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Linking brain to mind in a common genetic disease

Abnormal brain structure tied to spatial, numerical thinking problems when children lack part of chromosome

Children's Hospital of Philadelphia

Certain genetic diseases affect children's educational abilities in a distinctive pattern: impairing their numerical abilities more than their verbal skills. New research sheds light on this split in abilities by investigating how differences in brain structures may influence how the mind works.

Researchers at The Children's Hospital of Philadelphia, studying a common chromosome disorder, have used high-tech imaging tools to identify abnormal brain tissue associated with problems in perceiving spatial relationships and thinking about numbers.

Understanding the links between brain structure and brain function may offer clues to improving methods to help children with specific learning disabilities. By pinpointing specific sites in the brain associated with impaired mental functions, scientists hope to eventually help children retrain their brains to follow alternative pathways and work around their cognitive weaknesses.

Cognitive neuroscientist Tony J. Simon, Ph.D., led the studies of children with chromosome 22q11.2 deletion syndrome, the most common genetic deletion syndrome. In this disorder, a tiny portion of chromosome 22 is missing, causing symptoms such as heart defects, cleft palate, abnormal immune responses and cognitive impairments. Children's Hospital is a world center for research and treatment of the syndrome.

The current work draws on cognitive neuroscience - an emerging scientific field that investigates how the mind arises from the biology of the brain. One important factor driving the field is the application of tools such as magnetic resonance imaging (MRI) to yield more precise measurements of structures in the living brain. MRI can provide images and compute volumes of anatomical features. In addition, by measuring how water diffuses in the brain, it indicates the layout of nerve fibers and suggests how brain areas are connected to each other.

Dr. Simon is now at the M.I.N.D. Institute of the University of California, Davis. He recently published two studies of patients at The Children's Hospital of Philadelphia with chromosome 22q11.2 deletion syndrome.

One study, in the April 2005 issue of Cortex, measures impairments in the childrens' visual-spatial and numerical skills. A complementary study, in the March issue of NeuroImage, describes structural abnormalities in the brains of children with the syndrome. The abnormal structures occurred in and around the posterior parietal lobe, toward the back of the brain.

"Together, these studies strengthen our hypothesis that abnormalities in the brain's parietal lobe are a critical factor in the visual-spatial and numerical processing difficulties that we see in children with this syndrome," said Dr. Simon.

Researchers have known for some time that children with chromosome 22q11.2 deletion syndrome perform poorly in math skills compared to verbal skills. The current research provides evidence toward an explanation of that gap in cognitive abilities.

In the Cortex study, the Children's Hospital team compared 12 children with the syndrome to 15 healthy children. They found children with the chromosome deletion performed more poorly on experiments designed to test visual attention orienting, enumerating, and judging numerical magnitudes. All three tasks relate to how the children mentally represent objects and the spatial relationships among them. In previous research, Dr. Simon has argued that such visual-spatial skills are a fundamental foundation to the later learning of counting and mathematics.

"Studies in adults have shown that damage to the posterior parietal lobe impairs a person's visual-spatial and numerical thinking," said Dr. Simon. "These findings strengthen the evidence for a similar relationship in children."

The study in NeuroImage compared 18 children with the deletion to 18 healthy children. Using MRI techniques, the research team used newer methods to confirm previous findings of reductions in posterior brain volume and in grey and white matter. But the researchers also found something new: changes in the shape, size and position of the corpus callosum, a structure that connects the brain's two hemispheres.

"It may be that the basic problem lies in how parts of the brain are connected," said Dr. Simon. "It's like having a fuzzy signal on your cell phone--the phone is working, but the connections are defective."

Chromosome 22q11.2 deletion syndrome is one of the most common genetic sources of developmental disability. "The population of children with chromosome 22q11.2 deletion syndrome is growing, as improved heart care allows many more children to survive the heart defects that commonly occur in the condition," said clinical geneticist Elaine H. Zackai, M.D., a co-author of both studies and medical director of the 22q and You Clinic at Children's Hospital.

The findings may have implications for other diseases as well. "Chromosome 22q11.2 deletion syndrome is one of a number of conditions with a similar pattern of visual-spatial and numerical impairments, grouped as nonverbal learning disabilities," said Dr. Simon. "It may turn out that all these conditions have common changes to critical pathways in the brain."

"As we gain greater understanding of the details of how neural circuits are connected for particular brain functions, we can design strategies for therapies, because children's brains are more plastic than adult brains, and more capable of reconfiguring tasks through alternative paths," added Dr. Simon. "Our findings represent early steps toward that goal."


The National Institutes of Health and the Philadelphia Foundation provided funding for both studies. Dr. Simon's co-authors on the Cortex study were Carrie Bearden, Ph.D., Donna McDonald-McGinn, M.S., C.G.C., and Elaine Zackai, M.D., of Children's Hospital. His co-authors on the NeuroImage study were Lijun Ding, Joel P. Bish, Ms. McDonald-McGinn, and Dr. Zackai, of Children's Hospital; and James Gee, M.D., of the University of Pennsylvania.

The Children's Hospital of Philadelphia houses the 22q and You Center, the largest program in the world specializing in chromosome 22q11.2 deletion syndrome. The multidisciplinary center provides care for children needing specialists in medical genetics, cardiology, plastic surgery, immunology, endocrinology and neurology. In the early 1980s, geneticists at Children's Hospital were among the researchers that identified deletions in chromosome 22 as responsible for the syndrome, and later developed a diagnostic test for the syndrome that is now used around the world. With sponsorship from the National Institutes of Health, researches from Children's Hospital produced a map of chromosome 22 in 1995, and in 1999, collaborated with the Human Genome Project in publishing the sequence of chromosome 22, the first human chromosome to be sequenced under that Project.

The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit

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