approaches to vaccine therapy for Alzheimer’s disease, and that research continued in 2005. Two research groups uncovered preliminary evidence that injecting antibodies isolated from donat- ed blood into the bloodstream of patients with AD improves their cognitive skills. Previously, Marc Weksler and Norm Relkin at Weill Cornell Medical Center in New York City found that patients with AD had lower-than-normal levels of antibodies that bind to the beta- amyloid protein. Thus, they reasoned that if they transferred antibodies from healthy individuals to these patients, some of the beta-amyloid would be removed and the disease process might be slowed. Purified antibodies are already used for the treatment of other diseases and are called intravenous immunoglobulins (IVIg). To test the idea, these researchers and their team enrolled eight patients in a phase I study to test the safety of the drug.4 The drug was well tolerated and appeared to be safe, the team reported at the annual meeting of the American Academy of Neurology in April 2005. Although such small trials are not designed to test whether a drug is therapeutically effective, preliminary evidence suggests it might be. Of the seven patients who had enough follow-up time after starting the drug therapy, six showed improved cognition on standard tests. The seventh patient did not show

90 Five patients with AD showed improved cognition after IVIg therapy and had decreased levels of beta-amyloid protein levels in their cerebral spinal fluid. The fact that no adverse reactions to the drug were seen in either trial is noteworthy.

improvement but did stop declining. The researchers detected a decrease in the amount of beta-amyloid in their cerebral spinal fluid, which suggests that the amount in their brains also declined. Significantly, Weksler and Relkin’s work agrees with work published in 2004 in the Journal of Neurology, Neurosurgery, and Psychiatry by Richard Dodel and colleagues.5 That group found that five patients with AD showed improved cognition after IVIg therapy and had decreased levels of beta-amyloid protein levels in their cerebral spinal fluid. The fact that no adverse reactions 2006 Report to the drug were seen in either trial is noteworthy. Previous trials wherein researchers injected patients with a vaccine that induced patients’ own immune system to produce antibodies against the beta-amyloid protein did cause complications. Both research groups are expanding their trials to incorporate more patients. Relkin and colleagues plan to begin an efficacy trial in which some patients will receive IVIg therapy and others will receive placebo infusions. The pathology of AD is complex, and although many researchers focus on the abnormal accumulation of beta-amyloid in the brain, another major feature is a loss of synapses and neurons in certain areas of the brain. Thinking that this synapse and neuron loss might be a major cause of cognitive decline, Mark Tuszynski Thinking and Remembering and colleagues at the University of California at San Diego tested whether increasing neural growth could slow the disease.6 The team isolated skin cells from eight patients, all of whom had mild AD. With the cells growing in a culture dish, they transferred a gene that encodes nerve growth factor, or NGF. The cells, with their hyperactive NGF gene, then were injected into the basal forebrain of each patient. If the experiment worked, as it does in mice, the NGF would have induced neural growth, counteracting the losses caused by AD.

91 Two patients suffered physical trauma to the brain because of inadvertent head movement during the injection. The remaining six patients were given general anesthesia before the surgery and had no problems. Those six patients were evaluated after an average follow-up time of 22 months. No long-term adverse effects of the treatment were detected. All six seemed to have a slower rate of cognitive decline based on standard tests, the researchers reported in Nature Medicine. Also, positron emission tomography scans of the patients’ brains showed improved blood circulation to the area treated, which implies that more neural activity was taking place. One patient who had suffered trauma during the surgery died of cardiac arrest five weeks after the injection of the cells. Looking at the brain from this patient, the researchers saw that the NGF gene had been active and that remaining neurons had sprouted new connections with each other near the site of treatment. Like the IVIg therapy trials, the NGF gene therapy approach is far from having been proved effective, but the preliminary data are encouraging enough to warrant further trials.

The Role of Emotion in Memory

Memories formed around emotionally charged experiences are stronger than those of less emotionally important ones. Researchers already know that the amygdala, which is the center of emotional processing in the brain, acts to reinforce emotionally salient memories. In 2005, Philip Shaw and colleagues found evidence that reinforcement pathways or tracts between the amygdala and other parts of the brain are established early in development.7 Individuals who suffered bilateral damage to the amygdala before adulthood remembered neutral material better than emotionally arousing material. In contrast, individuals who suffered damage to the amygdala in adulthood as a result of surgery for epilepsy still retained the ability to preferentially store emotionally arousing material. These data, reported in Neurology, suggest a period exists during brain development that is critical to the estab- lishment of pathways necessary for the lifelong ability to distinguish between emotionally salient memories and neutral ones.

92 Meanwhile, Elizabeth Kensinger and Daniel Schacter at Harvard University reported in Neuropsychologia that the amygdala and left orbitofrontal cortex are involved not only in coding emotionally important memories but also in retrieving them.8 To find out what regions are involved in recall of neutral and emotionally laden memories, the team showed volunteers a random- ly mixed list of neutral words (such as “frog”) and ones that trig- gered agitation or arousal (such as “casket”) and asked them to form an image of each in their mind. Half of the words were followed by an image of the object; the other half were followed by a blank white screen. In the third step of the experiment, the volunteers were shown several pictures and asked if they had previously seen the items pictured in the word-only group, the word and picture group, or neither. In this last step, the volunteers were lying in a magnetic resonance imaging scanner so Kensinger and Schacter could see what regions of the brain participate in accurate recall. The left anteri- 2006 Report or hippocampus was active during accurate recall of both types of objects. However, the right amygdala and left orbitofrontal cortex became active only during recall of emotional items. In contrast, recalling neutral items activated the lateral inferior prefrontal cortex and the right posterior hippocampus. The fact that different regions were activated depending on the type of memory implies not only that these memories are coded differently on the way into the brain but also that they find their way back out via distinct pathways.

Identifying the Sites of Memory Recall in the Brain Thinking and Remembering Behavioral studies have suggested that knowing an object in the sense of being generally familiar with it versus remembering specifically when or if you saw it relies on different neural pathways in the brain. To find out just what regions are involved and to what extent the pathways overlap, Andrew Yonelinas from the University of California at Davis and colleagues devised an experiment to tease the activities apart using functional magnetic resonance imaging.9

93 The study was conducted in two phases with volunteers lying in the scanner for both. In the first phase, they were shown a series of words and asked to indicate whether each was a concrete object or an abstract concept. In the second phase, they were shown another series of words including some from the first list and some new ones. For this set, the volunteers were asked to indicate if they could remember anything in particular about the word, such as what it looked like on the screen or what they were thinking about when they first saw it. If they recalled nothing specific, then they rated on a scale of 1 to 4 how confi- dent they were that the word had been shown in the first phase. The research team reported in the Journal of Neuroscience that different regions of the brain are required for the different types of memories. Recall relied on the anterior medial region of the prefrontal cortex, the lateral parietal cortex, and the posterior cingulate. Familiarity was processed in the lateral regions of the prefrontal cortex, the superior parietal cortex, and the precuneus. The hippocampus was involved in specific recollection but was less active when the item was more familiar and more active when the item was less familiar. In related research, Martina Piefke and colleagues at the Institute of Medicine in Jülich, Germany, wrote in Human Brain

Regions for remembering The image on the computer screen behind researcher Martina Piefke compares the male and female brain in a recall exercise. Piefke’s team found that men and women use different parts of their brains when they recall emotional things that happened to them.

94 Mapping that the brain regions involved in recall of emotional autobiographical events, which is part of episodic memory, differ between men and women.10 Numerous neural processing differences already had been identified between the sexes. For example, males outperform females in spatial tasks, while females outperform males in verbal ones. Additionally, women tend to have more detailed and emotionally intense recollections of past events in their lives. However, the neural differences that underlie such observations had not been explored. Two main theories persist for the reporting of more detailed memories by women: they either experience events more intensely and thus encode them more efficiently or use different cognitive styles that impact memory storage and thinking of events. In their study, Piefke’s group asked ten men and ten women about emotionally negative and positive events in their recent lives and in their childhoods. The researchers found no differences in the subjects’ ability to remember events. However, 2006 Report activity in some regions of the brain did vary between the sexes during the tasks. Numerous brain regions were used by both men and women in such recall, but males showed more activation in the left parahippocampal gyrus relative to females in all types of memory tasks (negative versus positive, recent versus older). Females, in contrast, showed more activation in the right dorsolateral prefrontal cortex for all types of stimuli, and in the right insular cortex during recall of negative or older memories. Because the team did not see statistically significant differences between men and women in their ability to remember events, their data suggest that women use different cognitive strategies to encode, rehearse, and think about emotionally relevant memories, which ends up appearing as more efficient recall Thinking and Remembering mechanisms. The researchers conclude that there is no difference in the efficiency of memory storage, even though different brain regions are used during similar tasks.

95 NOTES

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Neuroimaging

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Disorders That Appear in Childhood

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98 Movement and Related Disorders

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Nervous System Injuries 2006 Report

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Neuroethics

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Neuroimmunology

1. Rus H, Pardo CA, Hu L, Darrah E, Cudrici C, Niculescu T, Niculescu F, Mullen KM, Allie R, Guo L, Wulff H, Beeton C, Judge SI, Kerr DA, Knaus HG, Chandy KG, and Calabresi PA. The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. Proceedings of the National Academy of Sciences 2005 102(31): 11094–11099. 2. Greter M, Heppner FL, Lemos MP, Odermatt BM, Goebels N, Laufer T, Noelle RJ, and Becher B. Dendritic cells permit immune invasion of the CNS in an animal model of multiple sclerosis. Nature Medicine 2005 11(3):328–334. 3. Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Del Carro U, Amadio S, Bergami A, Furlan R, Comi G, Vescovi AL, and Martino G. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 2003 422(6933):688–694. 4. Pluchino S, Zanotti L, Rossi B, Brambilla E, Ottoboni L, Salani G, Martinello M, Cattalini A, Bergami A, Furlan R, Comi G, Constantin G, and Martino G. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 2005 436(7048):266–271. 5. Muraro PA, Douek DC, Packer A, Chung K, Guenaga FJ, Cassiani- Ingoni R, Campbell C, Memon S, Nagle JW, Hakim FT, Gress RE, McFarland HF, Burt RK, and Martin R. Thymic output generates a new and diverse TCR repertoire after autologous stem cell transplantation in multiple sclerosis patients. Journal of Experimental Medicine 2005 201(5):805–816.

