The bar for normal

NEWBORNS sleep about 16 hours a day. When infants reach a year, they stand on their own, or at least wobble. At age 4, many children can tell stories -- and in the decade that follows, motor skills become bike rides; memory skills become math solutions; language skills turn into back talk -- as the brain prunes its billions of nerve cells and refines its trillions of connections.

And once they’re 18, they may again sleep 16 hours a day.

This path into adulthood is well worn, but developmental scientists know very little about the mental changes that guide the way -- limiting their ability to identify and understand many disorders that crop up en route.

Soon, however, a group of researchers will complete a major study of normal brain growth -- the first of its kind -- that will fill in this map of child development.

The National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development, an encyclopedic and unprecedented project, will track the growth and structural changes of healthy children’s brains as they develop from birth to late adolescence -- providing developmental researchers and pediatricians with a benchmark, finally, of what is “normal.”

“When you’re trying to study anything about brain abnormality, the assumption is you know what normal is,” says Alan C. Evans, professor of neurology and neuroscience at McGill University in Montreal, who is head of data collection for the project. “In fact -- we don’t.”

Once this project is complete and they do know, he adds, it will be possible to compare any number of psychiatric and cognitive disorders with the normal plot of brain development -- ADHD, autism, bipolar disorder, schizophrenia -- and have a better idea of just what goes wrong in the brain, and when.

“We can see what normal variation looks like, which we don’t really know,” says Deborah Waber, a psychology professor at Harvard Medical School and Children’s Hospital Boston. “We might be able to see how a brain veers off course.”

Such understanding, in turn, may guide researchers as they search for treatments and therapies that may prevent or mitigate the disorders.

The project, which began in 1999, involves researchers at six centers across the country and about 500 children. When most of the studies conclude this August, the scientists will have examined each child several times during the course of the study, compiling results from a battery of psychological and brain-imaging tests performed on children from 7 days to 18 years old. As findings emerge, so will a portrait of normalcy.

“We are very, very close to getting a true understanding of how the brain develops,” says C. Robert Almli, director of the developmental neuropsychobiology lab at Washington University in St. Louis School of Medicine.

The picture is already getting clearer. In mid-May, a group of researchers led by Waber published the results of behavioral tests on participants age 6 to 18 in the Journal of the International Neuropsychological Society -- the first paper based on data from the project.

The children took more than a dozen tests, assessing verbal fluency, memory, motor skills and general intelligence.

Even at these young ages, low-income children scored worse than middle- and high-income children on IQ tests -- a finding supported by prior research that may be the result of environmental factors.

But surprisingly, Waber notes, this gap was smaller than it had been in previous studies. In addition, children of different socioeconomic groups showed no difference on certain verbal exams and on organization tests.

The newer findings may well be more accurate because the data are so thorough and the children screened so rigorously for clean health.

Taken together, Waber says, these results suggest that a lot of disparity on cognitive tests disappears when all subjects are healthy, regardless of income.

Among the other conclusions: proficiency in most tasks improved greatly between ages 6 to 10 and then leveled off. Tests of verbal fluency (which in the past have favored girls) and calculation (which in the past have favored boys) showed no sex-related differences across all ages, a finding that Waber says is difficult to explain.

The first wave of results appeared on the project’s online database in late June, and researchers can now apply to access the information. Eventually -- perhaps in 2008 -- all the data will be made available to researchers looking for a sizable control group to compare with brains, or behavioral tests, of children who have disorders, or to clinicians wondering whether something they notice during a brain scan of a patient falls within the realm of normal.

The ability to pull off such a comprehensive database grew out of the development and establishment in the past decade of brain scanning technologies such as magnetic resonance and diffusion tensor imaging, Almli says. These tools, unlike older technologies such as CAT scans, don’t use radiation -- and thus are safe -- yet still produce high-quality images.

“For the first time we have a methodology to get good imaging,” Almli says. “We’re doing stuff I never thought I’d be doing.... Now we almost consider it a matter of course.”

In addition to the technology it employs, the project is unlike any other in its involvement of scientists of many disciplines and subjects of various backgrounds, says Judith Rumsey, project officer for the National Institute of Mental Health.

Generally, for research studies, scientists settle for convenient groups of people to represent normalcy -- college students, for example, or people from a surrounding community. But this project takes a representative slice of the United States in terms of gender, ethnicity and income. Thus, although this won’t be the first information on normal brain development, it is much more comprehensive, Rumsey says.

To ensure the healthiest brains possible, participants endured a wringer of screening tests. Anyone with potentially irregular brain development -- as noted by family history of neurological problems or prenatal exposure to cigarettes, for example -- was excluded.

“This is really a pristine group,” Waber says. “We needed to be able to assure that whatever disorder we’re studying, these kids didn’t have it.”

The inclusion of newborns and toddlers also distinguishes the study from previous looks at normal development, Almli says: Traditionally, researchers have trouble scanning the brains of children under age 10. But Almli’s lab has created a comfortable atmosphere in which youngsters can fall asleep in a bed within reach of a scanner, in the company of their parents.

This database of young, healthy brains will be a boon to clinicians and researchers alike. Suddenly, a neuroradiologist who might see one infant brain a year will have access to a significant resource of comparison.

“You can go through and superimpose a 6-month-old child’s brain on our template, and it’ll show you which areas are abnormal,” Almli says. “It’s going to revolutionize pediatric neuroimaging.”

Likewise, someone looking to study ADD can focus full energy and resources on children with the disorder, knowing that a thorough normal comparison sample exists.

Qualified researchers can access the data at www.bic.mni.mcgill.ca/nihpd/info, and general information about the project can be found at www.brain-child.org.

Some researchers caution against drawing too many conclusions from the data. The development of a certain brain region might coincide with the emergence of a particular behavior, but that doesn’t mean one caused the other, says BJ Casey, director of the Sackler Institute for Developmental Psychobiology at Weill Medical College of Cornell University, who is not affiliated with the project.

Stronger correlations will come with functional imaging studies -- which simultaneously measure behavior and brain activity -- guided by the normal results.

“Just like the human genome,” Casey says, “it’s a beginning point.”