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ADVANCES IN NEUROIMAGING

The 2006 Progress Report on


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

The 2006 Progress Report on

2006
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.
DANA PRESS

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 oper-
ations, 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
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A Dana Alliance for Brain Initiatives publication


Produced and distributed by Dana Press
Copyright 2006

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.

2006 Report
Progress in Brain Research in 2005

17 Disorders That Appear in Childhood

25 Movement and Related Disorders

33 Nervous System Injuries

41 Neuroethics

49 Neuroimmunology

56 Pain

63 Psychiatric, Behavioral, and Addictive Disorders Contents

72 Sense and Body Function

79 Stem Cells and Neurogenesis

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

W
inston Churchill is usually
considered the source of the
aphorism that we make a liv-
ing from what we get and we make a life

2006 Report
from what we give. Whoever is the source, the sentiment is as rele-
vant 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
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, Introduction
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
to outnumber homicides by almost two to one. The aging of our
population makes Alzheimer’s and other neurodegenerative dis-
eases 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 tech-
nologies with which to address these urgent public health chal-
lenges. 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 associ-
ated 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 individ-
ual 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 neu-
roimaging, 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.

2006 Report
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
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 Introduction
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
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 read-
ing,” and genomic assessment of disease risk is largely statistical),
neuroscientists are increasingly thinking into the future to con-
sider 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 pro-
grams on the neurobiology of disease, expanded collaborative
efforts in neurogenomics and pediatric neuroimaging, and creat-
ed a forum for all NIH institutes with an interest in neuroscience
to work together. Projects in the next year include the develop-
ment of transgenic mouse lines for neuroscience, training pro-
grams in neuroimaging, and the development of multi-institute
core resources for scientists at universities.
The 1990s were labeled the “Decade of the Brain.” The cur-
rent decade may, in retrospect, appear to be the “Decade of
Discovery,” with most of the major genes and proteins and path-
ways 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 intrica-
cies of the body’s most complex organ. Increasingly, the discov-
eries 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.

B
ridging the gap between descrip-
tions of human behaviors and
underlying neural events has
been a dream of both psychologists and
neuroscientists for quite some time.
William James, in his monumental, two-volume work The

2006 Report
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
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 opportuni-
ty 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
Neuroimaging
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, particular-
ly positron emission tomography (PET) and magnetic resonance
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 neu-
roscience, 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 labo-
ratory 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 rela-
tionship 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 neu-
roimaging 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 neurobi-
ology 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 opportu-
nity not only to make direct comparisons between neurophysiol-
ogy 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 facul-
ties and character with parts of the skull.11 In this regard, it is
worth noting that functional imaging researchers themselves

2006 Report
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
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, recent-
ly theories have abounded which, like phrenology, attempt to
localize complex mental activity such as memory, will, fantasy,
Neuroimaging
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 extraordi-
narily involved complexes of mental functions. … One cannot
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 differ-
ing numbers, in differing degrees and in differing combina-
tions.” 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, identi-
fy 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 focus-
ing 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 iden-
tify the elementary operations performed within such a network
and relate these operations to the task of interest. Very encour-
aging 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 matu-
ration), 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 neu-
roscience, 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 func-
tion from a developmental perspective. The developmental psy-
chology literature is very rich with details about developmental

2006 Report
milestones associated with the maturation of the human brain.
Missing, however, is a satisfactory understanding of the matura-
tion process within systems of the human brain. Brain matura-
tion at a systems level affects the development of attention, lan-
guage, memory, personality, and the management of distress, to
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 organiza-
tion 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 gen-
eral focus on the cellular and molecular level within develop-
mental neurobiology to the relative exclusion of a more integrat-
Neuroimaging
ed 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
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 generat-
ing 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 men-
tal 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.

A
s we age, some of us maintain our
cognitive functions, such as mem-
ory or language, quite well, while
others do not. Working with both humans
and animals, scientists have revealed spe-
cific conditions associated with maintain-

2006 Report
ing cognitive function. Their findings sug-
gest types of intervention that could mini-
mize or prevent cognitive decline at older
ages. Effective measures could combine
physical training, mentally stimulating
activities, and psychosocial approaches.

