Brain imaging method may
lead to better diagnosis
BY KATHLEEN O'TOOLE
Stanford neuroscientists have found a
clear difference in brain functioning between boys who
have attention deficit disorder [ADD] and those who do
not, a step that could lead to better diagnosis of the
most common developmental disorder of childhood.
Follow-up studies will be required
before the results of this study on a small number of
boys can lead to brain-based methods of diagnosis,
caution the lead researchers, Research Associate Chandan
Vaidya and Associate Professor John Gabrieli of
Stanford's Department of Psychology. Theirs is the first
study, however, to show that Ritalin, the drug most
commonly used to treat ADD, has different effects on the
brains of people with and without ADD, and where those
differences occur in the brain. The findings are reported
in the Nov. 24 issue of the Proceedings of the
National Academy of Sciences.
The study is also the first to use
functional magnetic resonance imaging [FMRI] in the study
of ADD. This imaging method can show brain differences in
individual people, instead of in averages of differences
of two groups. This is critical for diagnosis, which has
to be established on an individual basis. Unlike methods
used in other studies of ADD, FMRI does not require
injection or inhalation of radioactive substances. It
relies instead on naturally occurring changes in brain
function, which makes it appropriate for research and
clinical purposes for children.
Co-authors of the study are medical
doctors Glenn Austin and Hugh Ridlehuber and school
psychologist Gary Kirkorian of the Community/Academia
Coalition in Los Altos, Calif. and Gary Glover and John
Desmond of the Stanford Medical Center's Radiology
Department.
Child
with attention
deficit disorder
off
Ritalin (left), with Ritalin (right)
The green
rectangles highlight a brain region known as the striatum
where researchers found differences in brain activity
between boys with and without attention deficit disorder
while the boys were performing an impulse-control
activity.
Note that
the drug Ritalin, the most common treatment for attention
deficit disorder, increased activity in the striatum of
the 10-year-old boy diagnosed with attention deficit
disorder and decreased the activity in the brain region
for the 10-year-old boy who does not have ADD. The study,
using functional magnetic resonance imaging, is the first
to show that Ritalin has different effects on the brains
of people with and without ADD, which points to a
potential future method for diagnosis.
Child
without
attention deficit disorder
off
Ritalin (left), with Ritalin (right)
The findings have drawn
considerable attention from neuroscientists because
"ADD is so widespread, so controversial and
confusing, and these are among the few clear findings in
that field," said Gabrieli, who heads the brain
imaging laboratory where the research was done. Attention
deficit disorder, which often includes hyperactivity, is
currently diagnosed on the basis of subjective
observations of youngsters' behavior. If the new findings
can be replicated, he said, it might be possible to make
a biological diagnosis of the disorder by using FMRI.
Since the common treatment for ADD is a prescription drug
whose long-term effects on brain function are not known,
parents and pediatricians most likely would welcome a
more definitive way to diagnose the disorder.
In the study, 16 boys
between the ages of 8 and 13 were asked individually to
play a mental game while lying in a magnetic resonance
imaging device, which was set to image front portions of
the brain, including the frontal-lobe cortex and the
striatal structures below it. The boys, 10 of whom had
been diagnosed with ADD and 6 of whom had not, were
instructed to press a button when they saw any letter of
the alphabet except the letter X on a display screen.
Because most of the letters were not X, each child built
up a predisposition to press the button and needed to
control his impulse to press the button when he saw an X.
The task was expected to be, and in fact proved to be,
more difficult for the boys with ADD, because poor
impulse control is one of the disorder's symptoms.
Comparing the brain images
later, researchers found a clear difference in the
activation of neuronal tissue in two structures in the
striatal region, which is known to be involved in motor
control. The brain activation differences between the
boys with ADD and those without were even more dramatic
when the subjects were asked to perform the same task
after taking the drug Ritalin. Ritalin is a stimulant
medication used to temporarily relieve symptoms of ADD,
such as inattention, impulsivity and hyperactivity.
"Both the normal kids
and the ADD kids got better in their impulse control when
they had taken the drug," Vaidya said. "Ritalin
improved everyone's performance, but how it actually did
it differed in the brains."
The boys with ADD showed
more activity in the affected striatal structures
(specifically known as the caudate and putamen) when
taking the drug than when not. The healthy boys, in
contrast, showed the reverse less activity in those
areas when taking the drug than when not.
"From past work with
adults and children, some of which required injecting
radioactive material, a consensus developed that it is
the frontal striatal circuitry of the brain that is
what's not right with this disorder," Vaidya said.
"That is why we imaged this part of the brain, and
our study confirmed that these structures are, indeed,
important for ADD."
Ritalin primarily, but not
exclusively, influences dopamine neurotransmission. The
opposite effects of Ritalin on boys with ADD and boys
without the disorder suggest that ADD involves atypical
dopamine modulation in the striatum, she said.
The researchers caution
that the study was conducted with a small group and needs
to be replicated with girls as well as with more boys
before they can be certain they have found a universal
neurobiological marker for the disorder.
They also reported that
they tried the experiment on three other boys who had not
been diagnosed with ADD but who had siblings with the
diagnosis. Two of the three siblings of ADD boys showed
some Ritalin enhancement of the striatum, as did their
affected brothers.
"This would lend some
support to the idea that ADD may involve atypical genetic
influences on dopamine modulation," Vaidya said, but
more studies would be necessary to establish a genetic
influence.
Because of the widespread
interest in ADD, the researchers also were careful to
point out other limitations of their study. A fraction of
people diagnosed with ADD have not responded to Ritalin
treatment, and this study did not include such children,
they said. It also did not attempt to investigate
possible changes in brain activation that might occur
with the drug over time. The ADD boys did show a
different brain activation level when not on the drug,
but all of them had been taking Ritalin previously as
part of their ongoing treatment.
Despite these limitations,
the study points to new directions for research into
brain function that could improve individuals'
performance.
"This is one of the
few studies to examine brain function in children, and to
further our knowledge about normal and abnormal brain
development," Gabrieli said. "It suggests that
FMRI is a powerful tool to examine brain and behavior in
the context of both normal and abnormal
development."
Currently, ADD impairs the
function of an estimated 3 to 7 percent of youngsters in
home and school, and the long-term consequences include
lower educational and vocational accomplishments for them
as adults as well as an increased risk for drug abuse and
other risky behaviors.
The study was funded by a
grant from the El Camino Hospital District Board in
Mountain View, Calif. SR
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