Clues to Role of Brain Development as Risk for Mental Disorders May Also Lead to Better Treatments

May 6, 2008 • Science Update

WASHINGTON, DC, May 6 — Increasing evidence points to links between the timing and growth rates of specific brain areas in the young brain and the likelihood of developing a wide range of mental disorders later in life, say researchers convened by the National Institute of Mental Health (NIMH), a part of the National Institutes of Health. Included among these mental disorders are autism, anxiety, bipolar disorder, eating disorders, substance abuse, and attention deficit hyperactivity disorder (ADHD).

"Most psychiatric disorders, including those with adult onset such as schizophrenia, are increasingly recognized as being neurodevelopmental in origin," says NIMH's Jay Giedd, MD. "A greater understanding of the specifics of brain development, and where the path of development goes awry in illnesses, may be a key factor in devising better therapies."

The scientists spoke today at a press conference during the American Psychiatric Association Annual Meeting being held here.

A twenty-year ongoing longitudinal neuroimaging project of healthy children and adolescents being conducted at NIMH's child psychiatry branch shows the relationship between dynamic brain changes and the emergence of several classes of psychiatric disorders during adolescence.

The data set, which tracks participants aged three to 30 years every two years, consists of more than 6,000 magnetic resonance imaging (MRI) scans from 2,000 subjects. About half are from typically developing subjects and half have disorders such as attention deficit hyperactivity disorder, and childhood-onset schizophrenia. "The large number of typically developing subjects serves not only to provide a yardstick from which to assess developmental deviations but also because understanding the timing, mechanisms, and influences of healthy brain development may illuminate paths to intervention in illness," says Giedd, who oversees the study.

An emerging implication of the study is the importance of considering the trajectories — or changes in brain growth and size over time as opposed to only the final size — of brain development in linking brain and behavior. Studies show that the maturation of our brain, as we grow up, mirrors the development of the brain through evolution. Ancient areas that mature — reach peak thickness — earliest follow a simple, linear growth trajectory. New areas that support our uniquely human capacities mature latest and follow more complex patterns: initial childhood increase, followed by adolescent decline and then stabilization. Understanding the mechanisms and effects of genetic, environmental, and experiential factors that influence developmental brain trajectories in health and illness may provide targets for intervention or prevention.

"One hypothesis is that the reductions in brain volume result in part from an experience-dependent "pruning" during which neural circuitry becomes increasingly specialized to deal with the particular demands of its environment," says Giedd. "The age of peak size in volume varies by brain region but generally occurs during late childhood or early adolescence. Particularly late to mature is the prefrontal cortex — which is involved in functions such as impulse control, organization, judgment, and long term planning — and discussion regarding the implications of this have entered social, judicial, educational, and clinical realms," he says.

Functional MRI studies also show increasing frontal lobe involvement in the progression from child to adolescent to adult.

Imaging Shows That the Brain is Enlarged in Autism

In other investigations, imaging studies reveal that the brain is enlarged in individuals with autism. A 2005 MRI study on two-year-olds with autism, the youngest children with autism scanned to date, found that the brain volumes at age two years were enlarged by five percent to ten percent, says Joseph Piven, MD, of the University of North Carolina. In the same paper, Piven and his colleagues also reported that head circumference, an indirect measure of brain volume in young children, was significantly increased in autism.

In the same study, Piven and his colleagues compared the past health records of 113 autistic individuals with a large sample of normal controls and showed that head circumference was significantly increased in autism, but that the differences in size did not begin to appear until 12 months of age. This suggested that brain volume changes (driving the head circumference increase) had their origins at the end of the first year of life.

Their collaborator, Lonnie Zwaigenbaum, MD, and his group at McMaster University in Hamilton, Ontario, Canada, have also been studying infant siblings of autistic individuals, who are themselves at high risk for autism. Those infant siblings who eventually receive a diagnosis of an autism spectrum disorder — about 13 percent in his study at two to three years of age — did not show any of the defining behavioral features of autism at six months of age. However, by 12 months there were striking differences. These findings are consistent with other recent reports.

"These findings suggest that autistic behavior may have its onset in the latter part of the first year of life, and coincide with brain overgrowth that seems to occur around that same time," says Piven.

"The timing of these changes, occurring in the latter part of the first year of life, is consistent with an underlying neurobiological abnormality in synapse remodeling and remodeling of neuronal processes," Piven says. Synapses are physical gaps between two nerve cells that function as the site of information transfer from one cell to another.

"These results are also consistent with the findings of other studies, such as molecular genetic studies, that point to selected genes underlying autistic disorders and the findings regarding the neurobiological basis of disorders associated with autism, like Fragile X Syndrome, where neurobiology has been more clearly implicated," Piven adds.

Brain Maturation Delayed in ADHD

Ever since attention deficit hyperactivity disorder was first described, a debate has raged about whether it's due to delay in brain development, or a complete deviation away from patterns of normal development. By studying brain scans of more than 450 children with and without ADHD, NIMH's Philip Shaw, MD, and his colleagues found that the cortex — the outer mantle of the brain or gray matter — matured about three years later in ADHD.

The delay was most marked in the front parts of the brain important for the control of action and attention. However, while there was delay, the order or sequence in which the different parts of the brain matured was very similar between children with ADHD and unaffected children. "If ADHD was due to a complete deviation away from typical brain development, then this sequence of maturation would be disrupted, and we found it was not," says Shaw. "The study suggests we should look further into factors, such as genes, which might be responsible for this delay, especially as this delay can persist well into adulthood."

"This gives us the chance to develop novel treatments aimed at boosting normal maturation in ADHD, one of the most common childhood mental health problems worldwide," Shaw adds.

Safety of Psychiatric Medications is Concern

In another series of studies, scientists have looked at the untoward effects of psychiatric medications that are increasingly being used for the treatment of children and adolescents. Several highly publicized reports of harmful side effects of these medications have raised concern about their safety, thereby complicating decision-making for clinicians and families.

The primary areas of concern are adverse effects of antidepressant medications, particularly risk for suicide; developing diabetes and high cholesterol during treatment with second generation antipsychotics; possible changes in heart rate and blood pressure, and abnormalities in heart functioning during medication treatment of ADHD; and the stunted physical growth during treatment of ADHD; says NIMH's Benedetto Vitielo, MD, the organizer of a symposium on this topic.

Most important, Vitiello says, is for mental health practitioners to be able to interpret the data to make informed treatment decisions and weigh benefits and risk. The major issues include:

• Antidepressant treatment of adolescents requires monitoring as depression is the main risk factor for suicidal behavior. But the benefits of antidepressants, when properly used, outweigh the risks. Combination with psychotherapy seems to improve the overall safety of antidepressants and reduce the dose needed for improvement.
• The use of second generation antipsychotics among youths has been increasing. Some of these medications, such as olanzapine and risperidone, have been related to problematic weight gain and abnormalities in glucose and lipid metabolism. Recent research indicates that children and adolescents are at even higher risk for these complications than adults. Clinicians need to monitor weight and metabolic indexes during treatment with these medications.
• Stimulant medications, such as amphetamines and methylphenidate (Ritalin and other similar products), which are used to treat ADHD, have subtle, but potentially clinically significant effects on physical growth. While this effect has been known for decades, recent studies have better defined and quantified this phenomenon. It is therefore important to measure growth both in weight and height when treating children with these medications.
• Medications for ADHD also have been reported to have subtle effects on heart rate and blood pressure. It is not clear if and under which circumstances these effects can be clinically significant. Research is in progress to better understand the cardiovascular effects of stimulants given to children with ADHD.