Changes in Memory with Age

Does cognitive ability change as individu-


als get older, in the absence of disease? Researchers have focused
on studying optimally healthy subjects across the age range,
The Aging Brain
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 dis-
eases, we are studying the interaction of age and disease, rather
than aging per se.
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 mem-
ory is to ask someone to learn and recall new information. This
“episodic memory” is often examined by asking someone to lis-
ten to a story and recall its details, both immediately and after a
delay. When healthy individuals across the age range take a diffi-
cult memory test of this sort, we see significant changes in mem-
ory 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 poten-
tial 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 indi-
cate 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 demonstrat-
ed 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 mecha-
nism 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 compen-
sate for age-related changes in function. Functional imaging,

2006 Report
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-
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

The Aging Brain


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 stan-
dard ways of analyzing the effect of genetics is to compare the
behavior of identical twins reared together and separately. These
studies suggest that genetics accounts for approximately 50 per-
cent 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 under-
stand the underlying brain mechanisms, we must turn to experi-
mental 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 hip-
pocampus, a part of the brain critical for normal memory. They
also make increased amounts of substances required for the nor-
mal maintenance of nerve cells, so-called trophic factors, such as
brain-derived neurotrophic factor, or BDNF. These trophic fac-
tors, 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 cardio-
vascular 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 activi-
ty—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 com-
munity and how much they think they can influence what hap-
pens 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 reduc-
tion of stress hormones in the brain, and studies show that excess

2006 Report
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
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 meas-
ures 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
The Aging Brain
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”
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
Disorders That Appear in Childhood
Challenging Assumptions about ADHD 18

Investigating the Brain Basis of


Dyslexia 21

Seeking Early Signs of Autism 22

17
B
rain disorders that appear in
childhood often spark contro-
versy, with heated public
debate about proper diagnosis and treatment. In 2005
researchers continued the effort to better understand the neu-
rological basis of three such disorders: attention-deficit hyper-
activity 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 col-
leagues 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 sig-
nificant 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

2006 Report
along with ADHD.
Why are so many more boys than girls being referred for treat-
ment? Although the reasons are not clear, the cause could be refer-
ral bias, says Biederman. In his experience, boys with ADHD tend
to be more outwardly disruptive than girls, especially when they
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

Disorders That Appear in Childhood


often as they should. If the study is replicated in other communi-
ty populations, it could have important implications for the detec-
tion 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-
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, deter-
mined 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 con-
ducted 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,

2006 Report
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-
nal, Pediatrics, the medications studied in most detail were the
stimulants methylphenidate (Ritalin), dextroamphetamine
(Dexedrine), and pemoline, with some mention made of the tri-

Disorders That Appear in Childhood


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 anti-
depressant 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
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 abnor-
malities 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 chil-
dren with dyslexia showed reduced activation in the left inferior
occipitotemporal cortex while trying to read words or name pic-
tures—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 dyslex-
ia 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 disor-
der 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

2006 Report
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


Neuroscience, Lonnie Zwaigenbaum and colleagues at McMaster
University in Ontario report that some signs of autism are evi-
dent in babies as young as 6 months.9 Their pilot study involved

Disorders That Appear in Childhood


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 meas-
ure 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-
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 dis-
played 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
Movement and Related Disorders
Spotlight on Gene Mutations 26

Gumming Up the Works 28

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
T
he most active research on
movement disorders in 2005
continued 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 dis-
orders 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 elimi-
nated 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-associ-
ated Parkinson’s can vary, particularly with regard to the pres-
ence 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

2006 Report
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
other proteins. Dardarin mutations might also increase suscepti-
bility to Parkinson’s by promoting the formation of protein aggre-
gates or making nerve cells more vulnerable to degeneration.10

Movement and Related Disorders


Although no mutations were detected in thousands of unre-
lated, 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
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 associ-
ated with Parkinson’s disease. Some have proposed that genetic
testing for LRRK2 mutations could be useful in the clinical set-
ting 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 neu-
rodegeneration 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, nor-
mal 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

2006 Report
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
(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

Movement and Related Disorders


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
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 transplan-
tation.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 pro-
posed 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 reduc-
tion 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 dysfunc-
tion 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 dis-
orders. Researchers are fine-
tuning the technique, which
involves placing electrodes in
the brain that deliver electric
pulses to specific brain regions.

