Fall 2007 Vol. 13, No. 3 contents 1 A Question of Free Will? 2 A Systems Approach to Autism 3 Obesitys Right Brain Hypothesis 4 Alcohol Shrinks the Brain, but What are the Effects? t h e h a r v a r d m a h o n e y n e u r o s c i e n c e i n s t i t u t e l e t t e r Q uestions about free willthe capacity to choose a course of action from among various alternativeshave plagued philosophers since the beginning of time. These
questions also confront those who study, treat
and suffer from drug addiction. Drug addiction has been used as a yardstick for reward-based behavior, according to Harvard
University Provost Steven E. Hyman, M.D., who
discussed the issue of free will and addiction in
Harvards rst Provostial Lecture in May. With
addiction, there is a narrowing of life focus in
that drug-seeking behavior crowds out all other
motivations and goals. Dr. Hyman is a professor of neurobiology at Harvard Medical School and was the rst director
of Harvards Mind, Brain and Behavior Initiative.
He also served as director of the National Institute
of Mental Health. While free will is more of a philosophical construct than a neurobiological one, Dr. Hyman
says the concept can be discussed in terms
of addiction without addressing metaphysical
concerns. The relationship between the two stems
from the fact that certain brain processes and
neurochemical mechanisms govern our ability
to exert voluntary control over our actionsthe
essence of free will. A go signal for the brain Addictive drugs affect the brains prefrontal cortex
(PFC), which powers our ability to think, plan,
solve problems and make decisions, as well as the
limbic system, which contains the brains reward
circuit. Addictive drugs interfere with the way nerve cells send, receive and process information by
mimicking the chemical structure of neurotrans-
mitters, the brains chemical messengers. An
important end result caused by all addictive drugs is a highly excessive release of the neurotransmitter
dopamine in synapses, the structures across which
nerve cells communicate Dopamine plays a role in marking experiences as positive and highly signicant. Released whenever
we experience a new or unexpectedly strong reward,
dopamine instructs nerve cells to form memories
that will guide future behavior toward repeating
the actions that led to such positive or rewarding
experiences. Naturally rewarding experiences, such
as a good meal or a cold drink on a hot day, are
given different values by the brain and are stored
in the prefrontal cortex. As their novelty wears off
or we have other rewarding experiences, our brain
assigns them different values, and we are able to
make relatively free choices among them. Addictive
drugs take over the normal mechanisms by which
we make choices. Every time a person takes an
addictive drug, a big slug of dopamine is released
in the brain, both in the parts of the brain that
govern emotions and in the prefrontal cortex,
which guides our choices. Normally, the job of dopamine is to signal important life enhancing, positive survival goals,
says Dr. Hyman. Addictive drugs short-circuit the
natural mechanism that releases dopamine in the
brain. They basically hijack the normal survival
system involved in decision making by altering the
function of the prefrontal cortex and other brain
regions. Thus, drug-seeking behavior becomes the
addicts most important behavioral priority. Drugs have an advantage over natural rewards such as food because addictive drugs act directly
in the brain to release dopamine. For example,
when we go to a restaurant and have a tasty
new dish our reward system helps to consolidate
the memory and tells us, That was good. Lets
do it again, and lets remember how we did it. A Question of Free Will? ON THE BR A I N continued on page 3 Steven E. Hyman, M.D. O N T H E B RA I N A s far back as 1 943, when psychiatrist Leon Kanner published his paper Autistic Disturbances of Affective Contact in Nervous Child, the signs for a systems-based approach to autism
were evident, suggests Martha Herbert, M.D.,
Ph.D., a pediatric neurologist at Massachusetts
General Hospital. Of the 11 children Kanner studied,
most had signs of gastrointestinal problems
such as diarrhea and malabsorption or immune
abnormalities such as recurrent infections. Kanners ndings didnt mean much to the psychiatry, psychology and neurology communities
when they were published, but now several
scientists, including Dr. Herbert, an assistant
professor of neurology at Harvard Medical School,
are advocating the idea that autism is less a brain-
based disorder and more of a systemic condition.
