Researchers at the U.S. National Institute of Mental Health included previously never-medicated children among the patients studied over the course of the 10-year study. Magnetic resonance imaging found "strikingly smaller" white matter volumes in children who had not taken stimulant drugs. Still, the course of brain development in patients with the disorder paralleled that of normal subjects, suggesting that whatever caused the disorder happened earlier in development.

In 1991, investigators enrolled 152 children (89 male, 63 female) with attention deficit hyperactivity disorder aged 5 to 18 years. They used magnetic resonance imaging to study the brains of the pediatric patients and 139 age- and gender-matched controls, who were children and adolescents without the disorder. Most patients were scanned at least twice, and some up to four times over the decade.

As a group, the pediatric psychiatric patients showed 3 to 4 percent smaller brain
volumes in all regions. The more severe the symptoms of the disorder (as rated by parents and clinicians), the smaller were their frontal lobes, temporal gray matter, caudate nucleus, and cerebellum.

Although medicated patients' white matter volume did not differ from that of controls, white matter volume was abnormally small in 49 never-medicated patients. These findings held statistically even after adjustment for the fact that the unmedicated children tended to be younger.

"There is no evidence that medication harms the brain," said Xavier Castellanos, M.D., the lead author. "It's possible that medication may promote brain maturation."

White matter volume over time represents one gauge of the brain's maturation. "Children with attention deficit hyperactivity disorder are often described as less mature than their peers and this may relate to delays in white matter maturation," explained Castellanos. "While we do not yet know if medication can accelerate white matter growth, we do know that treating children with medication helps their behavior while they're taking the drugs. There is no evidence that it helps after they stop." Animal studies will be required to determine the impact of medication on brain maturation, he added.

In the current study, the psychiatric patients' developmental trajectories for nearly all brain regions paralleled growth curves for controls, but on a slightly lower track.

"Fundamental developmental processes active during late childhood and adolescence are essentially healthy [in patients with the disorder]," asserted the researchers. "Symptoms appear to reflect fixed earlier neurobiological insults or abnormalities." Evidence suggests that the disorder runs in families and may have genetic roots.

As might be expected with hyperactive subjects, the investigators had to discard 50 of 594 total scans due to blurring by motion in the scanner. Volumes of various brain structures and tissue were measured and analyzed by an automated system incorporating more than 100 networked computer workstations, developed in collaboration with researchers at the Montreal Neurological Institute.

Although the research group at the National Institute of Mental Health had earlier thought that only certain brain structures were smaller in affected patients, this largest and most sophisticated study found that the whole brain is affected. It's possible that a recently discovered gene that determines brain size could play a role in the disorder, Castellanos suggested.

He also suspects that what is now called one disorder may ultimately prove to be a group of disorders with different causes. To identify these subtypes, he suggests that the field begin studying "endophenotypes," factors that may predict the risk of the disorder in the same way that cholesterol predicts the risk of heart disease.

"Magnetic resonance imaging remains a research tool and cannot be used to diagnose attention deficit hyperactivity disorder in any given child, due to normal genetic variation in brain structure," noted another coauthor. "The measured influence of [the disorder] on brain volume can only be discerned statistically across groups of children with and without the disorder."