2006 Report
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
cases by replacing misplaced electrodes, reprogramming the
device, or adjusting medications. Because DBS is being per-
formed more frequently every year, the authors stressed the need

Movement and Related Disorders


for post-surgical follow-up and for more effective presurgical
screening to determine which patients are likely to have success-
ful 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
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, ultimate-
ly 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 lab-
oratory by correcting calcium levels. In the April 19 Proceedings
of the National Academy of Sciences, Scott Q. Harper and col-
leagues 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

Nervous System Injuries


Harnessing Stem Cells for the Spine 37

Stroke 38

Brain Tumors 39

Steroids and Traumatic Brain Injury 39

Neural Prosthetics for Post-Injury


Recovery 39

33
N
ervous system injuries com-
prise a diverse group of disor-
ders 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 mole-
cules 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 com-
plex role after spinal cord
Axon
injury. It must be restored to
Myelin sheath
axons that remain, yet it con-
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-

2006 Report
establish nerve connections. Continuing a trend begun in 2004,
spinal cord injury researchers are increasingly relying on com-
bined 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
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

Nervous System Injuries


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,
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 “commit-
ted” 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, methyl-
prednisolone, 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 labora-
tory 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 recep-
tor 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 inde-
pendent teams from Children’s Hospital Boston and from
Biogen Idec. Reporting separately in Neuron, the teams discov-
ered that a protein variously called TAJ or TROY is an impor-
tant 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

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

Nervous System Injuries


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
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, pub-
lished 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 sup-
port 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 fre-
quently 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 diffi-
cult 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 malig-
nant 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 cli-
nicians 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

2006 Report
protein that inhibits enzymes involved in tumor cell prolifera-
tion, 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
for another type of tumor that affects glial cells.17

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

Nervous System Injuries


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-
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 rep-
resent 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 com-
puter-controlled light switch. A
handful of specialized laboratories
continue to advance the develop-
ment of such “brain-machine inter-
faces.”
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

New Publications Add Perspective 42 2006 Report


Neuroethics

Technological Advances Pose Tough


Choices 43

Bridging the Worlds of Science and


Religion 45

Neuroethical Implications of the Schiavo


Case 45

Ethical Challenges in Neuroimaging 47

41
T
he newly developing field of
modern neuroethics encom-
passes both the ethics of neuro-
science 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 neuro-
science advances in 2002, by publishing papers in peer-
reviewed journals and special journal volumes and by partici-
pating 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 reli-
gion. 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 for-
mal or informal attention.
In October and November, concurrent with the annual meet-
ings 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 neu-
rodegenerative 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 explor-
ing 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 devel-
opment through old age; how neuroscience is redefining what is
understood about memory and how these findings might affect

2006 Report
the basis of the legal system; and finally, the insights neuro-
science is providing into the nature of moral reasoning—and
what implications these will have for the understanding of what
makes us human.

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
Neuroethics
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-
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 neuroimag-
ing 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 stimula-
tion 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 conse-
quences. 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 applica-
tions of such research too quickly and risk public backlash.
The participants deemed psychopharmacology, the final con-
ference 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

2006 Report
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
that can alter the brain and behavior, raising fundamental ques-
tions 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 neu-
Neuroethics
roscience 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.

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 vege-
tative state, a condition in which someone shows no signs of con-
scious behavior, while another 100,000 are in a minimally con-
scious 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 activa-
tion in healthy controls.7 Their findings suggest that certain brain
circuits in minimally conscious patients are able to handle infor-
mation 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 repre-
sents some kind of awareness and whether any form of recogni-
tion 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