In a 2005 paper in Clinical Neuropsychiatry, she wrote: ...autism is not conned to the brain, given
abnormalities in peripheral biomarkers and in
other organ systems, prominently gastrointestinal
and immune, that are common fellow travelers
with autism behaviors. Changing the thinking about autism Autism is dened as a neurodevelopmental disorder
that manifests before age 3 and is marked by impaired social interaction, communication and
restricted and repetitive behavior. The number
of children diagnosed with autism has risen
dramatically since 1980. Federal health authorities
say about one in every 150 children now have
autism spectrum disorder (ASD). The Massachusetts
Department of Education recently reported an
increase in autism diagnoses from 4,000 to 7,521 in
the past ve years. Autism affects each individual differently from mild delays in language to greater challenges
with social interaction. Some of the more common
characteristics of autism include: resistance to
change, difculty expressing needs, repeating
words or phrases, preference for being alone,
tantrums, difculty socializing with others, little or
no eye contact, sustained odd play, spinning
objects, obsessive attachments to objects, and
uneven gross and ne motor skills. For years, scientists and clinicians have considered autism to be a strongly genetic, brain-
based disorder; however, that thinking is now
changing, with many believing that the behavioral symptoms of autism are linked to less obvious
biological dysfunction. Quoted in an April 2007 Discover magazine article, Dr. Herbert said: What I believe is happening
is that genes and environment interact, either in
a fetus or young child, changing cellular function
all over the body, which then affects tissue and
metabolism in many vulnerable organs. And its
the interaction of this collection of troubles that
leads to altered sensory processing and impaired
coordination in the brain. A brain with these kinds
of problems produces the abnormal behaviors that
we call autism. Systemic dysregulation The most prominent aspect of a whole-body
approach, says Dr. Herbert, appears to be the high
level of gastrointestinal and immune disorders
in autistic children, including food and airborne
allergies, ear infections, eczema and chronic
diarrhea. Dr. Herbert says shes not willing to stop
at just the gut and immune system, since doctors
who see many autistic children note subgroups
with problems such as seizures, low muscle tone,
sleep disorders and sensory disturbances, as well as
osteoporosis, renal problems and hormonal issues. While scientists for years have considered the brain the primary target of autism, this new
approach to autism is attempting to determine if
the brain is affected at the same time as or even
downstream of other bodily changes. The brain may produce [autistic] behaviors, Dr. Herbert says, but theres also dysregulation at
other levels that makes the brain act differently.
We may nd some overlap [between the brain and
body biology]. Gene-environment interaction This newer model of autism considers autistic
behaviors as one of many effects of genetics and
the environment on the whole body, not just
the brain. While there is a certain component of
heritability to autism, no single gene explains the
prevalence of the disorder. Rather, says Dr. Herbert,
certain high-risk genes put you perilously close to
the disorder and just a little puff of stimulus from
the environment can push you over the edge. A Systems Approach to Autism O N T H E B RA I N A Question of Free Will? continued from page 1 The next time we go to the restaurant, however,
even if the dish is just as good as the last time,
dopamine is not released in our brain; it has already
done its job of consolidating the memory of where
and how to get this tasty dish. Addictive drugs, on
the other hand, directly release dopamine every
time they are taken, signaling regions of the brain
that set behavioral goals. Whatever the subjective
experience, says Dr. Hyman, the brain gets a
go signal, telling the individual to take the drug
again and again and again. Even if a smoker takes
a drag and has a painful cough, even if a drinker
feels nauseated or depressed, dopamine gets
released, and tells the brain, That was good. Lets
do it again. Rewiring the reward circuit Over time, regions of the addicted persons brain
that have mechanisms to encode memories
become rewired as a result of this bombardment by
dopamine. Brain cells dont deteriorate, per se, but
rather undergo a set of changes that, under normal
circumstances, would help one to remember
positive goals and experiences. Drugs, Dr. Hyman
says, provide a grossly excessive dopamine signal,
which alters the brains plasticity, or ability to
change, eliciting automatic drug craving and drug
