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Published in Print: May 9, 2001, as Research: Paying Attention

Research: Paying Attention

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Scientists scrutinize the brain for biological clues to the mysteries of ADHD.

Julie B. Schweitzer, a psychologist and researcher who studies attention deficit hyperactivity disorder, wants to know how children with ADHD learn differently from those without the disorder.

The answers, she says, are in their brains.

Schweitzer's office at the Maryland Psychiatric Research Center in Baltimore is filled with photographic images from brain scans she has conducted on adults with and without ADHD as they performed mathematical calculations. She says the results, which show that the two groups process information in the brain differently, could help classroom teachers better reach children with the condition.

At a time of unprecedented interest in ADHD, studies of the brain are providing more and more information on how the syndrome works. Schweitzer's work is part of a growing body of scientific research that is helping to identify the biological and genetic underpinnings of ADHD. And such work is being complemented by research using more traditional methodologies, including a major study conducted by the National Institute of Mental Heath on the most effective means of treating it.

Many teachers have come to know the symptoms of ADHD: Students are unable to sit still in their chairs, interrupt class with comments at inappropriate times, or run around the classroom when they are supposed to be sitting at their desks. With about 5 percent of American children diagnosed with ADHD, teachers find themselves on the front lines every day in spotting students who may have the condition and referring them for diagnosis and treatment.

In that role, over the years, educators have been embroiled in controversies over the nature of ADHD, how to treat it, and whether using stimulant medications such as Ritalin is the right course to take. Those debates, which continue to be waged in medical, political, legal, and education policy arenas, have generally been rooted in a lack of consensus on what ADHD really is.

Science Offers Answers

But now, science is beginning to provide some answers. Researchers have already identified which regions of the brain are involved in ADHD, what happens in those regions, how thoughts are processed, and how stimulants affect the brain's functioning. They have also identified genes associated with ADHD and are looking for others in the hope that genetic testing for the disorder won't be far off.

In the past few years, such work has contributed to growing agreement among specialists not only on the biology of ADHD, but also on the best way to treat it.

Findings from that work have the potential to alter debates familiar to educators: whether ADHD exists at all, whether Americans overdiagnose children as having the disorder, and whether such children are overmedicated, to name a few. Those studies and more like them that are in the works could also directly affect how teachers handle students with ADHD in their classrooms.

About 5% of American children are diagnosed with ADHD.

Just three years ago, a panel of medical experts convened by the National Institute of Mental Health to forge a consensus on ADHD called the lack of generally accepted methods of diagnosis, treatment, and follow-up for such children "a major public health problem."

Scientists involved in research aimed at addressing that problem believe that in the next five to 10 years, they will be able to use brain scans and brain imaging to diagnose children with ADHD. Such tests would supplement existing diagnostic methods that rely heavily on reports from parents and educators about children's behavior.

Researchers also say they hope they will be able to determine the exact levels of medication an individual needs, and even develop new medications based on a better understanding of how the brains of people with ADHD work.

'An Ethical Obligation'

Russell A. Barkley, a researcher who has written books on ADHD, says all known causes of the syndrome are biological. He said research has discredited theories that the symptoms associated with the condition are caused by too much sugar, bad parenting, or too much television. Such evidence should reassure school employees who advise parents to pursue a possible diagnosis of ADHD for their children, he adds.

"There is a lot of propaganda out there that might make teachers uncomfortable," says Barkley, the director of psychology and a professor of psychiatry and neurology at the University of Massachusetts Medical Center in Worcester, Mass. "Educators have an ethical obligation, and a duty to play a role in detection and referral of students with ADHD."

ADHD is not necessarily just a disorder of attention, but one also characterized by the inability to control impulsive responses, specialists say. It mars the ability of a person to put off immediate gratification, for instance, in order to experience a greater reward in the long run.

Imaging studies are clarifying which brain regions are involved in the processes that malfunction in people with ADHD. The research suggests two regions strongly involved are the prefrontal cortex, or part of the cerebellum, and at least two of the clusters of nerve cells found deep in the brain, known as the basal ganglia.

Dr. Xavier Castellanos and his fellow researchers at the National Institute of Mental Health found that the right prefrontal cortex and two basal ganglia are significantly smaller in children with ADHD than in those without it. The findings were published in the July 1996 issue of the Archives of General Psychiatry.

The study suggested that the areas of the brain that are reduced in size in children with ADHD are the same regions that regulate attention and impulse control. The right prefrontal cortex is involved in modifying behavior and resisting distractions. The areas of the basal ganglia, called the caudate nucleus and the globus pallidus, inhibit automatic responses and allow more careful deliberation by the cortex, Barkley says.