104 6. Hartman RE, Izumi Y, Bales K, Paul SM, Wozniak DF, and Holtzman DM. Treatment with an amyloid-beta antibody ameliorates plaque load, learning deficits, and hippocampal long-term potentiation in a mouse model of Alzheimer’s disease. Journal of Neuroscience 2005 25(26):6213–6220. 7. Masliah E, Rockenstein E, Adame A, Alford M, Crews L, Hashimoto M, Seubert P, Lee M, Goldstein J, Chilcote T, Games D, and Schenk D. Effects of a-synuclein immunization in a mouse model of Parkinson’s disease. Neuron 2005 46(6):857–868. 8. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, and Pardo CA. Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of Neurology 2005 57(1):67–81. 9. Yamano Y, Takenouchi N, Li HC, Tomaru U, Yao K, Grant CW, Maric DA, and Jacobson S. Virus-induced dysfunction of CD4+CD25+ T cells in patients with HTLV-I-associated neuroimmunological disease. Journal of Clinical Investigation 2005 115(5):1361–1368. 10. Opsahl ML and Kennedy PG. Early and late HHV-6 gene transcripts in multiple sclerosis lesions and normal appearing white matter. Brain 2005 128(Pt. 3):516–527. 2006 Report Pain

1. Gilron I, Bailey J, Tu D, Holden R, Weaver D, and Houlden R. Morphine, gabapentin, or their combination for neuropathic pain. New England Journal of Medicine 2005 352(12):1324–1334. 2. Ibrahim M, Porreca F, Lai J, Albrecht P, Rice F, Khodorova A, Davar G, Makriyannis A, Vanderah T, Mata H, and Malan T. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proceedings of the National Academy of Sciences 2005 102(8):3093–3098. 3. Zelcer S, Kolesnikov Y, Kovalshyn I, Pasternak A, and Pasternak G. Selective potentiation of opioid analgesia by nonsteroidal anti-inflammatory drugs. Brain Research 2005 1040:151–156. 4. Diatchenko L, Slade G, Nackley A, Bhalang K, Sigurdsson A, Belfer I, Notes Goldman D, Xu K, Shabalina S, Shagin D, Max M, Makarov S, and Maixner W. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Human Molecular Genetics 2005 14(1):135–143. 5. Bradshaw D, Nakamura Y, and Chapman C. National Institutes of Health grant awards for pain, nausea and dyspnea research: An assessment of funding patterns in 2003. Journal of Pain 2005 6(5):277–293.

105 Psychiatric, Behavioral, and Addictive Disorders

1. Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A, Poulton R, and Craig IW. Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: Longitudinal evidence of a gene x environment interaction. Biological Psychiatry 2005 57(10):1117–1127. 2. Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenham S, McInerney-Leo A, Nussbaum R, Weinberger DR, and Berman KF. Midbrain dopamine and prefrontal function in humans: Interaction and modulation by COMT genotype. Nature Neuroscience 2005 8(5):594–596. 3. Weissman MM, Wickramaratne P, Nomura Y, Warner V, Verdeli H, Pilowsky DJ, Grillon C, and Bruder G. Families at high and low risk for depression: A three-generation study. Archives of General Psychiatry 2005 62(1):29–36. 4. Gross C and Hen R. The developmental origins of anxiety. Nature Reviews Neuroscience 2004 5(7):545–552. 5. Ansorge MS, Zhou M, Lira A, Hen R, and Gingrich JA. Early-life block- ade of the 5-HT transporter alters emotional behavior in adult mice. Science 2004 306(5697):879–881. 6. Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, Egan MF, Mattay VS, Hariri AR, and Weinberger DR. 5- HTTLPR polymorphism impacts human cingulate-amygdala interactions: A genetic susceptibility mechanism for depression. Nature Neuroscience 2005 8(6):828–834. 7. Zhang X, Gainetdinov RR, Beaulieu JM, Sotnikova TD, Burch LH, Williams RB, Schwartz DA, Krishnan RR, and Caron MG. Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron 2005 45(1):11–16. 8. Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, and Kennedy SH. Deep brain stimulation for treatment-resistant depression. Neuron 2005 45(5):651–660. 9. Bart G, Kreek MJ, Ott J, LaForge KS, Proudnikov D, Pollak L, and Heilig M. Increased attributable risk related to a functional mu-opioid receptor gene polymorphism in association with alcohol dependence in central Sweden. Neuropsychopharmacology 2005 30(2):417–422. 10. Garbutt JC, Kranzler HR, O’Malley SS, Gastfriend DR, Pettinati HM, Silverman BL, Loewy JW, and Ehrich EW. Efficacy and tolerability of long- acting injectable naltrexone for alcohol dependence: A randomized controlled trial. Journal of the American Medical Association 2005 293(13): 1617–1625. 11. De Vries TJ and Schoffelmeer ANM. Cannabinoid CB1 receptors control conditioned drug seeking. Trends in Pharmacological Sciences 2005 26(8):420–426.

106 12. Kalivas PW, Volkow N, and Seamans J. Unmanageable motivation in addiction: A pathology in prefrontal-accumbens glutamate transmission. Neuron 2005 45(5):647–650.

Sense and Body Function

1. Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH, Takahashi JS, and Bass J. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005 308(5724):1043–1045. 2. Taheri S, Lin L, Austin D, Young T, and Mignot E. Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. PLoS Medicine 2004 1(3):210–217. 3. Spiegel K, Tasali E, Penev V, and Van Cauter E. Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Annals of Internal Medicine 2004 141(11):846–850. 4. Meier-Ewert HK, Ridker PM, Rifai N, Regan MM, Price NJ, Dinges DF, and Mullington JM. Effect of sleep loss on C-reactive protein, an inflam- 2006 Report matory marker of cardiovascular risk. Journal of the American College of Cardiology 2004 43(4):678–683. 5. Harris GC, Wimmer M, and Aston-Jones G. A role for lateral hypothal- amic orexin neurons in reward seeking. Nature 2005 437(7058):556–559. 6. Lee MG, Hassani OK, and Jones BE. Discharge of identified orexin/hypocretin neurons across the sleep-wake cycle. Journal of Neuroscience 2005 25(28):6716–6720. 7. Mileykovskiy BY, Kiyashchenko LI, and Siegel JM. Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 2005 46(5):787–798. Notes

107 8. Takakusaki K, Takahashi K, Saitoh K, Harada H, Okumura T, Kayama Y, and Koyama Y. Orexinergic projections to the midbrain mediate alter- nation of emotional behavioral states from locomotion to cataplexy. Online publication in Journal of Physiology 2005: http://jp.physoc.org/cgi/ content/abstract/jphysiol.2005.085829v1. 9. Cahill MT, Stinnett SS, Banks AD, Freedman SF, and Toth CA. Quality of life after macular translocation with 360 degrees of peripheral retinectomy for age-related macular degeneration. Ophthalmology 2005 112(1):144–151. 10. Cahill MT, Banks AD, Stinnett SS, and Toth CA. Vision-related quality of life in patients with bilateral severe age-related macular degeneration. Ophthalmology 2005 112(1):152–158. 11. Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY, Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, and Pericak-Vance MA. Complement factor H variant increases the risk of age-related macular degeneration. Science 2005 308(5720):419–421. 12. Edwards AO, Ritter R, Abel KJ, Manning A, Panhuysen C, and Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science 2005 308(5720):421–424. 13. Klein RJ, Zeiss C, Chew EY, Tsai J-Y, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, and Hoh J. Complement factor H polymorphism in age-related macular degeneration. Science 2005 308(5720):385–389. 14. Lin da Y, Zhang SZ, Block E, and Katz LC. Encoding social signals in the mouse main olfactory bulb. Nature 2005 434(7032):470–477. 15. Reisert J, Lai J, Yau KW, and Bradley J. Mechanism of the excitatory Cl- response in mouse olfactory receptor neurons. Neuron 2005 45(4):481–482.

Stem Cells and Neurogenesis

1. Moe MC, Varghese M, Danilov AI, Westerlund U, Ramm-Pettersen J, Brundin L, Svensson M, Berg-Johnsen J, and Langmoen IA. Multipotent progenitor cells from the adult human brain: Neurophysiological differentiation to mature neurons. Brain 2005 128(9):2189–2199. 2. Spalding KL, Bhardwaj RD, Buchholz BA, Druid H, and Frisen J. Retrospective birth dating of cells in humans. Cell 2005 122:133–143. 3. Muotri AR, Chu VT, Marchetto MC, Deng W, Moran JV, and Gage FH. Somatic mosaicism in neuronal precursor cells mediated by L1 retrotrans- position. Nature 2005 435(7044):903–910. 4. Kippin TE, Kapur S, and Van der Kooy D. Dopamine specifically inhibits forebrain neural stem cell proliferation, suggesting a novel effect of antipsychotic drugs. Journal of Neuroscience 2005 25(24):5815–5823.

108 5. Glass R, Synowitz M, Kronenberg G, Walzlein JH, Markovic DS, Wang LP, Gast D, Kiwit J, Kempermann G, and Kettenmann H. Glioblastoma- induced attraction of endogenous neural precursor cells is associated with improved survival. Journal of Neuroscience 2005 25(10):2637–2646. 6. Kohwi M, Osumi N, Rubenstein JLR, and Alvarez-Buylla A. Pax6 is required for making specific subpopulations of granule and periglomerular neurons in the olfactory bulb. Journal of Neuroscience 2005 25(30):6997–7003. 7. Hack MA, Saghatelyan A, de Chevigny A, Pfeifer A, Ashery-Padan R, Lledo PM, and Gotz M. Neuronal fate determinants of adult olfactory bulb neurogenesis. Nature Neuroscience 2005 8(7):865–872. 8. Tabar V, Panagiotakos G, Greenberg ED, Chan BK, Sadelain M, Gutin PH, and Studer L. Migration and differentiation of neural precursors derived from human embryonic stem cells in the rat brain. Nature Biotechnology 2005 23(5):601–606. 9. Chung Y, Klimanskaya I, Becker S, Marh J, Lu S-J, Johnson J, Meisner L, and Lanza R. Embryonic and extraembryonic stem cell lines derived from single mouse blastomeres. Nature 2005 doi10.1038/nature04277. 10. Meissner A and Jaenisch R. Generation of nuclear transfer–derived 2006 Report pluripotent ES cells from cloned Cdx2-deficient blastocysts. Nature 2005 doi10.1038/nature04257. 11. Darsalia V, Heldmann U, Lindvall O, and Kokala Z. Stroke-induced neurogenesis in the aged brain. Stroke 2005 36(8):1790–1795. 12. Komitova M, Mattsson B, Johansson B, and Eriksson P. Enriched environment increases neural stem/progenitor cell proliferation and neurogenesis in the subventricular zone of stroke-lesioned adult rats. Stroke 2005 36(6):1278–1282. 13. Snyder JS, Hong NS, McDonald RJ, and Wojtowicz JM. A role for adult neurogenesis in spatial long-term memory. Neuroscience 2005 130(4): 843–852.

Thinking and Remembering Notes 1. Billings LM, Oddo S, Green KN, McGaugh JL, and LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer’s disease–related cognitive deficits in transgenic mice. Neuron 2005 45(5):675–688. 2. Corrada MM, Kawas CH, Hallfrisch J, Muller D, and Brookmeyer R. Reduced risk of Alzheimer’s disease with high folate intake: The Baltimore longitudinal study of aging. Alzheimer’s and Dementia: The Journal of the Alzheimer’s Association 2005 1(1):11–18. 3. Rea TD, Breitner JC, Psaty BM, Fitzpatrick AL, Lopez OL, Newman AB, Hazzard WR, Zandi PP, Burke GL, Lyketsos CG, Bernick C, and Kuller LH. Statin use and the risk of incident dementia: The Cardiovascular Health Study. Archives of Neurology 2005 62(7):1047–1051.

