BIOLOGY OF BEHAVIOR / THE POSSIBLE LINK BETWEEN GENES, ATTENTION DEFICIT

DANIELLE SITS quietly for the moment, thinking, huddled in the corner of her
classroom closet, waiting for the proverbial shoe to drop. She had just
screamed at her teacher and left the floor awash in papers and pens and
books and, well, mess. She can't quite say why she gets so mad and confused,
but she knows that her life schedule revolves around taking medicine to
control her behavior and her ability to sit still and focus.

The 10-year-old has Attention Deficit Hyperactivity Disorder, so complex a
condition that doctors and teachers and parents have taken a hand in
diagnosing it. Since kindergarten, the school nurse has come up every lunch
hour to hand Danielle her medicine, Ritalin. This is an amphetamine-like
drug that has perplexing but positive effects on people with ADHD: the
stimulant calms them down.

Danielle speaks for the millions of children - and more recently adults -
treated for ADHD when asked what the medicine does: "It helps me behave,
think, and pay attention."

Researchers estimate that 5 percent of the child population suffers from
ADHD. Rachel Klein, a clinical psychologist in the psychiatry department at
Columbia University College of Physicians and Surgeons in Manhattan, says
that there is a great neuromythology when it comes to talking about the
condition. The behavioral deficit is obvious - inattention, disruptive
behavior, inability to sit still - but the underlying biological problem
is still elusive. What is it that makes these kids different?

Russell Barkley, an ADHD expert, has been thinking hard about this condition
for decades. Director of psychology and professor of psychiatry and
neurology at the University of Massachusetts Medical Center in Worcester,
Barkley has fashioned a theory that has been greeted with enthusiasm by
colleagues trying to understand what triggers these complex problems. His
ideas appear in his latest book, coauthored with Christine M. Benton: "The
Defiant Child: 8 Steps to Better Behavior," published by Guilford Press.

To understand why people with ADHD are different, Barkley says that you must
first know something about how people normally learn self-control. It
develops in the first few years of life, when children learn to inhibit, or
stop, themselves from responding to their environment. You want a snack?
Wait until dinner is over. You want a new video game? Get good grades and at
the end of the year it is yours. In other words, humans learn to delay
rewards.

"There are four executive abilities that children learn during these years
that help them delay, or wait, for rewards," Barkley said. Each of these
abilities develops slowly, and in sequential order.

The first is working memory, which is generally in place by the child's
first birthday. A child has the ability to hold a thought in his mind and
wait. The constant chattering over the next few years begins to take on new
flavors as the child learns to internalize speech. Around 8, they no longer
talk aloud to themselves. They can keep their thoughts in their heads. At
this age they are also able to internalize their emotions and don't make
public displays of their feelings. This is an important stage, Barkley said,
because it is during this time that children learn private motivation. They
can carry out a behavior even though rewards might be days, weeks or months
away.

Barkley said that the last of these executive functions is inventiveness.
The ability to invent new behavior when faced with an obstacle or old
strategy that doesn't work. Together, all of these high-order functions aid
in the regulation of self-control. Importantly, all of these abilities come
with a sense of time, a skill necessary to plan for the future.

Barkley contends that children with ADHD suffer from an impairment in the
development of this first skill: inhibition. With this system thrown out of
sync, the development of working memory is slowed and the other executive
functions never take shape naturally. The most obvious result is seen in
behavior: kids talk aloud for years longer than normal; they don't acquire
private motivation and constantly seek external rewards; they can't solve
problems; and finally, their sense of time is devastated. They can't
organize around time - they are governed by the "now" - and they are
very disorganized as a result. Barkley calls it "time blindness."

These executive functions seem to be unique to humans, which means that they
probably developed in the most recent evolution of the brain. These regions,
called the frontal lobes, have actually been found to be less active and
smaller in children - and adults - with ADHD.