Thinking Differently

A study of 12 men that Schweitzer conducted from 1997 to 1999 went further to reveal what happens in the brains of subjects with ADHD, compared with those without it, when given a set of mathematical tasks.

She found that the six men with ADHD performed the tasks by visualizing images in their heads rather than hearing the spoken numbers in their minds, the strategy employed by the six subjects without the diagnosis.

Does ADHD exist at all? Do Americans overdiagnose children as having the disorder? Are those children overmedicated?

In developing her study of adults, which was published in the February 2000 issue of the American Journal of Psychiatry, Schweitzer based her choice of tasks on knowledge that people with ADHD typically have trouble keeping old information in mind while new information is being given to them.

That's why, she says, people with ADHD sometimes blurt out a comment during class, because they fear they might forget it if they wait until someone is finished talking. She says note-taking during lectures presents students with the same difficulty.

So she asked her subjects to listen to a series of numbers. As each number was read, they were supposed to add it to the previous number. For example, if the numbers read aloud were: 1, 2, 3, and 4, the answers would be 3, 5, and 7.

The subjects with ADHD used the occipital regions of their brains, areas associated with visual processing, to perform the task, Schweitzer says. But the subjects without ADHD used the prefrontal cortex, where numbers are remembered, along with the parts of the brain that handle auditory functions.

The men without ADHD performed better on the task, which called for putting aside the total from the previous equation and remembering the previous number in the series before arriving at the next total.

Schweitzer says the subjects with ADHD were more inclined to add the new number spoken to the total of the two previous ones, rather than the previous number in the series. The task was difficult for them because it involved repeatedly "switching gears," she explains. That finding is consistent with the frequently observed difficulty that students with ADHD have in making transitions from one activity to another, she adds.

Another finding was that, over time, the men without ADHD needed less time to come up with the correct answers, and did the equations in a part of their brains that functions more automatically. Because the skill for doing the task was "learned," it no longer required as much effort, and therefore freed their brains up for new tasks.

That didn't happen in the subjects with ADHD, for whom the task did not become automatic.

Classroom Applications Suggested

Schweitzer says she still needs to test more subjects and has a long way to go before drawing specific conclusions on how teachers can better reach students with ADHD.

But one implication of her work, she says, is that "teachers need to remember to use different strategies for different learners. If you give an instruction verbally, maybe you could write it down as well," she suggests.

ADHD is not just a disorder of attention, but also one characterized by the inability to control impulsive responses.

What Schweitzer learned from her study of adult men, which relied on the use of positron emission tomography, often known as PET scans, may hold true for children as well, she says. But because PET scans involve injecting radioactive oxygen into subjects to measure increased blood flows in different parts of their brains while performing a particular task, the test is not used on children.

Schweitzer, an assistant professor at the University of Maryland's Baltimore campus, is about to embark on a study in which she will have children perform the same tasks as the adults in her earlier study. She plans to use a different imaging method more appropriate for younger people with ADHD: functional Magnetic Resonance Imaging, or fMRI, which requires no such injections to measure brain activity.

And she is currently gathering comments from teachers on whether the tasks she is designing will measure a relevant skill that students would use in the classroom.

Examining What Works

Arranging for proper treatment is critical for parents and teachers of children with ADHD, since such youngsters often have a hard time ignoring distractions, sitting still, or thinking before they act, and have trouble completing tasks. If untreated, the disorder can affect a child's ability to make friends or do well in school or in other activities.

Children with ADHD are at risk for depression, lack of self-esteem, and other emotional problems, according to the NIMH.

Last year, the Texas board of education passed a measure recommending that schools consider alternative, nonmedical solutions to behavior problems in the classroom. The Colorado school board took a similar step that year. The Texas measure urged schools to use "proven academic solutions" for dealing with hyperactive students.

But the largest study to date that compared various treatments for the disorder concluded that nonmedical methods were generally not the best course. In 1999, the NIMH's Multimodal Treatment Study of Children with Attention Deficit Hyperactivity Disorder found that medication alone, or medication in combination with intensive behavioral therapy, was significantly superior to other types of treatment.

The study was the first major clinical trial to look at a mental disorder in children, says NIMH spokeswoman Constance Burr. The study involved 18 national ADHD experts who used as subjects nearly 600 elementary school pupils of different socioeconomic backgrounds between the ages of 7 and 9.

‘Educators have an ethical obligation, and a duty to play a role in detection and referral of students with ADHD.’