109 4. Relkin N, Szabo P, Adamiak B, Monthe C, Burgut FT, Du Y, Wei X, Schiff R, and Weksler ME. Intravenous immunoglobulin (IVIg) treatment causes dose-dependent alterations in b-amyloid (Ab) levels and anti-Ab antibody titers in plasma and cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) patients. American Academy of Neurology 2005 abstract S15.002. 5. Dodel RC, Du Y, Depboylu C, Hampel H, Frolich L, Haag A, Hemmeter U, Paulsen S, Teipel SJ, Brettschneider S, Spottke A, Nolker C, Moller HJ, Wei X, Farlow M, Sommer N, and Oertel WH. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer’s disease. Journal of Neurology, Neurosurgery and Psychiatry 2004 75(10):1472–1474. 6. Tuszynski MH, Thal L, Pay M, Salmon DP, U HS, Bakay R, Patel P, Blesch A, Vahlsing HL, Ho G, Tong G, Potkin SG, Fallon J, Hansen L, Mufson EJ, Kordower JH, Gall C, and Conner J. A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nature Medicine 2005 11(5):551–555. 7. Shaw P, Brierley B, and David AS. A critical period for the impact of amygdala damage on the emotional enhancement of memory? Neurology 2005 65(2):326–328. 8. Kensinger EA and Schacter DL. Emotional content and reality-monitor- ing ability: fMRI evidence for the influences of encoding processes. Neuropsychologia 2005 43(10):1429–1443. 9. Yonelinas AP, Otten LJ, Shaw KN, and Rugg MD. Separating the brain regions involved in recollection and familiarity in recognition memory. Journal of Neuroscience 2005 25(11):3002–3008. 10. Piefke M, Weiss PH, Markowitsch HJ, and Fink GR. Gender differences in the functional neuroanatomy of emotional episodic autobiographical memory. Human Brain Mapping 2005 24(4):313–324.

110 THE DANA ALLIANCE

FOR

BRAIN INITIATIVES

MISSION STATEMENT,

GOALS, AND MEMBERSHIP

111 THE DANA ALLIANCE FOR BRAIN INITIATIVES

Imagine a world . . .

• in which Alzheimer’s, Parkinson’s, Lou Gehrig’s (ALS) diseases, and retinitis pigmentosa and other causes of blindness are commonly detected in their early stages, and are swiftly treated by medications that stop deterioration before significant damage occurs.

• in which spinal cord injury doesn’t mean a lifetime of paralysis because the nervous system can be programmed to rewire neural circuits and re-establish muscle movement.

• in which drug addiction and alcoholism no longer hold people’s lives hostage because easily available treatments can inter- rupt the changes in neural pathways that cause withdrawal from, and drive the craving for, addictive substances.

• in which the genetic pathways and environmental triggers that predispose people to mental illness are understood so that accurate diagnostic tests and targeted therapies—including medications, counseling, and preventive interventions—are widely available and fully employed.

• in which new knowledge about brain development is used to enhance the benefits of the crucial early learning years and combat diseases associated with aging.

• in which people’s daily lives are not compromised by attacks of depression or anxiety because better medications are being developed to treat these conditions.

lthough such a vision may seem unrealistic and utopian, we are at an extraordinarily exciting time in the history of neu- Aroscience. The advances in research during the past decade have taken us further than we had imagined. We have expanded our understanding of the basic mechanisms of how the brain works, and are at a point where we can harness the healing potential of that knowledge. We have already begun to devise strategies, new technologies, and treatments to combat a range of neurological diseases and disorders. By setting therapeutic goals, and applying what we know, we will develop effective treatments—and, in some instances, cures.

112 For all that has been learned in neuroscience recently, we are learning how much we do not know. That creates the urgency to continue basic research that looks at the broader questions of how living things work. This will help to formulate the complex questions that lead to scientific discovery. The coordinated work of thousands of basic and clinical scientists in multiple disciplines, ranging from molecular structure and drug design to genomics, brain imaging, cognitive science, and clinical investigation, has given us a pool of information that we can now build into therapeutic applications for all neurological diseases and disorders. As scientists, we will continue to move forward not just as individuals, exploring our particular areas of interest, but also in concert with colleagues in all areas of science, mining opportunities to collaborate across disciplines. Public confidence in science is essential if we are to be successful in our mission. To this end we recognize that dialogue between researchers and the public will be essential in considering the ethical and social consequences of advances in brain research. The Dana Alliance for Brain Initiatives and the European Dana Alliance for the Brain represent a community of neuroscientists will- ing to commit to ambitious goals, as seen in 1992 in Cold Spring Harbor, New York, where an American research agenda was set forth, and again in 1997 when the newly formed European group followed suit with its own goals and objectives. Both groups now are moving to build upon gains made so far. We are setting new goals to guide what can be achieved in the near term, and to project even further into the future. By allowing ourselves to imagine what benefit to humanity this new era in neuroscience is likely to bring, we can speed progress toward achieving our goals.

OUR COMMITMENT, BENCH TO BEDSIDE Today, neuroscience research benefits from an unprecedented breadth of opportunity. We have expanded our understanding of brain function, disease onset, and disease progression. A sophisticated arsenal of tools and techniques now enables us to apply our knowledge and accelerate progress in brain research. As scientists, we are committed to continue making progress “at the bench.” To attack major brain disorders such as Alzheimer’s, stroke, or Parkinson’s will require continued basic research from which clinicians can move toward development of new treatments and therapies. We have a responsibility to continue such research and to enlist its support by the public. We also have the obligation to explain those areas of scientific research that soon may have direct application to human beings. To progress beyond laboratory research, we need to take the next clinical steps in partnership with the public—translating science into real and genuine benefits “at the bedside.”

113 As our tools and techniques become more sophisticated, they may be considered threatening in their perceived potential for misuse. It is important to recognize the understandable fears that brain research may allow scientists to alter the most important aspects of our brains and behavior, changing the very things that make us uniquely human. Public confidence in the integrity of scientists, in the safety of clinical trials—the cor- nerstone of applied research—and in the assurance of patient confiden- tiality must be continually maintained. Putting research into a real-life context is always a challenge. People not only want to know how and why research is done, they also want to know why it matters to them. Allaying the public’s concerns that the findings of brain science could be used in ways that might be harmful or ethically questionable is particularly important. Meeting both of these challenges is essential if those affected by neurological or psychiatric disorders are to reap fully the benefits of brain research. Our mission as neuroscientists has to go beyond brain research. We accept our responsibility to explain in plain language where our science, and its new tools and techniques, are likely to take us. We, the members of the Dana Alliance and the European Dana Alliance, willingly embrace this mission as we embark on a new decade of hope, hard work, and partnership with the public.

THE GOALS

Combat the devastating impact of Alzheimer’s disease. In Alzheimer’s disease, a small piece of the amyloid protein accumulates and is toxic to nerve cells. The mechanism of this accumulation has been worked out biochemically and in genetic studies in animals. Using these animal models, new therapeutic drugs and a potentially powerful vaccine are being developed to prevent the accumulation of this toxic material or enhance its removal. These new therapies, which will be tried in humans in the near future, offer realistic hope that this disease process can be effectively treated.

Discover how best to treat Parkinson’s disease. Drugs that act on dopamine pathways in the brain have had significant success in treating the motor abnormalities of Parkinson’s disease. Unfortunately, this therapeutic benefit wears off for many patients after 5 to 10 years. New drugs are being developed to prolong the action of dopamine-based treatments and to slow the selective loss of nerve cells that causes this disease. For those in whom drug therapies fail, surgical approaches, such as deep brain stimulation, are likely to be of benefit. Newer forms of brain imaging have made it possible to determine if these treatments are rescuing nerve cells and restoring their circuits back toward normal.

Decrease the incidence of stroke and improve post-stroke therapies. Heart disease and stroke can be strikingly reduced when people stop smoking, keep their cholesterol levels low, and maintain normal weight

114 by diet and exercise, and when diabetes is detected and treated. For those with strokes, rapid evaluation and treatment can lead to dramatic improvement and less disability. New treatments will be developed to further reduce the acute impact of stroke on normal brain cells. New rehabilitation techniques, based on understanding how the brain adjusts itself following injury, will result in further improvement.

Develop more successful treatments for mood disorders such as depression, schizophrenia, obsessive compulsive disorder, and bipolar disorder. Although the genes for these diseases have eluded researchers over the past decade, the sequencing of the human genome will reveal several of the genes for these conditions. New imaging techniques, along with new knowledge about the actions of these genes in the brain, will make it possible to see how certain brain circuits go awry in these disorders of mood and thought. This will provide the basis for better diagnosis of patients, more effective use of today’s medications, and the development of entirely new agents for treatment.

Uncover genetic and neurobiological causes of epilepsy and advance its treatment. Understanding the genetic roots of epilepsy and the neural mechanisms that cause seizures will provide opportunities for preventive diagnosis and targeted therapies. Advances in electronic and surgical therapies promise to provide valuable treatment options.

Discover new and effective ways to prevent and treat multiple sclerosis. For the first time, we have drugs that can modify the course of this disease. New drugs, aimed at altering the body’s immune responses, will continue to decrease the number and severity of attacks of multiple sclerosis. New approaches will be taken to stop the longer-term progression caused by the breakdown of nerve fibers.

Develop better treatments for brain tumors. Many types of brain tumors, especially those that are malignant or have spread from cancer outside the brain, are difficult to treat. Imaging techniques, focused-radiation treatments, different forms of delivery of drugs to the tumor, and the identification of genetic markers that will assist diagnosis should provide the basis for development of innovative therapies.

Improve recovery from traumatic brain and spinal cord injuries. Treatments are being evaluated that decrease the amount of injured tissue immediately after an injury. Other agents are aimed at promoting the rewiring of nerve fibers. Techniques that encourage cellular regeneration in the brain to replace dead and damaged neurons will advance from animal models to human clinical trials. Electronic prostheses are being developed that use microchip technology to control neural circuits and return movement to paralyzed limbs.

115 Create new approaches for pain management. Pain, as a medical condition, need no longer be woefully undertreated. Research into the causation of pain and the neural mechanisms that drive it will give neuroscientists the tools they need to develop more effective and more highly targeted therapies for pain relief.

Treat addiction at its origins in the brain. Researchers have identified the neural circuits involved in every known drug of abuse, and have cloned major receptors for these drugs. Advances in brain imaging, by identifying the neurobiological mechanisms that turn a normal brain into an addicted brain, will enable us to develop therapies that can either reverse or compensate for these changes.

Understand the brain mechanisms underlying the response to stress, anxiety, and depression. Good mental health is a prerequisite for a good quality of life. Stress, anxiety, and depression not only damage people’s lives, they can also have a devastating impact on society. As we come to understand the body’s response to stress and the brain circuits implicated in anxiety and depression, we will be able to develop more effective ways to prevent them, and better treatments to lessen their impact.

THE STRATEGY

Take advantage of the findings of genomic research. The complete sequence of all the genes that comprise the human genome will soon be available. This means that we will be able, within the next 10 to 15 years, to determine which genes are active in each region of the brain under different functional states, and at every stage in life—from early embryonic life, through infancy, adolescence, and throughout adulthood. It will be possible to identify which genes are altered so that their protein products are either missing or functioning abnormally in a variety of neurological and psychiatric disorders. Already this approach has enabled scientists to establish the genetic basis of such disorders as Huntington’s disease, the spinocerebellar atax- ias, muscular dystrophy, and Fragile X mental retardation. The whole process of gene discovery and its use in clinical diagnosis promises to transform neurology and psychiatry and represents one of the greatest challenges to neuroscience. Fortunately the availability of microarrays, or “gene chips,” should greatly accelerate this endeavor and provide a powerful new tool both for diagnosis and for the design of new therapies.

Apply what we know about how the brain develops. The brain passes through specific stages of development from concep- tion until death, and through different stages and areas of vulnerability and growth that can be either enhanced or impaired. To improve treatment for developmental disorders such as autism, attention deficit

116 disorder, and learning disabilities, neuroscience will build a more detailed picture of brain development. Because the brain also has unique problems associated with other stages of development such as adolescence and aging, understanding how the brain changes during these periods will enable us to develop innovative treatments.

