Focus Narrows in Search for Autism's Cause
By SANDRA BLAKESLEE

Published: February 8, 2005

Stephanie Diani for The New York Times
At an autism summit, Dr. Pat Levitt, left, Dr. Marcel Just, Dr. Martha Herbert and Dr. William Greenough.

Here comes a point in every great mystery when a confusing set of clues begins to narrow. For scientists who study autism, that moment may be near, thanks to a combination of new tools for examining brain anatomy and of old-fashioned keen observation.

Within the last year, several laboratories have reported finding important new clues about the mysterious syndrome that derails normal childhood brain development.

For the first time, they say, a coherent picture is emerging.
In autism, subtle brain abnormalities are present from birth. Infants and toddlers move their bodies differently. From 6 months to 2 years, their heads grow much too fast. Parts of their brain have too many connections, while other parts are underconnected.

Moreover, their brains show signs of chronic inflammation in the same areas that show excessive growth. The inflammation appears to last a lifetime.

"Autism is still a confusing disorder, but one thing is now clear," said Dr. Pat R. Levitt, a neuroscientist who is the director of the Kennedy Center for Research on Human Development at Vanderbilt University in Nashville. "There is a specific disruption of circuitry in brain development. We can really dig in and begin to explain the splintered brains of autistic children."

To that end, Dr. Levitt and two dozen leading brain researchers held a three-day "autism summit" in Malibu, Calif., sponsored by the Cure Autism Now Foundation, to discuss this emerging view and to plan collaborative studies. The meeting ended Sunday.

"Up to now, there was no theory to link one anatomical study to the next," said Dr. William T. Greenough of the University of Illinois, an expert on brain development. "We now have a theoretical framework that can generate predictions to test."
People with autism have great difficulty with social interaction. Some cannot speak. Many are clumsy. A common trait is obsessive attention to certain details. Symptoms can be severe to mild.

Diagnoses of the disorder have increased in recent years, although no one knows why. One child in 166 born today may fall on the autism spectrum.

Researchers agree that an unknown number of genes interact with unidentified environmental factors to produce the disorder. The new clues focus on brain development and circuitry, and especially on the brain's white matter. White matter contains fibers that connect neurons in separate areas of the brain, whereas gray matter contains the neurons themselves. "You can think of this distinction as analogous to that between cables, or white matter, and circuit boards, or gray matter, inside a computer," said Dr. Matthew Belmonte, an autism researcher at the University of Cambridge in England. "Even though each individual circuit board may be intact, if the cables are disrupted then the computer can't function."

Using a new technique called morphometric analysis, in which post-mortem brain tissue is divided into tiny parcels and examined, Dr. Martha Herbert, a pediatric neurologist at Harvard Medical School, found an anomaly in the white matter of autistic brains - it is asymmetrical.

In autism, white matter grows normally until 9 months, Dr. Herbert said. Then it goes haywire. By 2 years, excessive white matter is found in the frontal lobes, the cerebellum and association areas, where higher-order processing occurs.
The right side of the brain, the nonverbal hemisphere, is especially encased in white matter. The two sides of the brain are poorly connected. Moreover, small functional regions in each hemisphere tend to be prematurely insulated by excess white matter.

Another clue was reported last year by Dr. Eric Courchesne, a neuroscientist at the University of California, San Diego. Using a simple tape measure, he found that newborns who later developed autism had smaller head circumferences than average. From 1 to 2 months of age, their brains suddenly begin to grow rapidly. Another spurt occurs between 6 months and 2 years, giving rise to exceptionally large heads.
At age 3, one child could wear his father's baseball cap, Dr. Courchesne said. The rate of brain growth gradually slows from 2 to 4 years, reaching a peak a year later. A 5-year-old with autism has the same size brain as a normal 13-year-old.
But by midadolescence, when normally developing children catch up, the autistic child's brain is again comparatively smaller.

Dr. Ruth Carper, who works with Dr. Courchesne, went on to show that the frontal lobes, the slowest and latest brain region to develop, have the biggest size increase of all. But the nerve cells in this region, which is responsible for social reasoning and decision making, are actually much smaller than normal and "underpowered," Dr. Carper said.
A third clue, from the laboratory of Dr. Marcel A. Just, a neuroscientist at Carnegie Mellon University in Pittsburgh, reaffirms the odd circuitry in autism. In a study published in November, he found that people with autism remembered letters of the alphabet in a part of the brain that ordinarily processes shapes. That is, the subjects used a basic sensory region to deal with higher-level concepts.

"Autism results from a failure of various parts of the brain to work together," Dr. Just said. "Distinct brain areas work independently. People with autism are good at details but bad at conceiving the whole."

Local networks are overconnected, he said. Long-range networks are underconnected. Skewed brain wiring could explain a fourth clue: clumsiness. Dr. Philip Teitelbaum, an expert on human movement patterns at the University of Florida, studies how babies with autism learn to roll over, sit up, crawl and walk. By looking at videotapes of their early months, before their disorders are diagnosed, he finds that autistic children use unusual strategies for locomotion. It is as if the parts of their brains that control movements are not properly connected.

A fifth clue, also reported in November, may turn out to be a major piece of the puzzle. Dr. Carlos Pardo-Villamizar, an assistant professor of neurology and pathology at Johns Hopkins, studied the brain tissue of 11 people with autism who died at ages 5 to 44. He found a pattern of inflammation in the same regions that appear to have excess white matter.
The brain has an innate immune system separate from the body's immune system, Dr. Pardo said. A sentinel cell type, called microglia, is always on the lookout for trouble. When activated, the cells elicit inflammation and growth factors.
Another cell type, astroglia, helps pattern the brain in fetal development and is later involved in synaptic activity. The astroglia were also elevated in the 11 brains.

Dr. Pardo then examined spinal fluid in six living children with autism. He found evidence of activated microglia, hence inflammation, along with astroglia.

It is not yet clear whether the inflammation is protective or destructive, Dr. Pardo said. In either case, inflammation is most marked in the same areas highlighted in all the other studies showing the same abnormal circuitry.

Other researchers have begun studies to find out whether genes involved in innate immunity and prenatal wiring are involved in the disorder.

A crucial question is why does the brain grow rapidly and then stop growing, Dr. Courchesne said. What accounts for the timing of the defect?

Dr. Herbert and others wonder whether the white matter is really larger."We don't know what is inside those enlarged areas," she said. "It could be more axons, more white matter, or more glial cells and astrocytes."

Dr. Robert Miller, a white matter expert at Case Western Reserve University School of Medicine in Cleveland, said he planned to examine white matter from autistic brains to see what gives them their "odd architecture" and perhaps discover the cause of the overgrowth. Studies are under way to dissect the white matter in greater detail.

While these new clues are exciting, they do not lead to immediate treatments. Parents should not, for example, rush to give their autistic children anti-inflammatory medications at this time, Dr. Pardo said, because the link between autism and inflammation is still preliminary, and in any case, the drugs do not affect the type of inflammation particular to the brain.
On the other hand, once autism is diagnosed, often around age 2 or 3, when the frontal lobes fail to activate properly, therapies might focus on activating multiple brain areas at the same time. This would not cure the disorder, Dr. Herbert said, but could theoretically lead to improvement.
Meanwhile, other clues remain elusive. "Parents will tell you that when their child spikes a high fever, the child becomes lucid and communicative," said Dr. Levitt, of Vanderbilt. "A fever is a neuroinflammatory response. That suggests the circuit defects could be reversible. We just don't know."