2006 Report
at the Library of Congress, deciding how to handle multiple chal-
lenges created by neuroimaging is not merely a theoretical prob-
lem but a rapidly evolving necessity. These issues were discussed
at several scientific meetings and in a number of journal articles.
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 consen-
sus 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
Neuroethics
brain form or structure in as many as 20 percent of study partic-
ipants, and clinically significant abnormalities in anywhere from
2 to 8 percent.10
Working to shape recommendations that would be adopted
by laboratories, institutional review boards, journals, and
research sponsors, the conferees reached consensus on many
questions. Others remained unresolved, and their work contin-
ues.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 pri-
vacy.13 Yet neuroimaging, far more than a genetic profile, pro-
vides 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 jour-
nals are not “pictures” in any traditional sense; they are comput-
er 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 neu-
roimaging scans for use outside the laboratory just yet.
Another prospective use for brain imaging, one that is partic-
ularly 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

Neuroimmunology
Immunotherapy for Neurological
Disorders 52

Viruses Implicated 55

49
T
he young field of neuroim-
munology continued to experi-
ence rapid growth in 2005,
with more research published and a wider variety of disorders
in the spotlight. Recent studies shed more light on the interac-
tions 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-autoim-
mune 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 grad-
ual 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 con-
siderably 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

2006 Report
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
signal. However, the findings of Becher and colleagues show that
the antigen-presenting cells are dendritic cells, a completely dif-
ferent cell type, and are located at a different site than previous-
ly 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

Neuroimmunology
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 dam-
aged myelin.3 In a more recent study, these scientists showed that
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 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 neu-
ral 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 treat-
ment 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 transplan-
tation” (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 transplanta-
tion, 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 learn-
ing 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

2006 Report
treated for several weeks with an antibody to beta-amyloid. As a
result, plaque levels were reduced by about 50 percent, and spa-
tial learning performance improved significantly.
According to the investigators, these data confirm that the
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 effec-
tive 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,

Neuroimmunology
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 accumula-
tion of a protein called alpha-synuclein is at least partly respon-
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 character-
ized 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, reac-
tions 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 infec-
tions 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 main-
taining 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

2006 Report
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
unknown. The study by Yamano and colleagues revealed that
patients with an uncommon virus-associated chronic, progres-
sive 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 autoim-

Neuroimmunology
mune 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 con-
firm previous reports finding increased human herpes virus HHV-
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
B
lood pressure, pulse, respira-
tion, and temperature are the
vital signs that help doctors
measure a person’s physical condition. Many doctors now con-
sider 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 effec-
tive treatment regimens for pain resulting from injury to periph-
eral nerves and for severe pain. Another investigation found that

2006 Report
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
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 pri-
mary focus.

A Drug Combination to Treat Neuropathic Pain

Neuropathic pain is pain that arises from nerve disease or dam-


age and is a common complication of diabetes, cancer, human
immunodeficiency virus, herpes zoster (shingles), and neurode-
Pain

generative diseases. The burning, searing nature of neuropathic


pain can have a profound impact on quality of life. The drugs to
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 dia-
betic neuropathy and acute nerve pain resulting from herpes can
significantly reduce pain more than either drug given individual-
ly. 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 neu-
ropathy. 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 addi-
tive interaction between the drugs. The researchers also discov-
ered 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 nat-
ural 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 nerv-
ous 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

2006 Report
this class of drugs.

Treating Severe Pain

Researchers at Memorial Sloan-Kettering Cancer Center identi-


fied 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
Pain

NSAIDs greatly increase the pain-relieving effect of two widely


prescribed narcotic drugs, hydrocodone and oxycodone, while
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-oxy-
genase. 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 test-
ing different combinations in the clinical setting may help iden-
tify 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 varia-
tions in genes can make people less sensitive to painful stimuli and
protect them from developing a common, debilitating pain condi-
tion 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 schizophre-
nia; 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
2006 Report
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.

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 condi-
tions, as well as strategies for treating pain. Based on their find-
ings, they are now investigating new drug therapies for TMJ and
related disorders.
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 sec-
ondary. 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

Psychiatric, Behavioral, and Addictive Disorders 2006 Report


Schizophrenia 64

Depression 66

Addictive Disorders 68

Future Directions 71

63
A
common theme in mental
health research in 2005 was the
role of genes in mental disor-
ders and the interaction of these genes with environmental fac-
tors 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 specif-
ic 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 activ-
ity. 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 schizo-
phrenia 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