Harness the immense potential of the plasticity of the brain. By harnessing the power of neuroplasticity—the ability of the brain to remodel and adjust itself—neuroscientists will advance treatments for degenerative neurological diseases and offer ways to improve brain function in both healthy and disease states. In the next 10 years, cell replacement therapies and the promotion of new brain cell formation will lead to new treatments for stroke, spinal cord injury, and Parkinson’s disease.

Expand our understanding of what makes us uniquely human. How does the brain work? Neuroscientists are at the point where they can ask—and begin to answer—the big questions. What are the mechanisms and underlying neural circuits that allow us to form memories, pay attention, feel and express our emotions, make decisions, use language, and foster creativity? Efforts to develop a “unified field theory” of the brain will offer great opportunities to maximize human potential.

THE TOOLS

Cell replacement Adult nerve cells cannot replicate themselves to replace cells lost because of disease or injury. Technologies that use the ability of neural stem cells (the progenitors of neurons) to differentiate into new neurons have the potential to revolutionize the treatment of neurological disorders. Transplants of neural stem cells, currently being done on animal models, will rapidly reach human clinical trial status. How to control the development of these cells, direct them to the right place, and cause them to make the appropriate connections are all active areas of research.

Neural repair mechanisms By using the nervous system’s own repair mechanisms—in some cases, regenerating new neurons and in others restoring the wiring—the brain has the potential to “fix” itself. The ability to enhance these processes provides hope for recovery after spinal cord injury or head injuries.

Technologies that may arrest or prevent neurodegeneration Many conditions, such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and ALS, are the result of degeneration in specific populations of nerve cells in particular regions of the brain. Our present

117 treatments, which modify the symptoms in a disease like Parkinson’s disease, do not alter this progressive loss of nerve cells. Techniques that draw on our knowledge of the mechanisms of cell death are likely to offer methods to prevent neurodegeneration and, in this way, stop the progression of these diseases.

Technologies that modify genetic expression in the brain It is possible to either enhance or block the action of specific genes in the brains of experimental animals. Mutated human genes that cause neurological diseases such as Huntington’s and ALS are being used in animal models to assist in the development of new therapies to prevent neurodegeneration. Such techniques have also provided valuable information about normal processes such as development of the brain, learning, and the formation of new memories. These technologies provide an approach to the study of normal and abnormal brain processes more powerful than there has ever been available before and, in time, may be used clinically in the treatment of many brain disorders.

Advanced imaging techniques There have been remarkable advances in imaging both the structure and the function of the brain. By developing techniques that image brain functions as quickly and accurately as the brain does, we can achieve “real-time” imaging of brain functions. These technologies will allow neuroscientists to see exactly which parts of the brain are involved as we think, learn, and experience emotions.

Electronic aids to replace nonfunctional brain pathways In time it may be possible to bypass injured pathways in the brain. Using multi-electrode array implants and micro-computer devices—which monitor activity in the brain and translate it into signals to the spinal cord, motor nerves, or directly to muscles—we expect to be able to offer the injured hope for functional recovery.

Novel methods of drug discovery Advances in structural biology, genomics, and computational chemistry are enabling scientists to generate unprecedented numbers of new drugs, many of which promise to be of considerable value in clinical practice. The development of new, rapid screening procedures, using “gene chips” and other high-throughput technologies, will reduce the time between the discovery of a new drug and its clinical evaluation, in some cases, from years to just a few months.

118 DANA ALLIANCE FOR BRAIN INITIATIVES MEMBERSHIP

Bernard W. Agranoff, M.D. James L. Bernat, M.D. University of Michigan Dartmouth Medical School Albert J. Aguayo, M.D. Katherine L. Bick, Ph.D. McGill University North Carolina Huda Akil, Ph.D. Anders Björklund, M.D., Ph.D. University of Michigan University of Lund Marilyn S. Albert, Ph.D. Ira B. Black, M.D. Johns Hopkins Medical Institutions UMDNJ-Robert Wood Johnson Duane F. Alexander, M.D. Medical School National Institute of Child Health and Peter M. Black, M.D., Ph.D. Human Development Brigham and Women’s Hospital Susan G. Amara, Ph.D. Colin Blakemore, Ph.D., ScD, FRS University of Pittsburgh School of Medical Research Council, Medicine United Kingdom Nancy C. Andreasen, M.D., Ph.D. Floyd E. Bloom, M.D. University of Iowa Hospitals and Clinics The Scripps Research Institute Arthur K. Asbury, M.D. Walter G. Bradley, D.M., FRCP University of Pennsylvania School of University of Miami Miller School of Medicine Medicine Jack D. Barchas, M.D. Xandra O. Breakefield, Ph.D. Weill Medical College of Cornell Massachusetts General Hospital University Monte S. Buchsbaum, M.D. Robert L. Barchi, M.D., Ph.D. Mount Sinai School of Medicine Thomas Jefferson University Mary Bartlett Bunge, Ph.D. Yves-Alain Barde, M.D. University of Miami School of Medicine Friedrich Miescher Institute for Rosalie A. Burns, M.D. (retired) Biomedical Research Thomas Jefferson Medical College J. Richard Baringer, M.D. John H. Byrne, Ph.D. University of Utah Health Sciences University of Texas Health Science Center Center Carol A. Barnes, Ph.D. Judy L. Cameron, Ph.D. University of Arizona Oregon National Primate Research Allan I. Basbaum, Ph.D. Center University of California, San Francisco Louis R. Caplan, M.D. Nicolas G. Bazan, M.D., Ph.D. Beth Israel Deaconess Medical Center Louisiana State University Health Benjamin S. Carson, Sr., M.D. Sciences Center Johns Hopkins Medical Institutions M. Flint Beal, M.D. William A. Catterall, Ph.D. Weill Medical College of Cornell University of Washington University Nicholas G. Cavarocchi Mark F. Bear, Ph.D. Cavarocchi Ruscio Dennis Associates Massachusetts Institute of Technology Verne S. Caviness, M.D., D.Phil. Ursula Bellugi, Ed.D. Massachusetts General Hospital The Salk Institute for Biological Studies

119 Connie L. Cepko, Ph.D. Marc A. Dichter, M.D., Ph.D. Harvard Medical School University of Pennsylvania Medical Dennis W. Choi, M.D., Ph.D. Center Merck Research Laboratories David A. Drachman, M.D. Harry T. Chugani, M.D. University of Massachusetts Medical Wayne State University Center Patricia S. Churchland, Ph.D. Felton Earls, M.D. University of California, San Diego Harvard Medical School David E. Clapham, M.D., Ph.D. Gerald M. Edelman, M.D., Ph.D. Boston Children’s Hospital The Scripps Research Institute Don W. Cleveland, Ph.D. Robert H. Edwards, M.D. University of California, San Diego University of California, San Francisco Robert C. Collins, M.D. (retired) Salvatore J. Enna, Ph.D. UCLA School of Medicine University of Kansas Medical Center Martha Constantine-Paton, Ph.D. Eva L. Feldman, M.D., Ph.D. Massachusetts Institute of Technology University of Michigan Robert M. Cook-Deegan, M.D. James A. Ferrendelli, M.D. Duke University University of Texas-Houston Medical Center Leon N. Cooper, Ph.D. Brown University Howard Fields, M.D., Ph.D. University of California, San Francisco Jody Corey-Bloom, M.D., Ph.D. University of California, San Diego Gerald D. Fischbach, M.D. School of Medicine Columbia University College of Physicians and Surgeons Carl W. Cotman, Ph.D. University of California, Irvine Kathleen M. Foley, M.D. Memorial Sloan-Kettering Cancer Joseph T. Coyle, M.D. Center Harvard Medical School Ellen Frank, Ph.D. Patricia K. Coyle, M.D. University of Pittsburgh School of SUNY at Stony Brook Medicine Antonio R. Damasio, M.D., Ph.D. Michael J. Friedlander, Ph.D. University of Southern California Baylor College of Medicine Hanna Damasio, M.D. Stanley C. Froehner, Ph.D. University of Southern California University of Washington Robert B. Daroff, M.D. Fred H. Gage, Ph.D. Case Western Reserve University School The Salk Institute for Biological Studies of Medicine Michael S. Gazzaniga, Ph.D. William C. de Groat, Ph.D. Dartmouth College University of Pittsburgh School of Medicine Apostolos P. Georgopoulos, M.D., Ph.D. University of Minnesota Mahlon R. DeLong, M.D. Emory University School of Medicine Alfred G. Gilman, M.D., Ph.D. University of Texas Southwestern Martha Bridge Denckla, M.D. Medical Center at Dallas Kennedy Krieger Institute Sid Gilman, M.D., F.R.C.P. J. Raymond DePaulo, Jr., M.D. University of Michigan Medical Center Johns Hopkins University Hospital Gary Goldstein, M.D. Ivan Diamond, M.D., Ph.D. Kennedy Krieger Institute Ernest Gallo Clinic & Research Center

120 Murray Goldstein, D.O., M.P.H. (retired) Kenneth M. Heilman, M.D. United Cerebral Palsy Research and University of Florida College of Educational Foundation Medicine Frederick K. Goodwin, M.D. Stephen F. Heinemann, Ph.D. George Washington University Medical The Salk Institute for Biological Studies Center John G. Hildebrand, Ph.D. Enoch Gordis, M.D. (retired) University of Arizona National Institute on Alcohol Abuse Susan Hockfield, Ph.D. and Alcoholism Massachusetts Institute of Technology Barry Gordon, M.D., Ph.D. Richard J. Hodes, M.D. Johns Hopkins Medical Institutions National Institute on Aging Gary L. Gottlieb, M.D., M.B.A. H. Robert Horvitz, Ph.D. Brigham and Women’s Hospital Massachusetts Institute of Technology Jordan Grafman, Ph.D. David H. Hubel, M.D. National Institute of Neurological Harvard Medical School Disorders and Stroke A. James Hudspeth, M.D., Ph.D. Bernice Grafstein, Ph.D. The Rockefeller University Weill Medical College of Cornell University Richard L. Huganir, Ph.D. Johns Hopkins University School of Ann M. Graybiel, Ph.D. Medicine Massachusetts Institute of Technology Steven E. Hyman, M.D. Michael Greenberg, Ph.D. Harvard University Children’s Hospital Boston Judy Illes, Ph.D. Paul Greengard, Ph.D. Stanford University School of Medicine The Rockefeller University Thomas R. Insel, M.D. William T. Greenough, Ph.D. National Institute of Mental Health University of Illinois at Urbana- Champaign Kay Redfield Jamison, Ph.D. Johns Hopkins University School of Diane E. Griffin, M.D., Ph.D. Medicine Johns Hopkins Bloomberg School of Public Health Richard T. Johnson, M.D. Johns Hopkins University School of Murray Grossman, M.D. Medicine University of Pennsylvania School of Medicine Edward G. Jones, M.D., Ph.D. University of California, Davis Robert G. Grossman, M.D. The Methodist Hospital Robert J. Joynt, M.D., Ph.D. University of Rochester Robert J. Gumnit, M.D. MINCEP Epilepsy Care Lewis L. Judd, M.D. University of California, San Diego James F. Gusella, Ph.D. School of Medicine Massachusetts General Hospital Jerome Kagan, Ph.D. Zach W. Hall, Ph.D. Harvard University California Institute for Regenerative Medicine Ned H. Kalin, M.D. University of Wisconsin School of Mary E. Hatten, Ph.D. Medicine The Rockefeller University Eric R. Kandel, M.D. Stephen L. Hauser, M.D. Columbia University College of University of California, San Francisco Physicians and Surgeons

