Brain Maturation Delayed, Not Deviant, in Kids With ADHD

Cortical development in children with attention-deficit/hyperactivity disorder (ADHD) generally lags behind that in other children by several years, NIMH researchers reported recently.¹ The greatest maturational delay occurs in prefrontal regions important for control of such cognitive processes as attention and working memory, they found.

There has been a long-standing debate as to whether ADHD is caused by a delay in brain development or is partly due to a complete deviation away from typical brain development, said Philip Shaw, MD, PhD, an NIMH staff clinician and leader of the research team.

To help resolve the controversy about the disorder that affects 3% to 5% of school-aged children, Shaw and his colleagues conducted a neuroanatomical MRI study and found evidence suggesting that ADHD is characterized by delay rather than deviance in cortical maturation.

"We looked at the development of the cortex, and we measured its thickness in 446 kids, half... with ADHD and half without the disorder," Shaw told Psychiatric Times.

The researchers scanned the brains of most of the study participants at least twice at about 3-year intervals. While the participants included preschoolers and young adults, most ranged in age from 7 to 16 years. Among the participants with ADHD, 92% had combined-type ADHD at baseline.

Using computational neuroanatomical techniques, the researchers estimated cortical thickness at more than 40,000 cerebral points from 824 MRI scans. They focused on the age of attaining peak cortical thickness-when cortex thickening during childhood gives way to thinning following puberty, as unused neural connections are pruned for optimal efficiency during the teen years.

"While healthy kids reached peak cortical thickness at age 7 or 8, the kids with ADHD reached... peak cortical thickness a few years later, around age 10," Shaw said.

The cortical maturation delay in ADHD was most prominent in the lateral prefrontal cortex, the region, according to the research team, that supports such cognitive functions as the ability to suppress inappropriate responses and thoughts, executive control of attention, evaluation of reward contingencies, and working memory. Delay was also found in the temporal cortex.

The only cortical area in which the ADHD group demonstrated slightly earlier maturation was the primary motor cortex.

"It is possible that the combination of early maturation of the primary motor cortex with late maturation of higher-order motor control regions may reflect or even drive the excessive and poorly controlled motor activity cardinal to the syndrome," the research team wrote.

Although there was a delay in the young people with ADHD, the order in which the different parts of the cortex matured was similar in both groups.

Shaw was asked whether the findings indicate that children will eventually grow out of ADHD. The study findings cannot be interpreted to mean that in ADHD the brain normalizes at age 10 or 12, he said.

"The delay we showed is carried forward into adolescence," he said. "Also we know from a host of other studies that there are very real persisting structural and functional differences between teenagers with ADHD and those who don't have the disorder." Frequently, he said, outcomes reported in previous studies depend on how ADHD is defined. If you use a strict definition, he explained, about one quarter of people who grow up with ADHD will still meet the definition in adulthood. If a broader definition is used, about two thirds of people with childhood ADHD will still have troublesome symptoms in adulthood.

Studies that measure brain volume or function also have detected differences between the brains of young people who have ADHD and those of individuals who do not have the disorder.

"One very striking thing about our findings is that they complement existing imaging studies from other groups that found structural and functional differences, and all of them are pointing to similar parts of the brain," Shaw said.

Why the delay?

Discussing factors that might underpin the delay, the research team mentioned psychostimulants and genetic factors. Most of those with ADHD in the study were receiving standard treatment with psychostimulants, but there were not enough medication-naive children to analyze them as a separate group, according to Shaw. In the published report, the research team wrote "trophic effects of treatment with psychostimulants in the ADHD group are possible, but unlikely, given our previous reports of no effect of psychostimulants on gray matter volume."

"Genetic factors will certainly play a role, with a perturbation in the developmental sequence of the activation and deactivation of genes that sculpt cortical architecture," the team wrote. "In this context, neurotrophins, essential for the proliferation, differentiation, and survival of neuronal and nonneuronal cells, emerge as promising candidates."

"The numbers needed to do genetic studies are enormous," Shaw said. "Of course, there are very good multisite collaborative studies going on, which are helping us identify the key genes."

There are a host of candidates and factors that could control neural growth, Shaw said, acknowledging that dopamine and other neurotransmitters in the brain also are important to the growth of the cortex.

While research continues on possible causes of ADHD, Shaw noted that his team would be using brain-imaging techniques to study what happens to children with ADHD as they grow older.

"There is a large cohort of children who have very persistent ADHD," he explained. "We want to compare them with the kids who get better from ADHD. That involves scanning the kids a little bit later when they are in their mid-teens."

Diagnosis and treatment

Brain imaging is not ready for use as a diagnostic tool in ADHD, Shaw said."It is still too early to use neuroanatomical scans for diagnosis," he said. "We had to scan hundreds of children to identify subtle differences. They [the differences] are very real, but they are subtle. So the scan of any one child will not tell you a great deal about whether [he or she has] ADHD or not. Currently, the diagnosis of ADHD remains clinical."

What's more, the brain imaging study was a "natural history study" and so it did not address treatment, he explained.

"We know the treatments that work for ADHD on the basis of very large clinical studies, including the Multimodal Treatment Study of Children With ADHD and the Treatment of Attention Deficit Hyperactivity Disorder in Preschool-Age Children study," he said.

While the Shaw et al study is not relevant to issues of diagnosis and treatment, it is nevertheless important in providing another facet of our increasing knowledge about the neurobiology of this disorder, said F. Xavier Castellanos, MD, Brooke and Daniel Neidich Professor of Child and Adolescent Psychiatry and director of research for the New York University Child Study Center.

In his own work, Castellanos said, his group is pursuing some novel methods of functional MRI that may well have diagnostic implications.^2,3

Also responding to the Shaw et al study was E. Clarke Ross, chief executive officer for Children and Adults With Attention Deficit/Hyperactivity Disorder, a national advocacy and support organization.

"In a time when a vocal minority denies the mountain of evidence showing ADHD to be a real disorder," he said, "it is nice to watch brain scans light up on televisions across the country with images actually showing the structural differences in the brains of those living with ADHD."

References:

References

1.

Shaw P, Eckstrand K, Sharp W, et al. Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation.

Proc Natl Acad Sci U S A.

2007. Nov 16; [Epub ahead of print].

2.

Castellanos FX, Margulies DS, Kelly C, et al. Cingulate-precuneus interactions: a new locus of dysfunction in adult attention-deficit/hyperactivity disorder.

Biol Psychiatry.

2007. Sep 20; [Epub ahead of print].

3.

Margulies DS, Kelly C, Uddin LQ, et al. Mapping the functional connectivity of anterior cingulate cortex.

Neuroimage.

2007;37:579-588.