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Anger and the Brain
continued from page 7
ON THE BRAIN
harvard mahoney
neuroscience institute
Perlis cautions that the success of anger
management and CBT depends on the quality of Council Members:
the program­ who designed it, who runs it, how
— Hildegarde E. Mahoney, Chairman
intensive it is, and the individual’s motivation. Steven E. Hyman, MD
“You need to be motivated to change your Caroline Kennedy Schlossberg
behavior,” he says. “When you get to the point
Ann McLaughlin Korologos
that you recognize what the anger is doing to
Joseph B. Martin, MD, PhD
yourself and others, that’s the time to get into an
anger management program and when anger Edward F. Rover
management is most successful.” Daniel C. Tosteson, MD
Other avenues for treating anger include Writers, Editorial Advisors:
medications such as antidepressants and anti- Scott Edwards, Tamsen S. McMahon,
convulsants, the latter of which help with Jennifer L. Montfort
impulsivity, and a class of drugs called serenics, Design:
which Dougherty says work primarily through Gilbert Design Associates, Inc.
dampening limbic system responses. Treating Harvard Mahoney Neuroscience Institute
underlying mood disorders or depression can also Landmark Center
help alleviate angry outbursts. 401 Park Drive, Suite 22
Boston, MA 02215
Perlis says it is important to remember, however,
that “everyone gets angry; not everyone needs Internet address:
www.hms.harvard.edu/hmni
treatment.”
Email address:
hmni@hms.harvard.edu
Views expressed by authors are their own and
do not necessarily reflect views of HMNI.

2. on the br ai n
the harvard mahoney neuroscience institute letter
Cognitive Neuroscience: Understanding Winter 2009
Vol. 15, No. 1
Complex Human Behavior and the Brain
contents
S
ince the dawn of civilization, humankind friendship, self-defense and courage, vanity,
has tried to answer vexing questions about the circumspection, sense of language, and kindness, 1 ognitive Neuroscience:
C
relationship between the body and the mind. among others. A person’s capacity for a given Understanding Complex
In the last 20 years or so, the scientific and medical personality trait was determined by the size of that Human Behavior and
communities have made great strides in answering “brain organ,” and could be measured by the area the Brain
the question of how physical matter (the brain) of the skull that covered a given region of the brain 3 he Stress of Poverty
T
relates to mental (cognitive) phenomena such as in which the specific trait was thought to reside. Affects Childhood Brain
perception, memory, learning and attention. In large While some of the assumptions of phrenology Development
part, the study of that relationship resides in the are still valid (such as certain mental processes
5 mall Amyloid Assemblies
S
relatively new field of cognitive neuroscience. being localized in the brain), the shape of a person’s
Provide New Target for
“Cognitive neuroscience is a discipline that skull is not a reliable predictor of personality. Alzheimer’s
merges psychology and basic neuroscience,” says “Gall and Spurzheim [Johann Gaspar Spurzheim
Dean F. Salisbury, PhD, an associate professor of was a German physician and chief proponent of 6 nger and the Brain
A
psychiatry at Harvard Medical School and director phrenology] went overboard on localization,” says
of the Cognitive Neuroscience Laboratory at Salisbury. “They said that when you have more of
McLean Hospital. “We’re trying to understand that personality trait, then that area of your brain
complex human behavior in the construct of is bigger. Looking at bumps on your head is a cute
plausible brain systems.” idea, but cognitive neuroscientists don’t have lot in
Taking a multidisciplinary approach to the common with that extreme form of phrenology.”
study of the brain and human behavior, cognitive While many cognitive neuroscientists still
neuroscience involves the study of internal mental follow the theory of localization, the more modern
processes and the chemistry, physiology and continued on page 2
anatomy of neurons and neural systems. It also
examines theories that explain the relationship
between the brain and behavior and compares
neural systems across species.
A “cute idea”
The roots of cognitive neuroscience lie in the same
work as the now defunct field of phrenology in
which personality traits were determined by
“reading” bumps and fissures on an individual’s
skull. Developed by German physician Franz
Joseph Gall around 1800, phrenology was based on
the concept of localization; that is, that certain
areas of the brain have specific, localized functions.