121 Stanley B. Kater, Ph.D. Rodolfo R. Llinas, M.D., Ph.D. University of Utah New York University School of Lawrence C. Katz, Ph.D. Medicine Duke University Medical Center Don M. Long, M.D., Ph.D. Robert Katzman, M.D. Johns Hopkins Hospital University of California, San Diego Peter R. MacLeish, Ph.D. School of Medicine Morehouse School of Medicine Claudia H. Kawas, M.D. Bertha K. Madras, Ph.D. University of California, Irvine Harvard Medical School Zaven S. Khachaturian, Ph.D. Robert C. Malenka, M.D., Ph.D. The Ronald and Nancy Reagan Stanford University Medical Center Research Institute William R. Markesbery, M.D. Masakazu Konishi, Ph.D. University of Kentucky California Institute of Technology Joseph B. Martin, M.D., Ph.D. Michael J. Kuhar, Ph.D. Harvard Medical School Yerkes National Primate Research Robert L. Martuza, M.D. Center of Emory University Massachusetts General Hospital Patricia K. Kuhl, Ph.D. Richard Mayeux, M.D., M.Sc. University of Washington Columbia University Medical Center Anand Kumar, M.D. Bruce S. McEwen, Ph.D. University of California, Los Angeles The Rockefeller University David J. Kupfer, M.D. James L. McGaugh, Ph.D. University of Pittsburgh School of University of California, Irvine Medicine Guy M. McKhann, M.D. Story C. Landis, Ph.D. Johns Hopkins University National Institute of Neurological Disorders and Stroke Lorne M. Mendell, Ph.D. SUNY at Stony Brook Lynn T. Landmesser, Ph.D. Case Western Reserve University Marek-Marsel Mesulam, M.D. Northwestern University Feinberg Anthony E. Lang, M.D., FRCPC School of Medicine University of Toronto Bradie Metheny Joseph E. LeDoux, Ph.D. Research Policy Alert New York University Brenda A. Milner, ScD Alan I. Leshner, Ph.D. McGill University American Association for the Advancement of Science William C. Mobley, M.D., Ph.D. Stanford University Allan Levey, M.D., Ph.D. Emory University Richard C. Mohs, Ph.D. Lilly Research Laboratories Irwin B. Levitan, Ph.D. University of Pennsylvania School of John H. Morrison, Ph.D. Medicine Mount Sinai School of Medicine Pat R. Levitt, Ph.D. Vernon B. Mountcastle, M.D. Vanderbilt University Johns Hopkins University Lee E. Limbird, Ph.D. Lennart Mucke, M.D. Meharry Medical College University of California, San Francisco Margaret S. Livingstone, Ph.D. Richard A. Murphy, Ph.D. Harvard Medical School The Salk Institute for Biological Studies

122 Lynn Nadel, Ph.D. Stanley B. Prusiner, M.D. University of Arizona University of California, San Francisco Karin B. Nelson, M.D. Dominick P. Purpura, M.D. National Institute of Neurological Albert Einstein College of Medicine Disorders and Stroke Dale Purves, M.D. Eric Nestler, M.D., Ph.D. Duke University Medical Center University of Texas Southwestern Remi Quirion, Ph.D., FRSC, CQ Medical Center at Dallas CIHR Institute of Neurosciences, Charles P. O’Brien, M.D., Ph.D. Mental Health, and Addiction University of Pennsylvania Marcus E. Raichle, M.D. Edward H. Oldfield, M.D. Washington University School of National Institute of Neurological Medicine Disorders and Stroke Pasko Rakic, M.D., Ph.D. John W. Olney, M.D. Yale University School of Medicine Washington University School of Judith L. Rapoport, M.D. Medicine National Institute of Mental Health Luis F. Parada, Ph.D. Allan L. Reiss, M.D University of Texas Southwestern Stanford University School of Medicine Medical Center at Dallas Richard M. Restak, M.D. Herbert Pardes, M.D. Neurology Associates New York-Presbyterian Hospital James T. Robertson, M.D. Steven M. Paul, M.D. University of Tennessee, Memphis Lilly Research Laboratories Robert G. Robinson, M.D. Audrey S. Penn, M.D. University of Iowa College of Medicine National Institute of Neurological Disorders and Stroke Robert M. Rose, M.D. University of Texas Medical Branch Edward R. Perl, M.D., M.S. University of North Carolina at Chapel Roger N. Rosenberg, M.D. Hill University of Texas Southwestern Medical Center at Dallas Michael E. Phelps, Ph.D. David Geffen School of Medicine at Allen D. Roses, M.D. UCLA GlaxoSmithKline Jonathan H. Pincus, M.D. Edward F. Rover, President Georgetown University Medical Center The Dana Foundation Fred Plum, M.D. Lewis P. Rowland, M.D. Weill Medical College of Cornell Columbia University Medical Center University Gerald M. Rubin, Ph.D. Jerome B. Posner, M.D. University of California, Berkeley Memorial Sloan-Kettering Cancer Stephen J. Ryan, M.D. Center Doheny Eye Institute Michael I. Posner, M.S., Ph.D. Murray B. Sachs, Ph.D. University of Oregon Johns Hopkins University School of Robert M. Post, M.D. Medicine National Institute of Mental Health William Safire, Chairman Donald L. Price, M.D. The Dana Foundation Johns Hopkins University School of Martin A. Samuels, M.D., FAAN, MACP Medicine Brigham and Women’s Hospital

123 Joshua R. Sanes, Ph.D. Larry Swanson, Ph.D. Harvard University University of Southern California Clifford B. Saper, M.D., Ph.D. Paula Tallal, Ph.D. Harvard Medical School Rutgers University at Newark Daniel L. Schacter, Ph.D. Carol A. Tamminga, M.D. Harvard University University of Texas Southwestern John L. Schwartz, M.D. Medical Center at Dallas Psychiatric Times and Geriatric Times Robert D. Terry, M.D. (retired) Philip Seeman, M.D., Ph.D. University of California, San Diego University of Toronto Hans F. Thoenen, M.D. Terrence J. Sejnowski, Ph.D. Max Planck Institute for Psychiatry The Salk Institute for Biological Studies Allan J. Tobin, Ph.D. Dennis J. Selkoe, M.D. MRSSI: Advisor to High Q and CHDI Inc. Brigham and Women’s Hospital James F. Toole, M.D. Carla J. Shatz, Ph.D. Wake Forest University School of Harvard Medical School Medicine Bennett A. Shaywitz, M.D. Daniel C. Tosteson, M.D. Yale University School of Medicine Harvard Medical School Sally E. Shaywitz, M.D. John Q. Trojanowski, M.D., Ph.D. Yale University School of Medicine University of Pennsylvania School of Medicine Gordon M. Shepherd, M.D., D.Phil Yale Medical School Richard W. Tsien, Ph.D. Stanford University School of Medicine Eric M. Shooter, Ph.D., ScD Stanford University School of Medicine Leslie Ungerleider, Ph.D. National Institute of Mental Health Ira Shoulson, M.D. University of Rochester David C. Van Essen, Ph.D. Washington University School of Donald H. Silberberg, M.D. Medicine University of Pennsylvania Medical Center Nora D. Volkow, M.D. National Institute on Drug Abuse Sangram S. Sisodia, Ph.D. University of Chicago Christopher A. Walsh, M.D., Ph.D. Beth Israel Deaconess Medical Center Solomon H. Snyder, M.D. Johns Hopkins University School of James D. Watson, Ph.D. Medicine Cold Spring Harbor Laboratory Larry R. Squire, Ph.D. Stanley J. Watson, M.D., Ph.D. University of California, San Diego University of Michigan Peter H. St. George-Hyslop, M.D. Stephen G. Waxman, M.D., Ph.D. University of Toronto Yale University School of Medicine Charles F. Stevens, M.D., Ph.D. Lynn Wecker, Ph.D. The Salk Institute for Biological Studies University of South Florida College of Medicine Oswald Steward, Ph.D. University of California, Irvine College Myrna M. Weissman, Ph.D. of Medicine Columbia University College of Physicians and Surgeons Thomas C. Südhof, M.D. University of Texas Southwestern Gary Westbrook, M.D. Medical Center at Dallas Oregon Health and Science University

124 Nancy S. Wexler, Ph.D. Columbia University College of Physicians and Surgeons Jack P. Whisnant, M.D. Mayo Clinic Peter C. Whybrow, M.D. University of California, Los Angeles Torsten N. Wiesel, M.D. The Rockefeller University Sandra F. Witelson, Ph.D., FRSC McMaster University Jan A. Witkowski, Ph.D. Cold Spring Harbor Laboratory C.C. Wood, Ph.D. Los Alamos National Laboratory Robert H. Wurtz, Ph.D. National Eye Institute Anne B. Young, M.D., Ph.D. Massachusetts General Hospital Wise Young, M.D., Ph.D. Rutgers State University of New Jersey Nicholas T. Zervas, M.D. Massachusetts General Hospital Earl A. Zimmerman, M.D. Albany Medical College

As of December 2005

125 INDEX B Bart, Gavin, on 118G allele and alcohol dependence, 69 A Bass, Joseph, on “clock” gene mutations and AD. See Alzheimer’s disease obesity, 73 addictive disorders, 68–70 Becher, Burkhard, on perivascular dendritic age-related macular degeneration (AMD), 76–77 cells in treating MS, 51 aging brain, the, 11–15 beta-amyloid protein Albert, Marilyn, on the aging brain, 11–15 and Alzheimer’s disease, 88–89, 90–91 alleles antibodies to, 53 and addictive disorders, 69 Biederman, Joseph, on ADHD and sex of child, and MDD research, 66–67 18–19 and schizophrenia research, 64–66 Biogen Idec alpha-synuclein protein Nogo receptor complex, 37 buildup of, 28–29 SCI treatment with methylprednisolone and immunization therapy for reducing, 53 a Nogo blocker, 36 and parkin protein, 26–28, 30 biological disorders Alvarez-Buylla, Arturo, on pax6 in development macular degeneration, age-related, 76–77 of dopamine-producing cells, 83–84 and orexin, 74–76 Alzheimer’s disease (AD) overview, 73 high folic acid intake reduces risk of sense of smell, 77–78 developing, 89 sleep, appetite, and obesity, 73–74 immunotherapy for treating, 52–53 bloodborne inflammatory cells, replacing with using antibodies against beta-amyloid, adult neural stem cells, 51–52 88–89 Bradley, Jonathan, on smell differentiation, 78 vaccine therapy for, 90–92 brain-derived neurotrophic factor (BDNF), American Academy of Pediatrics, on ADHD 14–15 treatment, 21 brain function, 8–10 American Society for Bioethics and Humanities, 42 brain-machine interfaces, 40 amygdala brain mechanisms associated with memory hyperactivity and depression risk, 67 changes and aging, 12–13, 14–15 and left orbitofrontal cortex in memory brain organization, 3, 6, 9 recall, 93 brain serotonin and depression risk, 67–68 pathways and other parts of the brain and, 92 brain tumors, 34, 38–39, 83 anterior cingulate cortex (ACC) and depression Brodman, Korbinian, on complex mental risk, 67 activity, 7 antigen-presenting cells, 51 broken cord repairs, 34–36 apoptosis from stem cells, 83 appetite disorders, 73–74 C Aston-Jones, Gary, on orexin’s influence on Calabresi, Peter, on Kv1.3 molecule and treat- reward and motivation, 74–75 ment for MS, 50–51 astroglia in brains of patients with autism, 54 cancer-fighting properties of neurogenesis, 83 atomoxetine for ADHD, 21 cancer of the brain, 34, 38–39, 83 attention-deficit hyperactivity disorder cannabinoid CB receptor and alcohol (ADHD), 18–21 1 addiction, 69–70 autism, 1, 22–24, 54 cannabinoid CB receptor and pain sensitivity, autistic regression, evidence of, 24 2 58–59 axons and nerve degeneration and regeneration cannabis-gene interaction, 65 in SCI, 34–36 Carbon-14 dating to determine age of cells, 80–81 cardiovascular system and changes in memory, 15

