ADHD Studies Target Circuitry, Stimulants’ Effects

by Brenda Patoine

March, 2009

A new brain-imaging study by researchers at the National Institute of Mental Health (NIMH) suggests that taking psychostimulant drugs for attention deficit/hyperactivity disorder, or ADHD, does not adversely affect development of the cortex.

About 9 percent of all boys and 4 percent of girls use psychostimulant drugs such as methylphenidate (Ritalin) and amphetamine (Adderall) for ADHD, according to the Centers for Disease Control and Prevention. Previous studies had indicated a modest slowing of growth in children taking the drugs, and evidence from animal studies suggests that high-dose stimulants can damage nerve cells.

But the NIMH study hints that stimulants may have a normalizing effect on the maturation of the cortex, the brain’s outer layer, which controls higher-order cognitive tasks.

“The biggest take-home message is that there is no evidence of adverse effects and some evidence of normalization from stimulant use,” says Judith Rapoport, chief of the NIMH Child Psychiatry Branch and senior author on the report.

In development, the cortex matures over two decades or more, first thickening as nerve cells form synaptic connections with other cells, and then thinning as little-used connections are pruned back. A study reported by the NIMH group in 2007 found that typically developing children reach peak cortical thickness in frontal areas—the last to mature—around age 7 or 8. Children with ADHD reach this milestone around age 10 or 11, suggesting a three-year lag in cortical maturation.

The new study, published in January in the American Journal of Psychiatry, compared cortical thickness in three groups: children with ADHD who were on psychostimulants, children with ADHD who were drug-free during the study period, and typically developing children without ADHD. They scanned each child twice with magnetic resonance imaging (MRI), at ages 12 and 16, on average. While there was no discernable difference in most areas of the cortex, certain discrete areas showed accelerated thinning in the drug-free ADHD group, and the group on medication had a cortical growth curve that was closer to normal.

A ‘Reassuring’ Finding, but Other Concerns Remain

“This is a reassuring study that indicates that the most robust change seen in adolescence—cortical thinning—does not seem to be adversely affected by psychostimulant medication,” says Bertha Madras, a Harvard psychobiology researcher who studies ADHD but was not involved in the study. “In fact, [having ADHD and] not having medication appears to be associated with abnormal cortical development, suggesting that the introduction of the drugs may normalize the rate at which the cortex thins.”

But cortical thickness is not the only question, Madras adds: “This does not rule out other possible changes, such as biochemical or molecular changes, that are invisible to an anatomical MRI scan.”

Philip Shaw, the report’s lead author, emphasizes that the clinical significance of the findings is not at all clear.

“I think we have to be extremely cautious in how we interpret the result, and it certainly shouldn’t influence treatment,” he says. “By and large, there were only minimal differences between the children taking stimulants compared to those who were not.”

One of the areas that were different was the dorsolateral prefrontal cortex, part of the forward-most region of the brain. This area acts as an executive control center, integrating information from across the brain, and matures last in normal children. Subtle differences were also detected in an “output” area of the motor cortex. The significance of differences in these areas is not known, Shaw says.

“We cannot say, for example, ‘Well, this effect is seen in a higher-order control center of the brain, so therefore stimulants are good.’ That is certainly not what I would want people to take away from this study.”

Activity May Drive Change

One possible explanation for the differences is the theory of activitydependent plasticity, the “use-it-or lose-it” concept by which an individual’s behavior drives brain changes. Many studies have supported this theory, including a classic study of people who learned to juggle and had subsequent structural changes in the part of the brain involved in complex motor control.

“If you change activity in the brain, sometimes you can change brain structure, even if temporarily,” Shaw says. “These drugs bring some aspects of attention and motor movement into more normal ranges. By inducing a change in attention and motor activity and action, those effects might actually feed back to the structural change in the brain. That is the theory.”

Martha Denckla, a cognitive neurologist at the Kennedy Krieger Institute, says it is “absolutely fascinating” that stimulants might be changing the brain in ways that depend on activity. Most drugs work by acting on some specific chemical, say, by shutting it down or pumping it up, and the targeted chemical in turn induces changes in physiology. But in this case, she says, “It may be that the chemical made people act in a certain way, and that activity was beneficial to the development of the part of the brain the activity utilizes.

Rapoport likens this idea to lifting weights: “If someone pumps iron regularly, and as a result bulks up their upper arms, you wouldn’t be surprised. It may be that when you’re taking stimulants, you use parts of the brain related to attention more and that’s why cortical maturation looks closer to the normal trajectory in those areas.”

Unraveling ADHD Circuits

Two other papers in the same journal issue add important details to the understanding of ADHD-related circuitry in the brain. The first, by a collaborative team from the National University of Singapore, Johns Hopkins University and Kennedy Krieger, examined the shape of a brain region involved in goal-directed behavior, the basal ganglia, comparing children with ADHD and normal children. Using an advanced MRI technique, the scientists found that the basal ganglia in boys with ADHD, but not girls, were compressed—suggesting underdevelopment—in every area but one. The most primitive part of the motor control center was actually larger in boys with ADHD.

Denckla, a study co-author, believes that the shape differences may be another example of activity driving structural changes.

Separately, a group at King’s College, London, used functional MRI to compare the neural circuitry that underlies ADHD and conduct disorder, two distinct conditions whose symptoms overlap clinically. They found abnormal activity in attention and control areas in ADHD, whereas conduct disorder was marked by anomalies in emotional processing centers.

Shaw of the NIMH calls it an intriguing finding. “It’s so important to be able to say that there is different neural circuitry going wrong in these disorders,” he says. “If we’re ever going to use neuroimaging for diagnosis and prognosis, we’ve got to be able to distinguish ADHD not just from typical development but from other childhood problems.”