Russell A. Barkley,
Researcher and professor,
University of Massachusetts Medical Center

Researchers randomly assigned the subjects, who participated at six different university medical centers and hospitals in locations including New York, California, Canada, and Pennsylvania, to one of four treatment programs: one that used medication management alone; another that used behavioral treatment alone; a plan that was a combination of both; or routine community care from physicians not involved with the study.

"All children tended to improve over the course of the study, but they differed in the relative amount of improvement," said Dr. Peter S. Jensen, a psychiatrist who was the lead investigator on the study when he was at the NIMH and is now the director of the Center for the Advancement of Children's Mental Health at Columbia University.

"Nonetheless, determining what treatment will be most effective for a particular child is an important question that needs to be answered by each family in consultation with their health-care professional," Jensen said in a statement released with the study in December 1999.

The study concluded that the use of stimulants was more effective than behavioral therapies in controlling the core symptoms of ADHD—inattention, hyperactivity/impulsiveness, and aggression. For anxiety symptoms, academic performance, and social skills, the combination of stimulants and intensive behavioral therapies was consistently more effective.

Still, the researchers involved in the study saw the children for monthly follow-up visits, and gained input from teachers to alter their doses of medicine as needed along the way.

By comparison, the children under the care of community physicians generally saw them face to face only once or twice a year, and for shorter periods of time each visit. The community physicians did not have any interaction with children's teachers, and generally prescribed lower doses of stimulant medication.

NIMH researchers will continue to track the children into adolescence to evaluate the long-term outcomes of those treatments, and will release periodic updates.

Responding to Medication

Methylphenidate, commonly known by the brand name Ritalin, has been used to treat ADHD for 40 years. But only recently has the scientific community begun to understand fully how it works.

In a study published in January of this year, researchers for the first time assessed the effects of therapeutic doses of oral Ritalin on the levels of the neurotransmitter dopamine in the human brain. Dopamine imbalances appear to be closely related to ADHD symptoms.

Although previous research demonstrated that methylphenidate administered intravenously increases dopamine levels in the brain, the new study was the first to assess the effects on dopamine levels when Ritalin is administered orally, the way most patients receive the drug.

No biological test for diagnosing ADHD is currently available.

Using PET scans, a team of investigators from the Brookhaven National Laboratory in Upton, N.Y., and the State University of New York at Stony Brook found that Ritalin increased dopamine levels in the brain.

Researchers at Brookhaven's Center for Imaging and Neurosciences studied dopamine levels in 11 healthy adult males. In two sessions, the volunteers were each given either a placebo or a dose of Ritalin. Based on the men's body weight, the doses were adjusted to correspond to the amounts given to children with ADHD. While their brains were scanned to record dopamine levels, the subjects were asked to rate their feelings of being restless and "high." Meanwhile, physicians monitored each subject's blood pressure and heart rate.

The results confirmed that brain dopamine levels increased significantly about an hour after the subjects swallowed the drug. Those who had taken the placebo showed no such effect. The study also showed that Ritalin works to suppress "background" firing of neurons that are not needed for performing a particular task. That allows the brain to transmit a clearer signal.

Schweitzer also conducted her test on ADHD subjects who were taking Ritalin, which she predicted would make them use the same parts of their brains to perform the tasks in her study as the subjects without ADHD. That did not turn out to be the case, however.

Ritalin did seem to change the way people with ADHD processed information. Specifically, it appeared to increase activity in certain regions of the brain—for example, the hippocampus, which is used in memory—and at the same time reduced involvement of frontal areas of the brain used in effort.

"With medication, the task was made easier for them," Schweitzer explains.

But a surprising finding from the study was what the medication did not do: It failed to activate the anterior singulate, a part of the brain involved in attention that a person uses for engagement and readiness to focus and act, Schweitzer says.

"I saw that medication helps [people with ADHD] find other, novel pathways, not using traditional regions of the other subjects," she says.

Biological Diagnosis on Horizon?

No biological test for diagnosing ADHD is currently available. Yet earlier this year, a company in Boston offered hopes for a long-sought medical test to diagnose the condition. ("Firm Moves Closer to Brain-Imaging Test for ADHD," March 28, 2001.)

Boston Life Sciences Inc. announced in February that the second of three studies of the company's diagnostic agent, dubbed Altropane, had been successful in identifying adults who had been clinically diagnosed with long-standing ADHD by mapping unusually high levels of dopamine in their brains. Three such studies are generally required by the federal Food and Drug Administration before a company can seek approval to market a product.

‘What is persistent with ADHD is behavior. Teachers have a strong role in distinguishing that behavior from other children's behavior to identify children with ADHD and get them early treatment.’

Russell A. Barkley,
Researcher and professor,
University of Massachusetts Medical Center

But the test, which involves injecting radioactive substance, cannot be used on children, says Barkley of the University of Massachusetts, who worked on developing the test. A version safe for children will likely follow, he predicts.

