Brain changes evident in autism.

STANFORD, CALIF. -- Increasing evidence suggests that children with autism have a normal head circumference at birth, but that many develop macroen-cephaly in childhood, Dr. Antonio Y. Hardan said at a recent pediatric update sponsored by Stanford (Calif.) University.

Distinguishing features within the brain are evident in utero, with abnormal neuronal migration and a decrease in the size of the cerebellum seen as early as the first trimester.

Both findings have important implications for research into the causes, and one day perhaps the prevention, of autism, he said.

The first suggestion of abnormal head circumference in children with autism appeared in 1943, with Dr. Leo Kanner's groundbreaking description of 11 children with what would come to be known as autistic features. He noted that five had "relatively large heads," and one had "markedly prominent" occipital and frontal regions.

Since the advent of modern neuroimaging techniques, nine studies have found increased brain size in individuals with autism, but four studies have had negative findings, said Dr. Hardan, director of the autism and developmental disabilities clinic at Stanford's Lucile Packard Children's Hospital.

Recent work in Dr. Hardan's laboratory and other centers may explain this discrepancy.

One of the negative studies measured only brain area, not total volume, and two included mostly adults.

It has now become clear that changes occur over time.

Head circumference at birth is no different in children who go on to exhibit autism than in normal children, but during childhood, the total brain volume of autistic children is significantly larger than their age-matched peers. In adulthood, the brain size of individuals with autism appears to normalize or even atrophy slightly, but the head circumference in about 20%-30% of individuals with autism will remain larger than normal.

"The brain can shrink, but the cranial box cannot," Dr. Hardan noted.

A study conducted at the University of Pittsburgh found that despite differences in early childhood, by age 12, brain volumes among children with autism were no different than in normally developing children, when controlling for height (Neurology 2002;59:175-83).

Research from the University of California, San Diego, found that patterns of brain growth were irregular in very young children with autism, with 2- and 3-year-olds possessing 39% more cerebellar white matter, 18% more cerebral white matter, and 12% more cerebral cortical gray matter than their peers, but with differences dissipating as the children grew older (Neurology 2001;57:245-54). Abnormally accelerated growth of some regions of the brain gave way over time to abnormally slowed brain growth.

New work from Dr. Hardan's group has found that among children aged 8-12 with autism, compared with healthy controls, increases in gray matter volume and total brain size may be explained by marked increases in total sulcal and gyral thicknesses in the cerebrum and temporal and parietal lobes, but not in the frontal and occipital lobes.

Cortical thickness, striking in young children, also decreases over time, he reported.

Importantly, cortical thickness abnormalities in autism can be distinguished from those in children with attention-deficit/hyperactivity disorder, which are thinner at baseline than in normal children and continue to decrease over time. The specific patterns of cortical thickness abnormalities may offer important new clues as to the underlying defects in neural circuitry that may explain behavioral and social deficits in children with autism, he explained.

Dr. Hardan also underscored the importance of functional MRI imaging for children with autism.

Rather than looking at the brain itself, this approach studies cortical activation within the brain as children with autism are shown images of faces or objects. Unlike in normal children, the fusiform gyrus is activated when children with autism look at objects, not faces.

Related research has been able to track the visual focus of very young children and has demonstrated that those with autism focus on the chin or cheek of a human face, rather than the eyes, as is the case for normal subjects shown still images or movies. The same pattern has now been seen in how toddlers at high risk of developing autism focus on their mothers' faces, he said.

The technique might be used to intervene early with children at risk for autism, and also can be used to objectively measure improvement when medications or behavioral interventions are employed in an attempt to improve the condition. "It's a very exciting area of research," Dr. Hardan said.

BY BETSY BATES

Los Angeles Bureau