"It's quite a provocative theory," Klein said. "We know how to diagnosis the
disorder, we know how to treat it, but what has been missing is the
underlying biological defect."

Recently, scientists from seven laboratories have confirmed an association
between ADHD and a gene linked to sensation-seeking behavior. It turns out
that 18 percent to 27 percent of people with ADHD have an abnormal number
of repeats on a gene called DRD4. Normally, a gene is composed of three
base pairs that repeat themselves like a string of letters three to four
times. In 7 percent to 10 percent of the population, scientists are now
finding seven repeats of this string of genetic letters, or code. The
result, some studies suggest, is that cells are less sensitive to dopamine,
a brain chemical. It's like the need to raise your voice when speaking to
someone who is hard of hearing. The cells require more dopamine to function
normally.

Because this gene is not found in the majority of ADHD children, however,
scientists are hunting for other candidates. As with any psychiatric
condition, once scientists understand what these genes do and how they go
awry, they can design medicines to help.

It is often only during the first year of school that ADHD children come to
the attention of people who may be able to help. A major problem for
Danielle and others with ADHD is that they act on impulse rather than
thought. When Danielle gets mad, she might pour soda over her sister's head,
or bring a room down around her. Does she know it's wrong? "Yes," she says.
Does she care? "No."

Danielle on medicine is an engaging child with far-reaching interests. She
can sit for hours at a computer game building puzzles; she can talk about
the Civil War with adult skills. She asks lots of questions about life going
on around her and is sincerely interested in the answers. In a group of
children, Danielle is often the one who feels most comfortable alone. The
difference between Danielle on medicine and off medicine is her impulsivity.

"I don't misbehave," she says, her smile revealing her shyness.

A federally convened panel met earlier this month to discuss the
state-of-the-art in ADHD. The group concluded, not without a firestorm, that
the psycho-stimulant Ritalin is the most effective treatment available. As
with any medicines, there are side effects. Some children complain of
feeling tense, irritable and unable to sleep. And no one knows how long a
person must stay on Ritalin. It seems that many of the overt behaviors -
the talking aloud, the impulsivity - begin to disappear in late
adolescence.

Behavior therapies have also helped parents learn to manage their children -
on and off medicines. These strategies, however, have to be practiced moment
by moment and can be exhausting for parents, teachers and the children
themselves. Doctors now say that the condition is lifelong, even though
symptoms are different in adults. Motivation and the ability to focus are
the primary complaints of adulthood.

Researchers at the State University at Stony Brook recently finished a
decade-long study to determine whether ADHD children were at greater risk
for drug abuse in late adolescence or adulthood.

Jan Loney, a psychologist at Stony Brook, began her work at the University
of Iowa, where she had a natural study design. There was one doctor who
always medicated the children he diagnosed, and another who never did.

The people selected for the study had been seen between 1967 and 1978, when
they were between 6 and 12 years old. In total, 187 boys were medicated and
37 had never been treated with Ritalin. They also pulled together a control
group: 49 junior high school students without attention or impulse
problems. The study followed up when the particpants were in their early
20s.

They were asked about their attitudes towards medication: if they ever
experimented with drugs, had friends who exposed them to drugs, and were
currently using illegal substances.

Those with an ADHD diagnosis had fewer episodes of experimentation and
involvement with illegal drugs. The ADHD patients were far more likely to
abuse alcohol, however, but there was a big difference between those who
had received medicines as a child and those who hadn't. According to
Loney, 30 percent of the medicated ADHD patients were alcoholics compared
with 45 percent of the unmedicated patients. By comparison, 18 percent of
the control group had a drinking problem.

These findings were presented earlier this month during the federal panel
convened by the National Institutes of Health. Loney stresses that this
study was conducted during a different drug-culture climate, and findings
could be different if conducted today. There is another important message,
Loney said. "Medication seems to be important, and that there could be
hazardous consequences if children don't receive treatment."

Checked-by: Rolf Ernst