Psychiatric, Behavioral, and Addictive Disorders 2006 Report


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
technique called positron emission tomography to provide evi-
dence 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 pre-
frontal cortex (blood flow is an indirect measure of neural activ-
ity). 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

“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 mem-
ory 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-gen-
eration 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 dis-
ruptive disorder. The grandchildren with a parent, but not a
grandparent, with depression were at no greater risk for any psy-
chiatric 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 neu-
ron 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 amyg-
dala, anterior cingulate cortex,
and posterior subcallosal cortex Prefrontal
cortex
in depression; and about the pre-
frontal cortex, which plays a role
in schizophrenia and addiction. Posterior
subcallosal
cortex Amygdala

Psychiatric, Behavioral, and Addictive Disorders 2006 Report


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-
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 life-
time psychiatric diagnosis or treatment, threatening visual stim-
uli 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 anxi-
ety-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-
tex (ACC), which is located along the midline of the brain. This
particular place in the ACC—called the rostral subgenual por-
tion, or “rACC”—is densely packed by neurons that are the tar-
get of serotonergic neurons from a lower region of the brain.
Previous studies have shown reduced rACC activity in depres-
sion and sadness.
Writing in Neuron, Marc Caron and colleagues have identified
another allele that appears to predispose individuals to depres-
sion. 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, com-
pared 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 antide-
pressants 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 treat-
ments, 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 pos-
terior 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 depres-
sion and stays overactive in patients who fail to respond to tra-
ditional treatments.
The researchers implanted electrodes in the neural pathways
from the PSC on both sides of the brain in six patients with treat-
ment-resistant depression. The delivery of high-frequency elec-
trical 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, con-
tinuous stimulation for six months led to long-term improve-
ments 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 opi-
ate 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 chemi-
cal 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

Psychiatric, Behavioral, and Addictive Disorders 2006 Report


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-
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 naltrex-
one reduced heavy drinking, more so with the high dose than the
low dose. For reasons that are unclear, men responded to the
treatment much better than did women.10
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-
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 asso-
ciated 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 trig-
gers 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 neurotransmit-
ter 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 alter-
ations 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 sig-
naling 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 sur-
rounding support cells (the glia) result in a larger release of glu-
tamate. 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 neuro-
science to determine how to promote and advance interdiscipli-
nary 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 nation-

Psychiatric, Behavioral, and Addictive Disorders 2006 Report


al repository of teaching materials in basic and clinical neuro-
science; developing strategies to maintain student interest in the
fields; and providing neurobiology Ph.D. candidates with expe-
rience in clinical disease to guide their future research interests.
Perhaps the most important discussion focused on the educa-
tional enterprise and the importance of an interdisciplinary
approach in medical school education and in residency training.

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
B
iological mysteries that have con-
founded scientists for decades
seem 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 lead-
ing to long-sought-after answers in other disorders is contribut-

2006 Report
ing to the development of procedures and technologies to aid
patients with macular degeneration.

Sleep, Appetite, and Obesity

Scientists long have suspected that biological pathways that con-


trol sleep and those that control appetite are somehow connect-
ed. 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

Sense and Body Function


“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-bal-
ance 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
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 regu-
lation. The findings are bolstered by studies in humans pub-
lished 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 lev-
els 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 essen-
tial, especially in the United States, where people tend to sleep
too little, high-calorie food is readily available, and rates of obe-
sity 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 orex-
in. 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 hypothala-
mus were involved in reward and motivation, but just which neu-
rotransmitters 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 inject-
ed 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

2006 Report
begin to fire just before animals emerge from rapid-eye-movement
6,7
sleep. The twin findings, published in the Journal of
Neuroscience and Neuron, respectively, suggest that orexin neu-
rons fire primarily during wakefulness, and that they fire fastest
in association with motor responses, particularly exploration.
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 loco-
motor 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 dur-
ing 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 read-
ing. 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 proce-
dure in which surgeons first restore function by rotating the reti-
na 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 sur-

2006 Report
gery, 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 comple-
ment factor H. Scientists have long suspected that the immune
system is somehow involved in the onset of AMD. Now, scien-
tists 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

Sense and Body Function


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-
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 non-
human 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, hear-
ing, balance, and fertility, also is important in helping the brain
sense odors.
Cells responsible for the sense of smell require charged chlo-
ride atoms, or ions, to communicate odor information to the
brain. Scientists knew that a transporter called NKCC1 regulat-
ed 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 process-
ing of smells in the brain.