seeking in response to reminders of drug use. This
rewiring of the brains circuitry and the resulting
loss of control over normal goal-setting and
goal-seeking behavior, makes relapse common,
even after someone has gone through painful
withdrawal symptoms to become drug-free. The action of dopamine in the addicts brain would seem like a natural target for drugs that can
help treat and cure addiction. If you block dopamine
release, however, you block the individuals
normal ability to experience pleasure and learn
new information. This, says Dr. Hyman, is not a
suitable approach to treating addiction. We need better pharmacological treatments that dont block pleasure, but rather weaken the
pathological neural connections made under the
influence of drugs so that the addicted person can
make new and healthy behavioral choices,
he adds. Behavioral therapies have had some success in treating addiction because they help addicts
modify their attitudes and behaviors related to
drug abuse and assist them in dealing with triggers
that may cause drug craving. Family, friends and
other caregivers, says Dr. Hyman, need to act as
a prosthesis for the brain functions that are
compromised by drug abuse. Because the addicts
brain has been rewired to prefer drugs, these
advocates must be implacable about getting the
addict into and staying in treatment. Despite the fact that drug addicts brains are compromised, diminishing their capacity to control
their behavior, Dr. Hyman says it doesnt help to
treat them as if they cannot be responsible for
themselves. Because they are addicted, we should
not be surprised when they slip. In the end,
despite needing help, they have to be the owners
of their lives. Other risk genes may need more of a second hit
from the environment before autism develops. In fact, she argues, the rising number of autism diagnoses points to an environmental role in the
disorder, since genetic changes dont occur as
quickly as the numbers have risen. Further, she
says, genes and environmental exposure are not
conned to a single body system. A genetic change may express itself in many bodily systems and an environmental exposure may
target a biochemical vulnerability that is widely
distributed in the body. . . Some bodily systems
more directly interface with the environment, such
as the gastrointestinal system, which is the rst port
of entry of many environmental exposures, and the
immune system, which deals with responses to outside intrusions into the body. From the
perspective of gene-environment interactions, it
should come as no surprise that we are seeing
gastrointestinal and immune problems in many
autistic individuals, she writes in the 2006 Autism Advocate. Interactions of the body and brain The whole-body model opens new avenues for
early identication of medical features, as well as
for potential treatments to halt or even reverse
the effects of autism. By identifying what is causing
the harmeither genetically or environmentally
scientists can work on preventive measures. continued on page 8 B y now, most of us know: Americans are getting
heavier and heavier, and the rates of obesity among both adults and children are rising to
epidemicand dangerouslevels. Thirty years ago,
15 percent of Americans were obese; by 2004, that
number had risen to nearly 33 percent, with
an alarming increase in the child and adolescent
populations. Today, nearly 65 percent of Americans
are either overweight or obese. The rise in obesity has also raised the risk for developing hypertension, Type 2 diabetes,
coronary heart disease, stroke, gallbladder disease,
osteoarthritis, sleep apnea and other respiratory
problems, as well as certain cancers. These
conditions carry an economic burden costing the
U.S. billions of dollars each year. While many people regard obesity as an eating disorder, research over the past decade has pointed
to the brains role in regulating food intake
and the mechanisms by which obesity occurs.
Studies have found that, in addition to other
health problems, obesity can cause a loss of brain
tissue and cognitive decline. Now, Harvard Medical
School researchers at Beth Israel Deaconess
Medical Center have developed what they call a
right brain hypothesis for obesity. That is, say
HMS neurology professor Alvaro Pascual-Leone,
M.D., Ph.D., and postdoctoral fellow Miguel
Alonso, M.D., M.Sc., both of BIDMCs Berenson-
Allen Center for Noninvasive Brain Stimulation,
the right hemisphere of the brains prefrontal cortex
(PFC) plays a critical role in the cognitive control of
food intake. The PFC is a region of the brain that
controls many complex behaviors that separate
humans from other species. Cognitive control of food intake is a general term that defines our capacity to process information,
apply knowledge, and make decisions, says Dr.