Still, Barkley says, even though a laboratory test is not yet available for ADHD, improved understanding of its biological basis should encourage more people to seek treatment.

"The lack of a lab test right now does not invalidate a disorder," Barkley says. "Most mental disorders do not have one. But what is persistent with ADHD is behavior. Teachers have a strong role in distinguishing that behavior from other children's behavior to identify children with ADHD and get them early treatment."

Barkley believes that in the future, brain scans will be used to diagnose not only ADHD, but also subtypes within the disorder.

According to a report in the March 1999 issue of the New England Journal of Medicine, children who could benefit from medical treatment for ADHD are being missed. That is especially true of girls, who are more likely than boys to suffer from the inattentive subtype of ADHD and therefore lack the tell-tale symptoms of hyperactivity, the report said.

At present, the diagnostic manual of the American Psychiatric Association lists three subtypes: primarily inattentive; primarily hyperactive/impulsive; and a combined type with the presence of both those groups of symptoms.

In light of those variations among individuals with attention problems, more research needs to be done to help educators, parents, and health professionals recognize that every student with ADHD is different and should be treated accordingly, says ADHD researcher Raun Melmed, who speaks to schools, school districts, and conferences about the disorder.

"When you hear a child has ADHD, you think you know what to do just by knowing the diagnosis," says Melmed, the director of the Phoenix, Ariz.-based Melmed Center and a co-director of the Southwest Autism Research Center. "The research is helping us to recognize the individual differences within kids with ADHD. The time has come for education to be far more individualized."

Genetic Research Advances

Research shows that ADHD tends to run in families. Further down the road, researchers hope to create a genetic test for the condition.

Children who have ADHD usually have at least one close relative who also has it. And at least a third of all fathers who showed symptoms of ADHD in their youth have children who display similar behavior. Even more suggestive of a genetic component to the disorder is that when one twin of a pair of identical twins has the disorder, the other is likely to have it, too, according to the NIMH.

Studies have suggested that the disorder could be caused by variations in genes that are active in the prefrontal cortex and basal ganglia. Research has shown the affected genes are likely to be the ones that regulate and transport dopamine, one of the chemicals in the brain called neurotransmitters that help deliver messages from one nerve cell to another.

‘With every research stride taken, we move one step closer toward giving our children a better chance for success.’

Peg Nichols,
Spokesman,
Children and Adults With Attention Deficit/Hyperactivity Disorder

Genetic researcher James Swanson, a psychologist at the University of California, Irvine, says the research on the genetics of ADHD has leapt ahead of that for other psychiatric conditions.

"Nobody's yet identified a clear gene for depression or other disorders," Swanson observes. "The ADHD area has done that for itself. There is this growing body of work that we can build on."

Swanson says research into the specific areas of the brain and specific functions in those areas involved in ADHD have helped identify "candidate genes," or genes likely to be associated with the disorder.

"When you have these kinds of clues, you don't have do laborious work through all genes to find the ones you want," Swanson says. "It's like knowing the location on an interstate freeway system, with mile markers."

Swanson and a team of colleagues used a candidate-gene approach to confirm that ADHD is associated with genes governing cells that both receive and transmit dopamine in the brain. Their work was published in a 1998 issue of the journal Molecular Psychiatry.

Researchers believe that variations in dopamine receptors or transporters, or both, may result in underactivity of brain regions that are involved in attention and behavior, Swanson says.

Researchers have a long way to go, though, in understanding how exactly genes play a role in ADHD. For example, Swanson says, scientists suspect that genes other than those affecting transmission of dopamine are involved.

"This is just the first step," he says. "It will be a long time before genetic research will be of use to educators."

Researchers are eager for what their future work can tell them about ADHD.

Schweitzer says she is hoping further research can help her determine the exact doses of medication needed to treat children, so doctors will no longer have to rely on trial and error until they prescribe the right amount.

Peg Nichols, a spokesman for Children and Adults With Attention Deficit/Hyperactivity Disorder, a national ADHD advocacy group based in Landover, Md., says more should be done to train teachers and teach parents about the information research has yielded about the condition.

"With every research stride taken, we move one step closer toward giving our children a better chance for success," Nichols says. "Yet equally important, we have to find ways to translate the research, bridge the gap between it and real-world practice, and ensure that people who work the front lines—the educators, mental-health professionals, parents, and other caregivers—receive the training, support, and resources they need in order to truly serve the child."


The Research section is underwritten by a grant from the Spencer Foundation

Vol. 20, Issue 34, Pages 26-29

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