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Brain Shrinkage not caused by Medications

A 10-year study by National Institute of Mental Health (NIMH) scientists has found that brains of children and adolescents with Attention Deficit Hyperactivity Disorder (ADHD) are 3-4 percent smaller than those of children who don't have the disorder — and that medication treatment is not the cause. Indeed, in this first major study to scan previously never-medicated patients, they found "strikingly smaller" white matter volumes in children who had not taken stimulant drugs. Still, the course of brain development in the ADHD patients paralleled that of normal subjects, suggesting that whatever caused the disorder happened earlier.

Drs. Xavier Castellanos, Judith Rapoport, NIMH Child Psychiatry Branch, and colleagues, report on their magnetic resonance imaging (MRI) study of 152 boys and girls with ADHD in the October 9, 2002 Journal of the American Medical Association.

Affecting 3-5 percent of school-age children, ADHD is characterized by over-activity, distractibility and impulsiveness. The disorder affects two to three times as many boys as girls, with as many as 20 percent of boys taking stimulant medication in some school systems. The new study strengthens the validity of the diagnosis by helping to put to rest criticism that structural brain abnormalities seen in ADHD might be drug-induced.

"There is no evidence that medication harms the brain," said Castellanos, who conducted the study at NIMH before joining New York University. "It's possible that medication may promote brain maturation."

Launched in l991, the study used MRI to scan 89 male and 63 female patients ages 5-18, with ADHD, and 139 age- and gender-matched controls, children and adolescents without ADHD. Most patients were scanned at least twice, and some up to four times over the decade.

As a group, ADHD patients showed 3-4 percent smaller brain volumes, in all regions. The more severe a patient's ADHD symptoms — as rated by parents and clinicians — the smaller were their frontal lobes, temporal gray matter, caudate nucleus and cerebellum.

While medicated patients' white matter volume did not differ from that of controls, white matter volume was abnormally small in 49 never medicated patients scanned. These results held up even after the researchers controlled for the fact that the unmedicated children tended to be younger.

Fibers that establish neurons' long-distance connections between brain regions, white matter normally thickens as a child grows older and represents one gauge of the brain's maturation. A layer of insulation called myelin progressively envelops these nerve fibers, making them more efficient, just like insulation on electric wires improves their conductivity.

"Children with ADHD 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, ADHD 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 ADHD," say the researchers. "Symptoms appear to reflect fixed earlier neurobiological insults or abnormalities." Evidence suggests that ADHD 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 (MNI).

While the NIMH group had earlier thought that only certain brain structures were smaller in ADHD, 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 ADHD 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 ADHD in the same way that cholesterol predicts the risk of heart disease.

"MRI remains a research tool and cannot be used to diagnose ADHD in any given child, due to normal genetic variation in brain structure," noted Rapoport. "The measured influence of ADHD on brain volume can only be discerned statistically across groups of children with and without the disorder."

Also participating in the research were: Drs. Patti Lee, Deanna Greenstein, Liv Clasen, Regina James, Jay Giedd, and Wendy Sharp, Christen Ebens, Jonathan Blumenthal, James Walter, NIMH Child Psychiatry Branch; Dr. Neal Jeffries, National Institute of Neurological Disorders and Stroke (NINDS); Drs. Alex Zijdenbos, Alan Evans, MNI, McGill University.

NIMH and NINDS are part of the NIH, the Federal Government's primary agency for biomedical and behavioral research. NIH is part of the U.S. Department of Health and Human Services.

ADHD brain development

Growth curves show that ADHD patients' brain development trajectories, although lower in volume, parallel those of normal volunteers (NV). Solid lines compare the total brain volume in milliliters (vertical axis) of normal and ADHD males (top) and females (bottom) at different ages (horizontal axis) through childhood and adolescence. Source: NIMH Child Psychiatry Branch
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