Pascual-Leone. We decide what to eat using our
ability to predict the future consequences of our
actions. We also take into account factors that can
be merely constructs of our mind. Good examples
of this are religious diet codes or our beliefs of the
impact of diet on health and body shape. This is a
uniquely human way to regulate food intake that
is not found in animals. It is mostly inhibitory, and
its dysfunction could represent a pathway that
contributes to overweight and obesity. Obesitys Right Brain Hypothesis Further, say the researchers, it is in thinking about the human dimensions of food intake
regulation that they point to the right PFC as a
critical brain structure. Neural circuits of obesity Simply put, obesity is a condition characterized by
the excessive accumulation and storage of body
fat. This means that obese people take in more
calories than they burn. The coordination of
food intake and physical activity is necessary for
regulating body weight. Appetite is a function of the brain, primarily the hypothalamus, an area of the brain that regulates
our basic bodily functions. A collection of neurons
in the hypothalamus, called the arcuate nucleus, is
the brains appetite center, coordinating the need
to eat in relation to our energy availability (i.e.,
how well our body is fed). This is accomplished by
crosstalk between the hypothalamus and signals
arising from the gastrointestinal system and
adipose, or fat-storing, tissue. Dr. Pascual-Leone says that two particular neural circuits connected to the arcuate nucleus
promote or suppress appetite, respectively. These
circuits help regulate the bodys nutritional state,
which is why we remain more or less the same
weight over the long-term. They help to provide
balance to our weight, he says. In addition, our limbic system, which includes the brains pleasure center, contains patterns of
food preferences acquired over our lifespan, based
on a set of hard-wired responses to the primary
aspects of food, such as tastes or smells, says
Dr. Alonso. Sensory organs send signals to the
brain about food that can release dopamine, a
neurotransmitter that plays an important role in
motivation and reward. Most of this process, he says, comes from learning of associations. For example, if we inspect
something brown, gooey and sweet-smelling, we
assume that it is chocolate. More than the food, he
says, it is the expectation that causes the secretion
of neurotransmitters. We associate certain foods with certain tastes and smells, says Dr. Alonso, so eating really starts
before the food even gets in our mouths. O N T H E B RA I N Critical area for food intake In a paper in the July 25 issue of the Journal of the American Medical Association, Drs. Pascual-Leone and
Alonso say that the current state of knowledge
may not include critical aspects of the cause of
obesity, and that means the role of the prefrontal
cortex in appetite control. The researchers write
that studies of obese patients with brain diseases
point to the PFC as a critical area involved in the
control of food intake. Indeed, studies from the mid-1990s found that damage to the right frontal lobe can cause so-called
gourmand syndrome, which is characterized by a
preoccupation with eating and a preference for
fine food. Another study found decreased blood
flow to the right PFC in Kleine-Levin syndrome, a
symptom of which includes excessive food intake.
A third study showed that increased activity in the
PFC could lead to anorexia-like symptoms. The hypothesis, says Dr. Pascual-Leone, is not that there is damage to the right PFC. Rather, theres
a certain amount of activity in the right PFC that is
needed to exert appetite control. In obese people,
this activity is decreased. The right PFC is not
necessarily damaged, but it is working too little. The BIDMC researchers also say that the right PFC is a critical area for what they call moral
cognition, the process by which we ascribe values
of good or bad to different foods, influencing
our perceptions and decisions about what to eat.
Neural circuits in the prefrontal cortex, especially
the right hemisphere, also mediate self-recognition
and self body image. Dysregulation of the right PFC,
then, could result in a failure to appropriately
weigh the adverse consequences of indulging in
a bad diet, which could lead to behaviors that
contribute to obesity, they write in JAMA. Some data suggest that obesity is associated with low
levels of body awareness and right hemisphere
dysfunction. Society sets us up with a double-edged sword, says Dr. Alonso. We offer more food than
we can eat, but we also have ideas about body
image that are unattainable for many of us. Some
of us will never look like Adonis; its difficult to
achieve this ideal with such easy access to food.
This creates a dangerous double-whammy to the
mechanism that controls appetite regulation.
Nowadays, more than ever, avoiding obesity and
keeping weight off may depend on our ability to
consciously decide and monitor what we eat. Targeting PFC activity to control appetite There are currently drugs on the market that
indirectly target the PFC through effects on
neurotransmitter systems, such as dopamine and
serotonin. These drugs, however, do not specifically
affect PFC activity. The challenge, says Dr.