Gall believed that the brain was made up of 27
different “organs” that created an individual’s
personality. These organs included affection and

3. Cognitive Neuroscience: Understanding Complex Human Behavior and the Brain
continued from page 1
thinking is that behavior is governed by both psychiatrists are using the newer methods of MRI,
local action and distributed networks throughout which provide better spatial resolution of activity
the brain. within the brain than earlier EEG-based tools.
Imaging drives science Clarifying thought disorders through imaging
Advances in imaging technology have driven In the Cognitive Neuroscience Laboratory at McLean
modern-day cognitive neuroscience. In the last 20 Hospital, Salisbury has spent the past 16 years
years, in fact, modern imaging techniques have studying brain structure and function, trying to
significantly contributed to the emergence of determine what regions of the brain are abnormal
cognitive neuroscience as a discipline. in mental illnesses such as schizophrenia and
While a host of imaging methods are used, bipolar disorder and what the brain looks like in
three techniques—EEG, functional MRI, and the early courses of these diseases. Among other
structural MRI—form the basis of much of the studies, he uses multimodal brain imaging to
work done in cognitive neuroscience. The first, EEG examine cognitive-level thought disturbances.
(electroencephalography), measures the electrical Thought disturbance is a cardinal symptom of
activity produced by the brain. Abnormal EEG schizophrenia, a mental disorder characterized by
results can indicate irregular brain structures and abnormalities in the perception and expression of
can be a sign of attention problems, seizure disorders, reality. The disease typically includes auditory
or confusion. Salisbury says EEG and extraction of hallucinations, paranoid or bizarre behavior, or
specific event-related brain activity from the EEG disorganized speech and thinking. Salisbury and
lets scientists see electrical activity changes “at the his colleagues are combining behavioral measures
speed of thought.” and brain activity measures to clarify the nature of
Secondly, through advances in magnetic thought disorder and cognitive dysfunction in
resonance imaging (MRI), researchers and clinicians schizophrenia with respect to actual brain structure
can see brain activity while a person is performing and function.
certain functional tasks. Functional MRI (fMRI) is a Until recently, it was thought that schizophrenia
relatively new procedure that uses MRI scans to was caused by poor interpersonal relationships
measure metabolic changes that take place in an between the patients and their mothers. Better
active part of the brain. This technology is used to imaging techniques, says Salisbury, allow researchers
examine the brain’s anatomy to determine which and clinicians to identify changes in the brains of
areas are handling critical functions such as thought, schizophrenics and develop interventions to halt
speech, movement and sensation. the process and possibly cure the disease.
Thirdly, structural MRI maps the water volume If a specific brain function is localized to a
inside the body. Because different tissues have certain area, MRI can measure that area to see if
different amounts of water in them, structural MRI varying gray matter volumes lead to different
gives a very detailed image of these tissues. Unlike brainwave patterns. Bigger brain areas might not
X-rays or CT scans, structural MRI is not affected mean better performance, Salisbury says, but even
by the skull bone and thus gives an extremely fine subtle pathology in the these areas generally leads
picture of brain structure, with the greatest contrast to functional consequences to which the brain
between gray and white matter. Gray matter waves are sensitive.
is akin to a computer, while white matter is like “If you believe the brain is important for human
the cables connecting the different computer behavior,” he says, “then cognitive neuroscience is
components to one another. By providing the relevant. It’s important to think about human
highest resolution of brain anatomy, Salisbury behavior and how it might be served by the
says, structural MRI is valuable for cognitive brain. Cognitive neuroscience gives us information
neuroscientists because is allows for very precise about the human condition based on plausible
measurement of brain volumes in specific areas. information about the brain. It helps us understand
“EEG has been large in cognitive neuroscience how we work and helps us design interventions
since the late 1960s, early 1970s,” says Salisbury. based on the brain mechanisms involved.”