78
STEM CELLS AND
NEUROGENESIS

2006 Report
Developmental Benchmarks for Stem Cells 80

Stem Cells and Neurogenesis


Nuclear Fallout Dates Stem Cells 80

Junk DNA Distinguishes Individual Brains 81

Dopamine Nixes Neurogenesis 82

Neurogenesis Helps Fight Brain Tumor 83

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
N
eurogenesis refers to the birth
of new brain cells; not until
the 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 func-
tion 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, func-
tional 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 prop-
erties and firing abilities of neurons; they developed several
kinds of ion channels (through which neurons exchange electri-
cal 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 neu-
ral 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 occur-
rence 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 use-
ful for dating more recent objects. However, a burst of 14C
entered the Earth’s atmosphere with the testing of nuclear

2006 Report
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 peo-
ple born before 1950 were identical to those in the pre-nuclear-test
atmosphere—meaning the cells were the same age as the individ-
ual. 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

Stem Cells and Neurogenesis


neurons in this area were younger than the individual. It also pro-
vides 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
make up about 15 percent of the human genome and were long
thought to be genetic junk, not only change the destiny of neu-
ral stem cells but may help make each brain unique.
The investigators introduced a line of human retrotrans-
posons 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 retrotrans-


posons 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 neu-


rogenesis in the brain, suggesting that the absence of neurogen-
esis 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 neu-
rogenesis 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 col-
leagues 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

2006 Report
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
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 ani-
mals. Because glioblastoma is rare in young people and peaks in

Stem Cells and Neurogenesis


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
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 infor-
mation 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 trans-
planted cells incorporate themselves into a brain is not under-
stood 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 con-
clude 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

2006 Report
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

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

Stem Cells and 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-
11
repair also operates in the aged brain.
A report in the June issue of the same journal shows that fol-
lowing a stroke, in rats at least, neurogenesis can be stimulated in
a surprisingly straightforward way: by providing an enriched envi-
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 signifi-
cance 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 neu-
rons 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 neuroge-
nesis plays a role in the formation and consolidation of long-
term, hippocampus-dependent, spatial memories.13

86
THINKING AND REMEMBERING

2006 Report
Thinking and Remembering
Familiar Alzheimer’s Culprit, New Location 88

The Impact of Diet on Dementia 89

New Approaches to Treating Alzheimer’s


Disease 90

The Role of Emotion in Memory 92

Identifying the Sites of Memory Recall


in the Brain 93

87
I
n a year when researchers found
significant new insights into how
we 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 tan-
gles 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 accu-
mulates inside neurons; their appear-
ance outside neurons occurs later. A
plaque, upper left, appears darker in
this image of tissue from the hippocam-
pus, 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 hav-
ing 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

2006 Report
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
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

Thinking and Remembering


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 vita-
mins 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
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 partic-
ipated 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, rela-
tive 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 pre-
liminary 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 anti-
bodies 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 fol-
low-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

2006 Report
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
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

Thinking and Remembering


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
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 treat-
ment. Like the IVIg therapy trials, the NGF gene therapy
approach is far from having been proved effective, but the pre-
liminary 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 emotion-
ally 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 emo-
tionally 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 emotional-
ly 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 distin-
guish between emotionally salient memories and neutral ones.

92
Meanwhile, Elizabeth Kensinger and Daniel Schacter at
Harvard University reported in Neuropsychologia that the amyg-
dala 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 emo-
tionally 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 fol-
lowed by an image of the object; the other half were followed by
a blank white screen. In the third step of the experiment, the vol-
unteers were shown several pictures and asked if they had previ-

2006 Report
ously 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 reso-
nance imaging scanner so Kensinger and Schacter could see what
regions of the brain participate in accurate recall. The left anteri-
or hippocampus was active during accurate recall of both types of
objects. However, the right amygdala and left orbitofrontal cor-
tex became active only during recall of emotional items. In con-
trast, recalling neutral items activated the lateral inferior pre-
frontal cortex and the right posterior hippocampus.