126 Carlsson, Thomas, on gene therapy with developmental neurobiology, 9 levodopa for PD, 30 Diatchenko, Luda, on TMJ development and Caron, Marc, on tryptophan hydroxylase-2 and pain sensitivity, 60–61 depression risk, 67–68 diet and dementia, 89–90 catecholamine-O-methyltransferase (COMT) Dodel, Richard, on intravenous immunoglobulins enzyme for treatment of AD, 91 and pain sensitivity, 60–61 dopamine and neurogenesis, 82–83 and schizophrenia, 64–66 dopamine D1 receptors and addiction, 70 CB2 cannabinoid receptor activation to eliminate dopamine’s affect on neuronal activity, 65–66 pain, 58–59 dyskinesia side effect of levodopa, 29 central nervous system (CNS), 50, 51–52 dyslexia, 21–22 childhood disorders ADHD, 18–21 E autism, 22–24 eating habits, “clock” gene and, 73 dyslexia, 21–22 Edwards, Phil, on dangers of treating TBI with overview, 18 corticosteroids, 39 Children’s Hospital Boston, on Nogo receptor electrical stimulation of PSC for antidepressant complex, 37 non-responsive patients, 68 chronic temporomandibular joint disorder embryonic stem cells, 84–85 (TMJ) and pain sensitivity, 60–61 emotion and memory, 92–93 Clinton, Gail, on herstatin for blocking growth energy cost of human brain, 9–10

of glioblastoma, 39 environmental influences 2006 Report cognitive ability of the brain, 11, 90–91 and memory function, 13–15 cognitive neuroscience, 6, 8–9 and post-stroke neurogenesis, 85–86 cognitive strategies for encoding, rehearsing, and psychosis, 65 and thinking about emotionally relevant Ephrin-B3 for nervous system injuries, 37 memories, 94 episodic memory tests, 11–12 complement factor H protein, 77 Eslamboli, Andisheh, on PD and dopamine-pro- “Convergence of Neuroscience, Behavioral ducing nerve cells, 30 Science, Neurology and Psychiatry” Ethical Brain, The (Gazzaniga), 43 conference, 71 executive functions in ADHD children, 20 Corrada, Maria, folic acid intake and AD, 89 exercise and memory retention, 14 corticosteroids contraindicated in TBI, 39 Cox-1 and Cox-2 forms of cyclo-oxygenase F enzyme, 59–60 Filbin, Mary, on Nogo receptor pathway, 37 Cummings, Brian, on adult neural stem cells for Fins, Joseph J., on severe brain injury and nature SCI, 38 of consciousness, 46–47 cyclo-oxygenase enzyme and NSAIDs, 59–60 fMRI. See functional magnetic resonance imaging folic acid intake and AD, 89 Index D Foster, Kenneth, on brain imaging as mental dardarin protein, 27 polygraph, 48 Dawson, Geraldine, on autistic regression, 24 Freedman, Sharon, on MT360, 76–77 de Vries, Taco, on cannabinoid CB1 receptor and Frisen, Jonas, on Carbon-14 dating to determine addiction process, 69–70 age of cells, 80–81 death, causes of, 1 functional magnetic resonance imaging (fMRI) deep brain stimulation (DBS) for movement averaging data from, 8–9 disorders, 30–31, 44 of brain activation in patients in a minimally dementia and diet, 89–90 conscious state, 46 depression and MDD, 66–68 of brain areas during memory tasks, 13 “Detection and Disclosure of Incidental Findings overview, 6–8, 10 in Neuroimaging Research” conference, 47

127 for study of neural pathways and memory “Hard Science, Hard Choices” conference, recall, 93–94 43–45 Harper, Scott Q., on RNA interference for HD, G 32 G2019S gene mutation, 27 Harris, Glenda, on orexin’s influence on reward gabapentin and morphine for treating neuro- and motivation, 74–75 pathic pain, 57–58 Hartman, Richard, on immunotherapy for AD, Gage, Fred, on retrotransposons and neural stem 52–53 cells, 81–82 hematopoietic stem cell transplantation (HSCT) Garbutt, James, on naltrexone and alcohol as MS treatment, 52 dependence, 69 Hen, Rene, on serotonin transporters, 66–67 Gazzaniga, Michael S., 43 herstatin for blocking growth of glioblastoma, 39 genetic predispositions hippocampus addictive disorders, 68–70 exercise and, 14 depression, 66–67 neurogenesis in, 86 macular degeneration, 77 and recall of emotional items, 93 memory function changes over time, 13 Hirsch, Joy, on brain activation in patients in a Parkinson’s disease, 26–28 minimally conscious state, 46 genetic therapy Hoh, Josephine, on complement factor H genes, and COMT enzyme, 60–61, 64–66 77 junk DNA and stem cells, 81–82 Human Genome Project, 2 for movement disorders, 30 human herpes virus (HHV-6) involvement in p53 regulatory gene for movement disorders, myelin damage in MS, 55 32 huntingtin protein, 32 for pain sensitivity, 60–61 Huntington’s disease, 31–32 pax6 for development of dopamine- hydrocodone with ibuprofen for treating pain, producing cells, 83–84 59–60 retrotransposons and neural stem cells, hypocretin (orexin) and biological disorders, 81–82 74–76 for schizophrenia, 64–66 ghrelin, irregular sleep and eating patterns and, I 73–74 Illes, Judy Gilron, Ian, on drug combination for treating as editor of Neuroethics, 42–43 neuropathic pain, 57–58 ethical dilemmas of neuroimaging, 48 glia and neuroimmune action in the development immune system T cells and Kv1.3 potassium of autism, 54 channel, 50–51 glial cell tumors, 38–39 immunotherapy for neurological disorders, glial-line derived neurotrophic factor (GDNF) 52–54 and movement disorders, 29–30 individual differences in brain function, 8–9 glioblastoma, herstatin for preventing, 39 inflammatory cells, replacing with adult neural Glioma Outcomes Project, on treatment of glial stem cells, 51–52 cell tumor patients, 38 Insel, Thomas R., on progress in brain research, globus pallidus interna (GPi) and DBS electrodes, 1–4 31 intermittent periods of consciousness, definition glomus cells within the carotid body, 30 of, 46 glutamate and compulsive addictions, 70 IVIg (intravenous immunoglobulins), 90–92

H J haloperidol for blocking dopamine receptors in James, William, 5, 10 neural stem cell development, 81–82 Johann Wolfgang Goethe University (Frankfurt, HapMap project, 2 Germany), on right-hemispheric strokes, 38

128 Jones, Barbara, on activity of orexin neurons, major depressive disorder (MDD), 66 75–76 Martino, Gianvito junk DNA and stem cells, 81–82 neural stem cells repair myelin, 51 stem cells protect CNS from chronic damage, K 51–52 Kalivas, Peter, on neural circuits involved in Masliah, Eliezer, on immunization therapy for addiction, 70 PD, 53 Katz, Lawrence, on smell differentiation, 78 Mayberg, Helen, on electrical stimulation of PSC Kennedy, Peter G., on involvement of viruses in for treatment of antidepressant-unresponsive development of MS, 55 patients, 68 Kensinger, Elizabeth, on amygdala and left McCrory, Eamon J., on patterns of brain orbitofrontal cortex in memory recall, 93 activation in children with dyslexia, 22 Kerschensteiner, Martin, on nerve degeneration McKhann, Guy, on the aging brain, 11–15 and regeneration in SCI, 34 Meissner, Alexander, on Cdx2 gene alteration of Kettenmann, Helmut, on neurogenesis response blastocytes, 85 to brain tumors, 83 Memorial Sloan-Kettering Cancer Center, on Kierstead, Hans, on oligodendrocytes developed combining NSAIDs with narcotics for from embryonic stem cells for SCI, 37 treating pain, 59–60 Kippin, Tod, on dopamine and neurogenesis, memory 81–82 age-related changes, 11–12 Koyama, Yoshimasa, on orexin and motor brain mechanisms associated with changes

function regulation, 76 in, 12–13, 14–15 2006 Report Kv1.3 molecule and treatment for MS, 50–51 emotion and, 92–93 genetic and environmental influences, 13–15 L identifying sites of memory recall, 93–95 LaFerla, Frank, on treating AD with beta-amy- and neurogenesis, 86 loid antibodies, 88–89 mental faculties, complexity of, 7 Langleben, Daniel, on brain imaging as mental mental faculties, neuroethics of enhancing with polygraph, 48 drug therapy, 44–45 Lanza, Robert, on creating embryonic stem cells mental health research without compromising the embryo, 84–85 addictive disorders, 68–70 leptin and irregular sleep and eating patterns, depression, 66–68 73–74 overview, 64, 71 leucine-rich repeat kinase 2 (LRRK2) gene and schizophrenia, 64–66 Parkinson’s disease, 26–28 thinking disorders, 88–92 levodopa for treating PD, 29, 30 meta-analysis, 18 Levy, Florence, on ADHD and sex of child, methionine (Met) amino acid, 64 19–20 Meyer-Lindenberg, Andreas, on dopamine’s Lewy bodies and Parkinson’s disease, 26, 27 affect on neuronal activity, 65–66 Index Liu, Chang-Wei, on alpha-synuclein aggregation, microglia in brains of patients with autism, 54 27 Mignot, Emmanuel, on body mass index and Llinas, Rodolfo, on brain function, 10 quantity of sleep, 73–74 mind and brain science, defining, 5 M Moe, Morten, on neural stem cell maturation, 80 Machemer, Robert, inventor of macular Moffitt, Terrie, on individuals’ increased risk of translation, 76 temporary disorder resembling schizophrenia, macular degeneration, age-related, 76–77 64–65 macular translation with 360-degree peripheral morphine and gabapentin for treating neuro- retinectomy (MT360), 76–77 pathic pain, 57–58 MAG (myelin-based inhibitor), 36 movement and related disorders magnetic resonance imaging, 5–6 alpha-synuclein buildup, 28–29