“Other [technologies] that came along in the A long way, indeed, from feeling a bump on
’90s have taken over.” He adds that increasing someone’s head.
numbers of cognitive neuroscientists and research
on the brain

4. The Stress of Poverty Affects Childhood Brain Development
T    of developmental diffi-
culties among poor, disadvantaged children
has been chronicled for years. We don’t, says
brain. In early childhood, the brain is genetically
programmed to develop many more synapses than
it will ever use, with different circuits being formed
Jack P. Shonkoff, MD, need another study simply in different areas of the brain at different times.
documenting that association. This brain circuitry is influenced by a blend of
“We’ve known for a very long time that there’s genetics and experience.
a link between low income or low parent education “The brain expects the environment to influence
and poor school achievement as well as increased its evolving circuitry,” says Shonkoff. “These circuits
risk for physical and mental health problems,” are literally shaped by personal experience.”
says Shonkoff, the Julius B. Richmond FAMRI This process of circuit building results in what
Professor of Child Health and Development and some scientists call biological embedding; that is,
director of the Center on the Developing Child at experience gets built into our bodies and has
Harvard University. physiological effects on the brain as well as other
The big question, he says, is why? What is it developing organ systems. Stable, predictable rela-
about poverty and low parent education that leads tionships and a nurturing environment, he adds,
to children having more problems in school and in may create stronger brain circuits. Likewise, sound
life? Shonkoff and his colleagues at the Center on circuits for learning may require an environment
the Developing Child are among those who are with plentiful opportunities for interaction and
trying to understand the causal mechanisms that safe exploration.
link highly stressful experiences with later problems Parents who are preoccupied with the daily
in learning, behavior and health. struggle of putting food on the table and shelter
According to the National Poverty Center at over their family’s head often don’t have the
the University of Michigan, children represent a resources, education or time necessary to provide
disproportionate percentage of the poor in the the kinds of experiences that could be required to
United States. Children make up nearly one- facilitate healthy brain circuit development in their
quarter of the total U.S. population, but account children. Shonkoff says that in poor, less educated
for 35 percent of the poor. In 2007, 13.3 million families there is reduced language interaction
children, more than 17 percent of the children in between parents and children, and the stresses
the country, lived in poverty. associated with poverty can produce physiological
responses that derail the healthy development of
The developing brain brain circuitry.
At the time of birth, the architecture of the human According to The Ounce of Prevention Fund,
brain is underdeveloped. The brain, as it grows, is an organization dedicated to helping children
constantly wiring and refining the connections in low-income families overcome the challenges
among its trillions of nerve cells and the synapses continued on page 4
through which messages are sent throughout the
“The brain expects
the environment
to influence its
evolving circuitry,”
says Shonkoff.
“These circuits
are literally shaped
by personal
experience.”
—Jack P Shonkoff, MD
.
ON THE BRAIN

5. The Stress of Poverty Affects Childhood Brain Development
continued from page 3
of poverty and prepare for successful schooling, High quality programming to help
“Infants and children who are rarely spoken to, the brain develop
who are exposed to few toys, and who have little The principles of neuroscience inform “reasonably
opportunity to explore and experiment with their good” guidelines for clinicians and policymakers
environment may fail to fully develop the neural who want to promote healthy brain development
connections and pathways that facilitate later in poor children, says Shonkoff. An environment
learning. Despite their normal genetic endowment, of stable, nurturing relationships and varied
these children are at a significant intellectual opportunities for learning produce positive effects.
disadvantage.” Healthy brain development can also be promoted
by protecting children from chronic adversity. Exactly
‘Toxic stress’ alters brain circuitry
how to do this in the most effective way, however,
Significant and continuing stress can have a has been a public policy challenge for decades.
negative impact on early brain development. The The place to start is to think about how
day-to-day adversity of severe poverty and communities support families with young children,
parental mental health problems such as maternal says Shonkoff. Many times parents are not aware
depression, which has a higher prevalence among of how their interactions affect their children’s
poor women, can compromise parent-child development. This includes talking and playing
interaction. The resulting lack of responsiveness— with them or reading to them at an early age. In
as well as violence, abuse, drugs and alcohol— situations where parents can’t provide what children
is incredibly stressful for children, says Shonkoff. need, due to extreme poverty, substance abuse,
Unrelenting stress in the absence of supportive mental illness, or violent relationships, interventions
relationships with adults —referred to as “toxic targeting the source of the stress as well as the
stress”—causes a prolonged activation of the needs of the family and children are essential.