Thinking and Remembering


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

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 path-
ways 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 magnet-
ic 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 con-
crete 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 pre-
cuneus. 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, dif-
fer between men and women.10 Numerous neural processing dif-
ferences 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

2006 Report
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 differ-
ences in the subjects’ ability to remember events. However,
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 activa-
tion in the left parahippocampal gyrus relative to females in all
types of memory tasks (negative versus positive, recent versus

Thinking and Remembering


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 differ-
ences 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 rele-
vant memories, which ends up appearing as more efficient recall
mechanisms. The researchers conclude that there is no differ-
ence in the efficiency of memory storage, even though different
brain regions are used during similar tasks.

95
NOTES

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2006 Report
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2006 Report
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2006 Report
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Thinking and Remembering


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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 com-
monly 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 neu-
ral circuits and re-establish muscle movement.

• in which drug addiction and alcoholism no longer hold peo-


ple’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 com-
bat 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.

A
lthough such a vision may seem unrealistic and utopian, we
are at an extraordinarily exciting time in the history of neu-
roscience. 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 dis-
orders. 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 ques-
tions that lead to scientific discovery.
The coordinated work of thousands of basic and clinical scien-
tists in multiple disciplines, ranging from molecular structure and
drug design to genomics, brain imaging, cognitive science, and clin-
ical 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 opportuni-
ties 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 ethi-
cal 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 func-
tion, disease onset, and disease progression. A sophisticated arsenal of
tools and techniques now enables us to apply our knowledge and accel-
erate 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 impor-
tant 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 confi-
dence 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 dis-
orders 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 vac-
cine are being developed to prevent the accumulation of this toxic mate-
rial 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 dramat-
ic 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 develop-
ment 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 multi-


ple sclerosis.
For the first time, we have drugs that can modify the course of this dis-
ease. 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 pro-
gression 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 tech-
niques, focused-radiation treatments, different forms of delivery of drugs
to the tumor, and the identification of genetic markers that will assist diag-
nosis 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 tis-
sue 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 ani-
mal models to human clinical trials. Electronic prostheses are being devel-
oped 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 mecha-
nisms 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 vulnerabili-
ty 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 mecha-
nisms 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 neu-
rons have the potential to revolutionize the treatment of neurological
disorders. Transplants of neural stem cells, currently being done on ani-
mal 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 dis-
ease, 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 infor-
mation about normal processes such as development of the brain, learn-
ing, 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 CB1 receptor and alcohol
(ADHD), 18–21
addiction, 69–70
autism, 1, 22–24, 54
cannabinoid CB2 receptor and pain sensitivity,
autistic regression, evidence of, 24
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

2006 Report
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
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
Index

cyclo-oxygenase enzyme and NSAIDs, 59–60 fMRI. See functional magnetic resonance imaging
folic acid intake and AD, 89
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

2006 Report
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
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
Index

19–20 Meyer-Lindenberg, Andreas, on dopamine’s


Lewy bodies and Parkinson’s disease, 26, 27 affect on neuronal activity, 65–66
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

2006 Report
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
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
Index

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
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 sul-
fasalazine for gliomas, 39

132
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Floyd E. Bloom, M.D., M. Flint Beal, M.D., and David J. Kupfer,
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Guy McKhann, M.D., and Marilyn Albert, Ph.D.
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IN SEARCH OF THE LOST CORD
Solving the Mystery of Spinal Cord Regeneration
Luba Vikhanski
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THE LONGEVITY STRATEGY


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New Discoveries about How Our Brains Make Us Who We Are
Roberta Conlan, Editor
Adapted from the Dana/Smithsonian Associates lecture series by
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THE DANA SOURCEBOOK OF IMMUNOLOGY


Resources for Secondary and Post-Secondary Teachers and Students
An introduction to how the immune system protects us, what
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139
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Brain Disease and Disorders
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140
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Cover image: Courtesy of Marcus Raichle, M.D.


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141
ADVANCES IN NEUROIMAGING
The 2006 Progress Report on
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

The 2006 Progress Report on

2006
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.
DANA PRESS

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