129 DBS for, 30–31 and neurotechnology, 44 GDNF, 29–30 overview, 3, 42 gene mutations, 26–28 and psychopharmacology, 44–45 gene therapy for, 30 publication of materials about, 42–43 Huntington’s disease, 31–32 Schiavo case, 45–47 overview, 26 science, religion, and, 45 multiple sclerosis (MS), 50–52 stem cell lines and, 84–85 multiple system atrophy (MSA), 27–28 Neuroethics (Illes, ed.), 42–43 mu-opiod receptor (MOR) and addictive neurogenesis disorders, 68–69 cancer-fighting properties of, 83 myelin and dopamine, 82–83 destruction of, in MS patients, 50 and memory, 86 HHV-6 involvement in myelin damage in overview, 80 MS, 55 post-stroke, 85–86 inhibitors for nervous system injuries, 36–37 See also stem cell research and nerve degeneration and regeneration in neuroimaging SCI, 34–36 ethical challenges of, 43–44, 47–48 neural stem cell repair of, 51 overview, 2–3, 5, 8–10 and perivascular dendritic cells in treating PET and MRI, 5–6 MS, 51 See also functional magnetic resonance and potassium channel Kv1.3 for treating imaging MS, 50–51 neuroimmunological research glia and neuroimmune action in the N development of autism, 54 naltrexone (MOR blocker) and alcohol immunotherapy for neurological disorders, dependence, 69 52–54 narcotics with NSAIDs for treating pain, 59–60 multiple sclerosis treatments, 50–52 National Institutes of Health (NIH) overview, 50 Neuroscience Blueprint, 4 viruses and, 55 spending on pain research, 61–62 neuron and synapse loss in AD patients, 91–92 nerve degeneration and regeneration in SCI, 34 neuron creation with haloperidol, 81–82 nerve growth inhibition, 36–37 neuron creation with retrotransposons, 81–82 nervous system injuries neurons, beta-amyloid protein inside and AD, from brain tumors, 38–39 88–89 broken cord repairs, 34–36 neuropathic pain, drug combination for treating, and Ephrin-B3, 37 57–58 and myelin-based inhibitors, 36–37 Neuroscience Blueprint, 4 neural prosthetics for post-injury recovery, neurotechnology, neuroethics and, 44 39–40 Nicolelis, Miguel, on neural prosthetics for post- overview, 34 TBI recovery, 40 and stem cells, 37–38 NIH Roadmap, 4 from strokes, 38 NKCC1 transporter and odor-sensing cells, 78 traumatic brain injuries and steroid use, 39 Nogo blocker, 36 nervous system injuries and stem cells, 37–38 NSAIDs (nonsteroidal anti-inflammatory drugs) neural circuits involved in addiction, 70 with narcotics for treating pain, 59–60 neural pathways and memory recall, 93–94 nuclear fallout dates stem cells, 80–81 neural prosthetics for post-injury nervous system nucleus accumbens (NA) and prefrontal cortex recovery, 39–40 circuit, 70 neural stem cells for treating MS, 51 nucleus basalis, 12–13 neuroethics and neuroimaging, 43–44, 47–48

130 O R obesity disorders, 73–74 Racine, Eric, on ethical dilemmas of neuroimaging, odor-sensing cells and NKCC1 transporter, 78 48 oligodendrocytes Raichle, Marcus, on neuroimaging, 5–10 alpha-synuclein aggregates in, 28, 29 Rea, Thomas, on impact of statin use on AD for myelin restoration in SCI, 37, 38 risk, 89–90 OMG (myelin-based inhibitor), 36 referral bias and ADHD, 19 orexin (hypocretin) and biological disorders, regulatory T cells and virus-encoded proteins, 55 74–76 religion, science, and neuroethics, 45 “Our Brains and Us” conference, 45 Relkin, Norm, on intravenous immunoglobulins oxycodone with ibuprofen for treating pain, for treatment of AD, 90–91 59–60 research-imaging centers, 6 retrotransposons and neural stem cells, 81–82 P rimonabant for addictive cravings, 69–70 p53 regulatory gene, 32 RNA interference for HD, 32 pain rostral migratory stream, 84 genetic base for pain perception, 60–61 rostral subgenual portion of anterior cingulate identifying underfunded areas, 61–62 cortex (rACC) and depression risk, 67 neuropathic, 57–58 Rubia, Katya, on patterns of brain activation, overview, 57 20–21 severe pain, treatments for, 59–60

suppressing pain outside the brain, 58–59 S 2006 Report Pain and Related Conditions Database (PRCD), Schiavo case, neuroethics and, 45–47 62 schizophrenia, 64–66 Parada, Luis, on Ephrin-B3 inhibition of nerve Schoffelmeer, Anton, on cannabinoid CB1 fiber outgrowth in myelin, 37 receptor and addiction process, 69–70 Pardo, Carlos A., on neuroimmune action and Schwartz, Andrew, on robotic prostheses, 40 glia in the development of autism, 54 science, religion, and neuroethics, 45 Parkinson’s disease (PD), 26–28, 29, 30, 84 Seamans, James, on neural circuits involved in pax6 gene and stem cell research, 83–84 addiction, 70 Pearse, Damien, on nerve degeneration and sense of smell, 77–78 regeneration in SCI, 35 serotonin neurotransmission and depression, perception of pleasure, orexin and, 75–76 66–67 perivascular dendritic cells in treating MS, 51 severe pain, treatments for, 59–60 persistent vegetative state, definition of, 46 Shaw, Philip, on reinforcement pathways personality, neuroimaging as window into between amygdala and other parts of the aspects of, 48 brain, 92 phrenology and fMRI compared, 7 Siegel, Jerry, on activity of orexin neurons, 75–76 Piefke, Martina, on recall of emotional autobio- sleep disorders, 73–74 Index graphical events in men and women, 94–95 smell, sense of, 77–78 pleasure, orexin and perception of, 75–76 social stimulation and cognition maintenance, 15 positron emission tomography (PET), 5–6, 27 Society for Neuroscience, 42 posterior subcallosal cortex (PSC), electrical Sperling, Anne J., on dyslexia as inability to dis- stimulation for treatment of antidepressant- criminate visual cues from noise, 22 unresponsive patients, 68 spinal cord injury (SCI), 34–36 potassium channel Kv1.3 and MS, 50–51 statin use for AD risk, 89–90 potentiation, memory and decline in, 13 statistics on causes of death, 1 prefrontal cortex (PFC), 65–66, 70 stem cell research Principles of Psychology, The (James), 5 creating embryonic stem cells without com- psychopharmacology, neuroethics and, 44–45 promising the embryo, 84–85 developmental benchmarks, 80

131 embryonic stem cells, 84–85 University of Arizona, on activation of CB2 hematopoietic stem cell transplantation, 52 receptor to eliminate pain, 58–59 and junk DNA, 81–82 University of Utah on NIH funding of pain neural stem cells for repairing myelin, 51 research, 61–62 nuclear fallout and, 80–81 and pax6 gene, 83–84 V progress in the past, 3 vaccine therapy for AD patients, 90–92 protecting CNS from chronic damage, valine (Val) amino acid, 64 51–52 Villadiego, Javier, on GDNF production in and SCI, 37–38 receptor cells in the carotid body, 29–30 SCI treatments with glial-restricted pre- viruses and neuroimmunological disorders, 55 cursor cells, 35–36 Volkow, Nora, on neural circuits involved in See also neurogenesis addiction, 70 steroids contraindicated in TBI, 39 stimulant drug treatment for ADHD, 21 W Strittmatter, Steven, on Nogo receptors, 37 Weinberger, Daniel, on depression from effect strokes, nervous system injuries from, 38 of s allele, 67 strokes, neurogenesis after, 85–86 Weisman, Myrna, on gene transmission of subcortical nuclei, 12–13 MDD, 66 subthalamic nucleus (STN) and DBS Weksler, Marc, on intravenous immunoglobu- electrodes, 31 lins for treatment of AD, 90–91 sulfasalazine for gliomas, 39 Werner, Emily, on autistic regression, 24 synapse and neuron loss in AD patients, 91–92 Whittemore, Scott, on combining stem cells with gene therapy for SCI treatment, 35–36 T Wojtowicz, Martin, on neurogenesis and Tabar, Viviane, on transplanted embryonic memory retention, 86 stem cell development, 84 Wolpe, Paul Root, on brain imaging as mental TAJ protein in Nogo receptor complex, 37 polygraph, 48 T cells and Kv1.3 potassium channel, 50–51 Women’s Health Study, on vitamin E and T cells and virus-encoded proteins, 55 strokes, 38 temporomandibular joint disorder (TMJ) and pain sensitivity, 60–61 Y Tessier-Lavigne, Marc, on genetic deletion of Yamada, Masanori, on gene therapy for Nogo receptors, 36 Parkinson’s disease, 30 thinking disorders Yamano, Yoshihisa, on virus-encoded protein AD, 88–89, 90–92 inducing dysfunction of regulatory diet and dementia, 89–90 T cells, 55 Toth, Cynthia, on MT360, 76–77 Yazawa, Ikuru, on MSA, 28 traumatic brain injury (TBI), 34, 39 Yonelinas, Andrew, on neural pathways and tricyclics for ADHD, 21 memory recall, 93–94 trophic factors, exercise and, 14 TROY protein in Nogo receptor complex, 37 Z Turek, Fred, on “clock” gene mutations and Zwaigenbaum, Lonnie, on signs of autism in obesity, 73 babies and infants, 23–24 Tuszynski, Mark, on increasing neural growth to slow the progression of AD, 91–92

U University Hospital (Lund, Sweden), on post- stroke neurogenesis, 85 University of Alabama at Birmingham, on sulfasalazine for gliomas, 39

132 OTHER DANA PRESS BOOKS AND PERIODICALS THE CREATING BRAIN The Neuroscience of Genius Nancy C. Andreasen, M.D., Ph.D. Andreasen, a renowned psychiatrist and bestselling author, explores how the brain achieves creative breakthroughs—in art, literature, science, and business—including such questions as how creative people are different and the difference between genius and intelligence. A unique appreciation of the arts that awe us together with an inspiring vision of how each of us can nurture and develop our creative capacity. 33 illustrations/photos. 225 pp. 1-932594-07-8 $23.95

THE ETHICAL BRAIN Michael Gazzaniga, Ph.D. Explores how the lessons of neuroscience can help us resolve today’s ethical dilemmas, ranging from when life begins to “off-label” use of drugs such as Ritalin by students preparing for exams, and other topics, from free will and personal responsibility to public policy and religious belief. The author, a pioneer in cognitive neuroscience, is a member of the President’s Council on Bioethics. 225 pp. 1-932594-01-9 $25.00

FATAL SEQUENCE The Killer Within Kevin J. Tracey, M.D. An easily understandable account of the body’s ability to go into the fatal spiral of sepsis, a crisis that most often affects patients fighting off nonfatal illness or injury. Tracey puts the scientific and medical story of sepsis in the context of his battle to save a burned baby, a sensitive telling that renders cutting-edge science human and unforgettable. 225 pp. 1-932594-06-X $23.95

A WELL-TEMPERED MIND Using Music to Help Children Listen and Learn Peter Perret and Janet Fox. Foreword by Maya Angelou Five musicians enter elementary school classrooms, helping children learn about music and contributing both to higher enthusiasm and improved academic performance. This charming story gives us a taste of things to come in one of the newest areas of brain research: the effect of music on the brain. 12 illustrations. 225 pp. 1-932594-03-5 $22.95

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134 A GOOD START IN LIFE Understanding Your Child’s Brain and Behavior from Birth to Age 6 Norbert Herschkowitz, M.D., and Elinore Chapman Herschkowitz Updated with the latest information and new material, the authors show us how young children learn to live together in family and society and explain how brain development shapes a child’s personality and behavior, discussing appropriate rule-setting, the child’s moral sense, temperament, language, playing, aggression, impulse control, and empathy. Cloth, 283 pp. 0-309-07639-0 $22.95 (Updated version with 13 illustrations) Paper, 312 pp. 0-9723830-5-0 $13.95