body’s stress response system, which includes the Universal access to prenatal and primary
release of stress hormones such as cortisol. Released health-care services is also essential, so all children
by the adrenal gland, cortisol circulates in the can benefit from early diagnosis and preventive
brain during the body’s fight-or-flight response to measures, and affordable, accessible, high-quality
stress. Under normal circumstances, cortisol has childcare programs can provide nurturing
short-term benefits that help protect us from environments that promote learning. In a study
danger. When the cortisol system is repeatedly in the late 1990s, the National Center for Early
activated, however, levels of cortisol remain high Development and Early Learning found that,
and can actually damage the brain. because childcare providers are often poorly
“The area of the brain most sensitive to elevated trained, a majority of children in lower quality
cortisol is the hippocampus,” says Shonkoff, “the daycare programs “do not have the opportunity to
region of the brain where basic memory and early form the kind of comfortable, secure relationships
learning circuits are developing. High levels of with a caregiver who will promote their healthy
cortisol can kill brain cells and disrupt circuit emotional development.”
development in this region.” Shonkoff says that childcare and educational
Constant adversity also produces what scientists programs for low-income children can be organized
call allostatic load, or the physiological costs of “based on what the brain needs to develop in a
chronic stress, which include high blood pressure, healthy way.” The quality of these programs—in
increased heart rate, and elevated blood sugar and terms of staff training and stability, a language-rich
cortisol levels. Shonkoff says this may help explain environment, high ratio of adults to children, and
why rates of hypertension, diabetes and heart disease safety, among other aspects—is essential.
are higher in low-income populations. “Chronic “We know the characteristics of good quality
activation of the stress response system precipitated programs,” he says, “and if a program has those
by deep poverty,” he says, “causes phys­ological
i features, we know it will be more successful in
changes that can affect the cardiovascular system, helping children develop.”
brain circuits that influence learning and memory,
and other metabolic systems.”
on the brain

6. Small Amyloid Assemblies Provide New Target for Alzheimer’s
I n the early 1 990s, Dennis Selkoe, the Vincent
and Stella Coates Professor of Neurological
Diseases at Harvard Medical School and neurologist
a key role in memory, attention, language and
perceptual awareness.
Two abnormal structures—plaques and tangles
at Brigham and Women’s Hospital, made a discovery —are the primary culprits that cause damage to
that provided an important clue to the development nerve cells in the brains of Alzheimer’s patients.
of Alzheimer’s disease. He and a group of researchers Plaques, which build up between nerve cells
found that even normal brain cells produce soluble (including outside the synapses), contain large,
forms of amyloid beta-peptide (Abeta), the protein insoluble fibers of Abeta protein. Tangles are twisted
found in the plaques of patients with the disease, fibers of another protein, called tau, that form inside
raising the possibility—since confirmed—that some nerve cells. Scientists have long debated what
Alzheimer’s might actually be a direct consequence roles plaques and tangles play in Alzheimer’s, but
of Abeta over-production. Selkoe and his colleagues they now believe that plaques precede tangles and
soon showed that when mutant forms of certain that the two lesions act in concert to block
genes are present in Alzheimer’s patients, the communication among nerve cells and disrupt the
cellular production of Abeta is doubled, or more. activities required for neurons to survive.
Now, Selkoe and his coworkers have taken that The early stages of Alzheimer’s occur when
knowledge a step further. Using extracts of human memory begins to diminish, although the patient
brain tissue obtained from patients who died of usually needs little or no assistance with daily
Alzheimer’s, Selkoe has found that dimers of Abeta, routines at that point. After diagnosis, patients
the smallest possible assembly of the protein, can gradually progress beyond early-stage disease,
lead to the dysfunction and loss of synapses that reaching a more advanced stage that is associated
are the hallmark of early Alzheimer’s disease. A with confusion, irritability, aggression, mood swings,
synapse is the point of connection between two and long-term memory loss for which there is
nerve cells through which chemical signals travel. currently no cure. Eventually, bodily functions are
“Like most things with Alzheimer’s, these lost, ultimately leading to death.
dimers [so-called because they consist of two small
molecules that bond together] appear very early in Destructive dimers
the disease process, even many years before In their study, published in Nature Medicine in June
clinical symptoms,” says Selkoe. “We don’t know 2008, Selkoe and his team, which included Ganesh
precisely how they induce synaptic dysfunction, Shankar, Shaomin Li and Bernardo Sabatini, all of
but we speculate it is because they bind to Harvard Medical School, tested extracts of cerebral
neuronal membranes and perturb important cortex taken from the brains of people who died of
proteins within them.” Alzheimer’s or other dementias, as well as those
Selkoe says the findings are significant because without dementia. They found significant amounts
this is the first time Abeta assemblies have been of soluble Abeta in the brains of Alzheimer’s
isolated from the brains of actual Alzheimer’s patients and little in any of the others.