Pascual-Leone, is to understand these drugs and
modify them to take action in a specific part of the
brain. Higher specificity is needed for them to be
effective. We dont know yet how to do this. O N T H E B RA I N W hile many people regard obesity as an eating disorder, research over the past decade has pointed to the brains role in regulating food intake and the mecha- nisms by which obesity occurs. Studies have found that, in addition to other health problems, obesity can cause a loss of brain tissue and cognitive decline. There are also safety concerns with these drugs. Because obese people are at higher risk for
other medical conditions, says Dr. Pascual-Leone,
they may not be able to handle the side effects of
obesity drugs. In their JAMA paper, the researchers say that their neuromodulation-based approaches
may also enhance activity in the right PFC to
decrease appetite and reestablish inhibitory
mechanisms controlling eating. The researchers say that, while their hypothesis sheds new light on the brains structural role in
controlling appetite, the behavioral aspects of eating
must not be discounted. There has been little
focus on the human dimension of eating, says Dr.
Pascual-Leone, and until there is, we probably
wont overcome obesity. While work continues on ways to reestablish the inhibitory mechanisms in the brain that control
eating, Drs. Pascual-Leone and Alonso say particular
attention needs to be paid to the behavioral
aspects of obesity for diets and other interventions
to be successful. Obesity is not just an accumulation of fat, says Dr. Alonso. We need to look at what leads to
obesity, and that is behavior. We need to turn
obesity into a behavioral issue, because a key
factor [for obesity] is in the brain where all
behaviors start. O N T H E B RA I N A recent study found that the brains of heavy drinkers shrink more than the brains of people who dont drinkand more than is associated
with normal aging. The study also showed that
there is no beneficial effect on brain volume from
even light or moderate drinking, a finding in stark
contrast to earlier studies showing that small
amounts of alcohol can have a protective effect on
brain cells. What the research does not showand what still confounds scientistsis how this loss of
volume affects how the brain functions. Conducted by Carol Ann Paul, a researcher at Wellesley College, the study examined MRI scans
acquired from 1999 to 2002 of more than 1,800
participants from the Framingham Offspring Study
and was designed to determine whether the
cardiovascular benefits associated with light-to-
moderate alcohol consumption could also be seen
in the brain. The study found that people who had
more than 14 drinks per weekconsidered heavy Alcohol Shrinks the Brain, but What are the Effects? drinkers had an average 1.6 percent reduction in
brain volume compared with people who never
drank. Further, the study found that brain volume
decreased 0.25 percent for every increase in
drinking category (non-drinkers, former drinkers,
low drinkers, moderate drinkers and high drinkers).
Even light drinking had no beneficial effect,
contradicting studies showing the cardiovascular
benefits of a daily drink. On the whole, says Bruce H. Price, M.D., chief of neurology at McLean Hospital and professor
of neurology at Harvard Medical School, the
Wellesley College study adds to the immensely
controversial and not at all definitive nature of
the study of alcohols effects on the brain. The findings of this study of brain volume, presented at a recent meeting of the American
Academy of Neurology but not yet published,
contradict earlier findings that small amounts of
alcoholone to one-and-a-half glasses of red wine
dailycan protect brain cells. The point at which O N T H E B RA I N the effects of drinking on brain size outweigh the
previously shown cardiovascular benefits of light
drinking remains unknown. Slowing down brain activity What is well known is that alcohol is a depressant
that slows down brain activity. After one or two
drinks, most people begin to feel relaxed. While
producing a sense of pleasure, alcohol can also
distort judgment and lower ones inhibition.
As more alcohol is consumed, it reaches the
cerebellum, the brains center for movement and
balance, affecting coordination and perception.