NEUROSCIENCE AND THE LAW Brain, Mind, and the Scales of Justice Brent Garland, Editor. Foreword by Mark S. Frankel. With commissioned papers by Michael S. Gazzaniga, Ph.D., and Megan S. Steven; Laurence R. Tancredi, M.D., J.D.; Henry T. Greely, J.D.; and Stephen J. Morse, J.D., Ph.D. How discoveries in neuroscience influence criminal and civil justice, based on an invitational meeting of 26 top neuroscientists, legal scholars, attorneys, and state and federal judges convened by the Dana Foundation and the American Association for the Advancement of Science. 226 pp. 1-932594-04-3 $8.95

BEYOND THERAPY Biotechnology and the Pursuit of Happiness. A Report of the President’s Council on Bioethics Special Foreword by Leon R. Kass, M.D., Chairman. Introduction by William Safire Can biotechnology satisfy deep and familiar human desires—for better children, superior performance, ageless bodies, and happy souls? This landmark report says these possibilities present us with profound ethical challenges and choices. 376 pp. 1-932594-05-1 $10.95

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135 NEUROETHICS Mapping the Field. Conference Proceedings. Steven J. Marcus, Editor Proceedings of the landmark 2002 conference organized by Stanford University and the University of California, San Francisco, at which more than 150 neuroscientists, bioethicists, psychiatrists and psychologists, philosophers, and professors of law and public policy debated the implications of neuroscience research findings for individual and societal decision-making. 50 illustrations. 367 pp. 0-9723830-0-X $10.95

BACK FROM THE BRINK How Crises Spur Doctors to New Discoveries about the Brain Edward J. Sylvester Goes into two academic medical centers, Columbia’s New York Presbyterian and Johns Hopkins Medical Institutions, to watch a new breed of doctor, the neurointensivist, save patients with life- threatening brain injuries. 16 illustrations/photos. 296 pp. 0-9723830-4-2 $25.00

THE BARD ON THE BRAIN Understanding the Mind Through the Art of Shakespeare and the Science of Brain Imaging Paul Matthews, M.D., and Jeffrey McQuain, Ph.D. Foreword by Diane Ackerman Explores the beauty and mystery of the human mind and the workings of the brain, following the path the Bard pointed out in 35 of the most famous speeches from his plays. 100 illustrations. 248 pp. 0-9723830-2-6 $35.00

STRIKING BACK AT STROKE A Doctor-Patient Journal Cleo Hutton and Louis R. Caplan, M.D. A personal account with medical guidance for anyone enduring the changes that a stroke can bring to a life, a family, and a sense of self. 15 illustrations. 240 pp. 0-9723830-1-8 $27.00

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136 THE DANA GUIDE TO BRAIN HEALTH Floyd E. Bloom, M.D., M. Flint Beal, M.D., and David J. Kupfer, M.D., Editors. Foreword by William Safire A home reference on the brain edited by three leading experts collaborating with 104 distinguished scientists and medical professionals. In easy-to-understand language with cross-references and advice on 72 conditions such as autism, Alzheimer’s disease, multiple sclerosis, depression, and Parkinson’s disease. 16 full-color pages and more than 200 black-and-white illustrations. 768 pp. (Published by The Free Press) 0-7432-0397-6 $45.00

UNDERSTANDING DEPRESSION What We Know and What You Can Do About It J. Raymond DePaulo Jr., M.D., and Leslie Alan Horvitz. Foreword by Kay Redfield Jamison, Ph.D. What depression is, who gets it and why, what happens in the brain, troubles that come with the illness, and the treatments that work. (Co-published with John Wiley & Sons, Inc.) Cloth, 304 pp. 0-471-39552-8 $24.95 Paper, 296 pp. 0-471-43030-7 $14.95

KEEP YOUR BRAIN YOUNG The Complete Guide to Physical and Emotional Health and Longevity Guy McKhann, M.D., and Marilyn Albert, Ph.D. Every aspect of aging and the brain: changes in memory, nutrition, mood, sleep, and sex, as well as the later problems in alcohol use, vision, hearing, movement, and balance. (Co-published with John Wiley & Sons, Inc.) Cloth, 304 pp. 0-471-40792-5 $24.95 Paper, 304 pp. 0-471-43028-5 $15.95

THE END OF STRESS AS WE KNOW IT Bruce McEwen, Ph.D., with Elizabeth Norton Lasley. Foreword by Robert Sapolsky How brain and body work under stress and how it is possible to avoid its debilitating effects. (Co-published with Joseph Henry Press) Cloth, 239 pp. 0-309-07640-4 $27.95 Paper, 262 pp. 0-309-09121-7 $19.95

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137 IN SEARCH OF THE LOST CORD Solving the Mystery of Spinal Cord Regeneration Luba Vikhanski The story of the scientists and science involved in the international scientific race to find ways to repair the damaged spinal cord and restore movement. 21 photos; 12 illustrations. 269 pp. (Co-published with Joseph Henry Press) 0-309-07437-1 $27.95

THE SECRET LIFE OF THE BRAIN Richard Restak, M.D. Foreword by David Grubin Companion book to the PBS series of the same name, exploring recent discoveries about the brain from infancy through old age. 201 pp. (Co-published with Joseph Henry Press) 0-309-07435-5 $35.00

THE LONGEVITY STRATEGY How to Live to 100 Using the Brain-Body Connection David Mahoney and Richard Restak, M.D. Foreword by William Safire Advice on the brain and aging well. (Co-published with John Wiley & Sons, Inc.) Cloth, 250 pp. 0-471-24867-3 $22.95 Paper, 272 pp. 0-471-32794-8 $14.95

STATES OF MIND New Discoveries about How Our Brains Make Us Who We Are Roberta Conlan, Editor Adapted from the Dana/Smithsonian Associates lecture series by eight of the country’s top brain scientists, including the 2000 Nobel laureate in medicine, Eric Kandel. (Co-published with John Wiley & Sons, Inc.) Cloth, 214 pp. 0-471-29963-4 $24.95 Paper, 224 pp. 0-471-39973-6 $18.95

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138 FREE EDUCATIONAL BOOKS (order through www.dana.org)

THE DANA SOURCEBOOK OF IMMUNOLOGY Resources for Secondary and Post-Secondary Teachers and Students An introduction to how the immune system protects us, what happens when it breaks down, the diseases that threaten it, and the unique relationship between the immune system and the brain. 5 color photos; 35 black-and-white photos; 11 black-and-white illustrations. 116 pp.

PARTNERING ARTS EDUCATION A Working Model from ArtsConnection This free publication illustrates the importance of classroom teachers and artists learning to form partnerships as they build successful residencies in schools. Partnering Arts Education provides insight and concrete steps in the ArtsConnection model. Information about ordering and a downloadable PDF are available at www.dana.org. 55 pp.

THE DANA SOURCEBOOK OF BRAIN SCIENCE Resources for Secondary and Post-Secondary Teachers and Students A basic introduction to brain science, its history, current understanding of the brain, new developments, and future directions. 16 color photos; 29 black-and-white photos; 26 black-and-white illustrations. 160 pp.

ACTS OF ACHIEVEMENT The Role of Performing Arts Centers in Education Profiles of 60-plus programs, eight extended case studies, from urban and rural communities across the United States, illustrating different approaches to performing arts education programs in school settings. Black-and-white photos throughout. 164 pp.

PLANNING AN ARTS-CENTERED SCHOOL A Handbook A practical guide for those interested in creating, maintaining, or upgrading arts-centered schools. Includes curriculum and development, governance, funding, assessment, and community participa- tion. Black-and-white photos throughout. 164 pp.

139 PERIODICALS

CEREBRUM: The Dana Forum on Brain Science A journal for general readers with feature articles, debates, and book reviews dealing with the latest discoveries about the brain and their implications for individuals and society. Back issues available online. For more information, e-mail [email protected] or see www.dana.org/books/press.

BRAINWORK: The Neuroscience Newsletter A bimonthly, full-color, eight-page newsletter for general readers reporting the latest findings in brain research. Free: order through or download from www.dana.org/books/press

BRAIN IN THE NEWS A monthly, eight-page newspaper reprinting news and feature articles about brain research from leading newspapers and magazines in the United States and abroad during the previous month. Free: by mail only; order through www.dana.org/books/press

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BRAIN CONNECTIONS: Your Source Guide to Information on Brain Disease and Disorders Pocket-size, 48-page booklet listing more than 275 organizations that help people with a brain-related disorder and those responsible for their care and treatment. A publication of the Dana Alliance for Brain Initiatives. Listings include toll-free numbers, Web site and e-mail addresses, and regular mailing addresses. Free: order through or download from www.dana.org/books/press

140 Editor in Chief: Jane Nevins Editor: Dan Gordon

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Cover image: Courtesy of Marcus Raichle, M.D. Pg. 1: Photograph courtesy of Thomas Insel Pg. 5: Photograph courtesy of Marcus Raichle Pg. 11: Photographs courtesy of Marilyn Albert and Guy McKhann Pg. 17: Will & Deni McIntyre / Science Photo Library Pg. 20: Reprinted with permission from the American Journal of Psychiatry, (© 2005). American Psychiatric Association. Pg. 23: Screen captures courtesy of Dr. Geraldine Dawson Pg. 25: © Royalty-Free / Corbis Pg. 28: Diagram courtesy of Dr. Harry Baker Pg. 31: Photograph courtesy of the Cleveland Clinic Pg. 33: John Bavosi / Science Photo Library Pg. 35: Illustration by Benjamin Reece Pg. 40: Photograph by Les Todd Pg. 41: Photograph by Don Carstens / PictureQuest Pg. 49: Brand X Pictures Pg. 53: Martin M. Rotker / Science Photo Library Pg. 54: © 2005 Pardo et al. Reprinted with permission of John Wiley & Sons, Inc. Pg. 56: Romilly Lockyer / Brand X Pictures Pg. 61: Graph courtesy of Luda Diatchenko Pg. 63: BananaStock Pg. 65: Photograh courtesy of Dr. Andreas Meyer-Lindenberg, NIH/NIMH Pg. 67: © 2005, Kathryn Born Pg. 72: Bill Longcore / Science Photo Library Pg. 75: Illustration courtesy of Gary Aston-Jones and Glenda-Harris Pg. 76: Photograph by Les Todd Pg. 79: Bill Longcore / Science Photo Library Pg. 82: Photograph courtesy of Fred Gage, The Salk Institute Pg. 87: Anthony Harvie / Getty Images Pg. 88: Science Photo Library Pg. 94: Photograph courtesy of Martina Piefke

141 The 2006 Progress Report on ADVANCES IN NEUROIMAGING BRAIN RESEARCH

Disorders That Appear in Childhood Movement and Related Disorders Nervous System Injuries Neuroethics Neuroimmunology Pain

Psychiatric, Behavioral, and Addictive Disorders PROGRESS REPORT Sense and Body Function Stem Cells and Neurogenesis Thinking and Remembering

2006 The 2006 Progress Report on BRAIN RESEARCH

www.dana.org Introduction by Thomas R. Insel, M.D. and A Report on THE AGING BRAIN by Marilyn Albert, Ph.D., and Guy McKhann, M.D. AAPRESS DANA

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