patients and their effects established. “Others have Previous postmortem brain studies showed
studied Abeta effects in genetically engineered that soluble forms of Abeta correlate most strongly
mice or with synthetic Abeta in cell culture,” he with the cognitive symptoms of Alzheimer’s. The
says, “but not from a human host. We feel this is researchers found that small soluble Abeta
the real significance of the study.” assemblies taken from patients’ cortices inhibited
long-term potentiation (LTP) and encouraged long-
Plaques, tangles are culprits in Alzheimer’s term synaptic depression. LTP is an electrical correlate
Alzheimer’s disease is a progressive, fatal disease of the strengthening of the connection between
that destroys brain cells, causing problems with two neurons and is commonly regarded as a
memory, thinking, and behavior severe enough to surrogate for the cellular basis of memory. Long-
interfere with daily life. According to the Alzheimer’s term synaptic depression is the selective weakening
Association, the disease affects nearly 5 million of neuronal synapses.
Americans and begins its development in the “We’re not certain why these dimers are so
hippocampus, the part of the brain responsible for destructive,” says Selkoe. “We think small is bad
memory. From there, it appears to spread to the because the dimers are easily diffusible and can go
cerebral cortex, the brain’s outer layer, which plays continued on page 7
on the brain

7. Anger and the Brain
This is the first
in a series of
articles on how
T he physical sign s of anger are unmistak-
able. Our heart rate increases, sometimes
climbing from a normal 80 beats per minute to
MD, a psychiatrist at Massachusetts General Hospital
and associate professor at HMS. “Most people have
intact, functional OFCs, so they are able to avoid
internal and more than 180; our blood pressure elevates to frequent bouts of rage. Of course, our findings are
external forces often dangerously high levels. Breathing becomes that patients who do have frequent bouts of rage,
affect the brain. more rapid as we try to get additional oxygen into do not activate their OFCs to the degree that healthy
our bodies, the muscles used for the fight-or-flight volunteers do.”
reaction tighten, and the energy outburst can Perlis, whose work focuses on regions of the
cause a deficiency in our blood sugar that makes brain influenced by genetics, says there is likely a
us literally “shake” from anger. But, what is going genetic component that influences how we respond
on in our brain when we get angry? to anger, either controlling our own or responding
to others who are angry. Some studies suggest that
twins are more likely to act similarly to hostility
and anger than are unrelated people.
“There is some inherited factor [that predisposes
one to angry outbursts],” he says. “There’s some
normal variation in the population, so we know it’s
not pathological, just like we know there are some
people who are 6 feet tall and others who are 5’9”.”
Psychiatric disorders, including depression and
bipolar disorder, influence how prone one is to anger.
More than half of those with major depression
report significant problems with irritability, says
Perlis, so “as often as depression is about sadness,
it can also be an angry state.” Bipolar disorder is also
tied to anger, with irritability often being a primary
“A lot goes into anger,” says Roy Perlis, MD, an feature of the illness. In addition, substance abuse
assistant professor of psychiatry at Harvard Medical has a strong effect on anger and its consequences.
School who studies anger and the brain. “There’s In general, Perlis adds, anger is a normal,
the physical: the pounding heart, sweating, sometimes even healthy, emotion. “People shouldn’t
gestures: and the mental: thinking about why be afraid to get angry,” he says. “We worry about
you’re angry and what you’re going to do about it. it when it impacts the individual’s or others’ lives
So, as far as the brain is concerned, anger is both or becomes pervasive.”
cortical [higher cognitive aspects] and subcortical
[physiological aspects].” Emotion and control
Imaging studies have shown that in normal In 2004, Dougherty and his colleagues published
individuals (those without underlying mental or findings in the Archives of General Psychiatry, showing
physical illnesses), there is increased activity in the that people suffering from major depressive
orbitofrontal cortex (OFC), the area of the brain disorder (MDD) and anger attacks have decreased
behind the forehead that controls reasoning and blood flow to the OFC and amygdala, which
other higher cognitive functions. At the same time, reduces their ability to control impulsive acts and
blood flow to the amygdala, the almond-shaped the feelings about the consequences of their actions.