When alcohol reaches the midbrain, reflexes
become diminished and confusion and stupor set
in, often followed by loss of consciousness. Once the
alcohol reaches deep within the brains inner core,
the medulla (which controls the bodys automatic
functions), heart rate decreases, breathing becomes
shallow, and body temperature drops. At this point,
alcohol intoxication can become life-threatening. Many of the impairments that result from drinkingdifficulty walking, blurred vision,
slurred speech, and impaired memoryusually
resolve once the drinking stops and the alcohol
has left the system. Over the long term, however,
heavy alcohol consumption can cause extensive
damage to the brain and body, resulting in simple
memory problems to more permanent, debilitating
conditions that require lifelong care such as liver
disease, heart failure, and impaired immunity. Advanced imaging technologies, including MRI, diffusion tensor imaging (DTI), positron emission
tomography (PET), and electrophysiological brain
mapping, now allow researchers to study, in more
detail, the effects of alcohol on how our brains
function. MRI and DTI are being used to study how long-term heavy drinking leads to deficiencies in
the white matter fibers that carry information
between brain cells. MRI studies are also helping
researchers determine how alcohol affects memory
and attention. PET scans allow scientists to examine
the living brain to determine the effect alcohol
has on neurotransmitters (parts of the brains
communications system), brain cell metabolism,
and blood flow in the brain. Other studies, using
electroencephalography, help to show real-time
electrical activity in the brain. Effect on function is unknown While the Wellesley study shows a relationship
between total brain volume and alcohol consump-
tion, Dr. Price says the findings need to be more
fully parsed out. Because the study did not also
show effects on cognition, we dont know what effect
the shrinkage has on brain function, nor what, if
any, correlation exists with other well-known
effects of heavy drinking. Nor, adds Dr. Price, do we know what role diet, mood, recurrent depression or chronic stress may
have played in the volume loss. Scientists do know
that a gene associated with increased risk for
developing Alzheimers disease, called APOE4,
along with alcohol and a poor diet, can cause
brain shrinkage greater than normal aging would
suggest. In addition, he says, scientists know that
chronic alcoholics lose subcortical white matter,
resulting in decreases in total brain volume. The question, however, remains: what does all this mean in terms of brain function? Scientists are
still seeking the answer. Favoring a protective effect for the brain The plus side, however, is that the brain volume of
alcoholics expands if they abstain from drinking
for more than a year or so. Dr. Price likens this to
a muscle that grows if it is exercised after periods
of disuse. But, he adds, we dont know about the
cognitive correlates. Theres no solid evidence that
brain function improves with volume increases.
Wed like to think thats the case, but theres
no proof. The caveat about the Wellesley study, adds Dr. Price, is that the devil is in the details. The study
is probably more of a minority view in that it
shows no beneficial effect on brain volume even in
small doses. But neither does it definitively prove
that decreases in brain volume adversely affect
brain function. While Dr. Price says the favored view among scientists will continue to be that a drink of wine
or two a day does, indeed, protect the brain, he
cautions that the negative effects of heavy drinking
must factor into ones decision about just how
much alcohol to consume. O N T H E B RA I N harvard mahoney
neuroscience institute Council Members: Hildegarde E. Mahoney, Chairman Steven E. Hyman, MD Caroline Kennedy Schlossberg Ann McLaughlin Korologos Joseph B. Martin, MD, PhD Edward F. Rover Daniel C. Tosteson, MD Writers, Editorial Advisors:
Scott Edwards, Tamsen S. McMahon Design:
Gilbert Design Associates, Inc. Harvard Mahoney Neuroscience Institute
Landmark Center
401 Park Drive, Suite 22
Boston, MA 02215 Internet address:
www.hms.harvard.edu / hmni Email address:
hmni@hms.harvard.edu Views expressed by authors are their own and do not necessarily reect views of HMNI. ON THE BR A I N nonprofit org. US Postage Paid Boston, MA Permit No. 53825 correspondence /circulation Landmark Center 401 Park Drive, Suite 22 West Boston, MA 02215 Knowing how particular causes or triggers
contribute to autism, researchers may be able to
develop blood or urine tests, as well as biomedical
therapies. Additionally, understanding interaction
between the brain and body in autism may lead
to interventions that treat the body and also have
an impact on brain function and behavior. Studies of how autism develops have been conducted tracking high-risk younger infant siblings
of children diagnosed with autism, but until now
these studies have only measured behavior and
have not studied body and medical issues. My hunch, says Dr. Herbert, is that when we do whole-body studies of how autism develops, the
biological responses will change before behaviors.
Its important to identify autism early, and well do
a better job [with early identication] when we
understand whats going on not just behaviorally
but also in the whole body. Remember that when
we call autism a systems disorder, we arent down-
playing the brain part. Were just saying that the
brain is in the body, and that there are multiple
dimensions at work here, not just the brain. A Systems Approach to Autism continued from page 3 For additional subscriptions or changes to the On the Brain mailing list, please contact Jennifer Montfort at 617-384-8483 or by e-mail at jennifer_montfort@hms.harvard.edu