Subtle Brain Circuit Abnormalities Confirmed in ADHD

Brain imaging studies of ADHD children provide clues as to why some children with ADHD have difficulty staying focused.

Subtle structural abnormalities in the brain circuit that inhibits thoughts have been confirmed in the first comprehensive brain imaging study of Attention Deficit Hyperactivity Disorder (ADHD). Difficulty staying mentally focused is a primary symptom of ADHD, which affects about 5 percent of school age children. Magnetic Resonance Imaging (MRI) scans of 57 boys with ADHD, aged 5-18, also revealed that their brains were more symmetrical than those of 55 age-matched controls. F. Xavier Castellanos, M.D., of the National Institute of Mental Health and colleagues report on their findings in the July issue of the Archives of General Psychiatry.

Three structures in the affected circuit on the right side of the brain -- prefrontal cortex, caudate nucleus and globus pallidus -- were smaller than normal in the boys with ADHD, when examined as a group. The prefrontal cortex, located in the frontal lobe just behind the forehead, is believed to serve as the brain's command center. The caudate nucleus and globus pallidus, located near the middle of the brain, translate the commands into action. "If the prefrontal cortex is the steering wheel, the caudate and globus are the accelerator and brakes," explained Castellanos. "And it's this braking or inhibitory function that is likely impaired in ADHD." ADHD is thought to be rooted in an inability to inhibit thoughts. Finding smaller right hemisphere brain structures responsible for such "executive" functions strengthens support for this hypothesis.

The NIMH researchers also found that the entire right cerebral hemispheres in boys with ADHD were, on average, 5.2% smaller than those of controls. The right side of the brain is normally larger than the left. Hence, the ADHD children, as a group, had abnormally symmetrical brains.

Although the same brain circuit had been implicated earlier, Castellanos and colleagues examined a dozen times more brain areas in a three-fold larger sample than had been studied previously.

"These subtle differences, discernible when comparing group data, hold promise as telltale markers for future family, genetic and treatment studies of ADHD," said Judith Rapoport, M.D., senior author on the paper and chief of the NIMH Child Psychiatry Branch. "However, because of normal genetic variation in brain structure, MRI scans cannot be used to definitively diagnose the disorder in any given individual."

The newly confirmed markers may provide clues about the causes of ADHD. The investigators found a significant correlation between decreased normal asymmetry of the caudate nucleus and histories of prenatal, perinatal and birth complications, leading them to speculate that events in the womb may affect the normal development of brain asymmetry and may underlie ADHD. Since there is evidence for a genetic component in at least some cases of ADHD, factors such as a predisposition to prenatal viral infections could be involved, said Dr. Rapoport.

The NIMH researchers are currently following up on a recent discovery of a link between ADHD and a gene variant known to code for a particular receptor subtype for the neurotransmitter dopamine. "We want to see the extent to which children with this gene variant also have the brain structural abnormalities revealed in this study," said Dr. Castellanos. The researchers are currently extending confirmation of the markers in girls as well as boys who have not been exposed to medication. They are also using functional MRI scanning to visualize brain activity in ADHD.

Other NIMH researchers participating in the study were: Jay Giedd, M.D., Wendy Marsh, Susan Hamburger, Catherine Vaituzis, Yolanda Vauss, Debra Kaysen, Amy Krain, Gail Ritchie, and Jagath Rajapakse. Also participating were: Daniel Dickstein, Brown, U.; Stacey Sarfatti, U. Of Pennsylvania; John Snell, Ph.D., U. Of Virginia; and Nicholas Lange, Ph.D., National Institute of Neurological Disorders and Stroke.

The National Institute of Mental Health is a component of the NIH, an agency of the U.S. Public Health Service, part of the U.S. Department of Health and Human Services.

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