region deep in the brain that controls emotions, Thus, they suffer both a lack of emotion and a lack
also increases its activity. Angry emotions in the of control. Dougherty’s team found significantly less
amgydala are thus cooled by activity in the OFC, activation of the OFC in patients with MDD with
inhibiting our thoughts of rage. anger attacks when compared to a control group,
But, why then, do we not fly into a fit of rage but did not find a difference in amygdala activation
every time we become angry? between the groups. The amygdala came into play
“Our, and others’, hypothesis is that the OFC when they looked at areas of the brain that
plays a crucial role as a brake when our limbic correlated with OFC activation. In normal patients,
system [which includes the amygdala] is active; that they found a healthy inverse reciprocal relationship
is, when we are emotional,” says Darin Dougherty, in function between the two structures, whereas
ON THE BRAIN

8. this relationship was exactly the opposite in MDD Changing the way we think, feel, act
patients with anger attacks (with MDD patients While it is hard to change a habitual behavior such
without anger attacks falling in the middle). as anger, formal anger management programs that
“We don’t know that the underlying neurobiology focus on reducing both emotional feelings and the
of frequent rage attacks in patients with major physiological arousal that contributes to anger can
depression with anger attacks is any different than help individuals control their reactions. Perlis says
that in other populations who have frequent rage that anger management programs that are based
attacks,” says Dougherty. “In fact, studies of patients on cognitive behavioral therapy, or CBT, are often
with borderline personality disorder (BPD) or the most successful.
intermittent explosive disorder (IED) exhibit results CBT is an umbrella term for several types of
very similar to ours. We chose patients with major therapies. These are all based on the idea that our
depression with anger attacks as a convenient thoughts, not external things like other people,
vehicle for studying rage attacks, whereas others situations and events, cause our feelings and
have studied BPD and IED.” behaviors. The benefit of this is that we can change
Harvard researchers, including Ronald Kessler, the way we think, feel and act even if the situation
PhD, a professor of health-care policy at HMS, found doesn’t change.
that IED, a disorder characterized by frequent bouts “The approach to anger would be to either lessen
of angry and potentially violent outbursts, affects the limbic response, strengthen the brakes in the
nearly 16 million adults and may predispose them OFC, or a combination of the two,” says Dougherty.
to other mental illnesses and substance abuse. “CBT utilizes cortical regions, such as the OFC and
other prefrontal areas, and strengthens them so
they are better able to suppress limbic responses.”
continued on page 8
Small Amyloid Assemblies Provide New Target for Alzheimer’s
continued from page 5
into the synaptic cleft, bind to membranes, and Four related clinical trials are currently being
cause local damage.” conducted in the United States and Europe to
The HMS team also collaborated with scientists determine if an N-terminus antibody can neutralize
at University College Dublin to test human Abeta’s the adverse effects of Abeta dimers in Alzheimer’s
effect on behavior. They injected soluble Abeta patients. Unpublished results of a Phase II study,
dimers isolated from patients’ brains into the conducted by Elan Corporation and Wyeth
brains of adult rats and found that the dimers Pharma­ euticals, showed some encouraging results
c
induced certain characteristics of Alzheimer’s in in patients with mild to moderate stages of
the rats, specifically disrupting the memories of Alzheimer’s.
newly learned behaviors. The dimers, they further The HMS research has implications beyond
determined, acted directly on synapses, damaging Alzheimer’s disease. The same Abeta process that
the connections that are essential for neuron-to- causes Alzheimer’s, Selkoe says, can also contribute
neuron communication. to age-related mild memory loss. “There are other
reasons [for age-related memory loss] than Abeta,”
Neutralizing Abeta he says, “but some percentage is represented by
The findings provide a potential new target for Abeta attacks on neuronal synapses.”
anti-Alzheimer’s drugs, including antibodies that Selkoe says the next step in the research is to
effectively neutralize Abeta dimers, says Selkoe. fully purify Abeta dimers and trimers from patients’
His team found that antibodies that target the first brains, label them with radioactive chemicals, and
amino acid at the beginning of the Abeta protein bind them to slices of mouse brain to determine
worked best at neutralizing the protein. which specific neuronal receptors are impaired by
human Abeta. These receptors may provide
additional targets to attack with drugs.
on the brain