Landmark Imaging Studies Help Explain Teen Brains - 2006

by Brenda Patoine

What goes on inside a teenager’s head?  It’s a question parents and teachers may find themselves asking frequently, with little hope of an answer.  Now that neuroscience has taken on the question, the often illogical and frequently impulsive behaviors that mark the teenage years are beginning to make sense – at least from a brain-development point of view.

It’s been 10 years now since a nationwide team of neuroscientists, under the auspices of the Child Psychiatry Branch of the National Institute of Mental Health (NIMH), began systematically applying magnetic resonance imaging to a large group of children and adolescents to better understand the development and maturation of their brains.  Several hundred MRI scans later, the study has to a large extent turned conventional thinking about brain development on its ear, and continues to provide fundamental insights that are shedding ever more light on the perennial question of what makes a teenager tick. 

As the study enters a new phase – switching from basic mapping of brain changes throughout childhood and adolescence to understanding what influences these changes, for good or ill – it is revealing important clues about the impact of gene-environment interactions and about childhood-onset disorders such as schizophrenia and attention deficit-hyperactivity disorder (ADHD). 

“This study has transformed the field.  It is having profound effects on our understanding of the brain and how it works, whether in cognition or disease,” says Judith Rapoport, the head of the Child Psychiatry Branch at NIMH and a member of the Dana Alliance for Brain Initiatives. While she cautions that the study has not yet provided information that can be used to diagnose childhood diseases, it has yielded essential data not only about what can go wrong in disease, but also about what’s going on in the brains of those children who recover or have good outcomes.

A Dynamic, Lengthy Process
In terms of normal brain development, the fundamental messages that have emerged from this longitudinal investigation are that it is a much more dynamic process than was previously thought, and that it lasts longer.  In the developing brain, gray matter in the cortex follows a course of gradually increasing volume up to about the age of adolescence, and then sharply declines as the brain prunes away neuronal connections that are deemed superfluous to the adult needs of the individual.  While the “pruning” phenomenon had been previously recognized as a critical aspect of early brain development in the first years of life, the second wave of neuronal pruning has only become clear as a result of the scanning study.

NIMH child psychologist and study coordinator Jay Giedd likens the process to Michelangelo’s creation of the exquisitely detailed David sculpture from a rough block of granite, or to a master gardener trimming back an overgrown tree.  “The end result is better and more effective,” Giedd says.  Which neural connections are trimmed vs. which are retained is driven by the individual’s experience, in classic “use it or lose it” fashion. “You sort of have to train your brain to be specialized in one thing or another,” he says. 

During this period of rapid change in the brain, the impact of the environment may be particularly crucial, and this may make the brain more vulnerable to either good or bad influences, Giedd says.  If an adolescent is using drugs extensively during this time of pruning, he says, “you’re telling your brain that this is what it needs to be optimized for, and the brain circuitry is laid down accordingly.”

That doesn’t mean, of course, that every adolescent who experiments with drugs is destined to be an addict, but there is evidence that adolescents are particularly sensitive to addictive drugs.  A new report from the U.S. Substance Abuse and Mental Health Services Administration says that 14 percent of people in treatment for drug abuse began using at least one of their problem drugs before the age of 13.

Risky Business
Teenagers may have a greater propensity for risk-taking behaviors such as drug use just by the nature of how their brains are developing.  Another key finding from the MRI study is that the prefrontal cortex, the part of the brain responsible for understanding the consequences of one’s actions and inhibiting inappropriate actions, is not fully mature until around the mid-20s.  Without these neural “brakes” in place, teens may be more prone to act impulsively.

“I don’t think there’s any question that teenagers are more vulnerable to impulsive actions, as are even younger children,” says Jordan Grafman, a Dana Alliance member and chief of cognitive neuroscience at the National Institute of Neurological Disorders and Stroke. “Partly because of the immaturity of the prefrontal cortex, adolescents do not have access to stored social rules that might otherwise inhibit impulsive tendencies regulated by other, more mature brain structures.”

The bigger question, Grafman says, is why some areas of the brain, including the prefrontal cortex, don’t mature until we reach our 20s.  The areas that are slowest to mature, he points out, are precisely the areas most involved in social knowledge, including understanding social norms and behaving appropriately.  In American culture at least, children’s social lives are typically tightly controlled until the late teen years – in part because of their relative lack of cognitive or social sophistication.  It’s a chicken-or-egg question, Grafman suggests: “Is the relatively late maturation of these areas because the brain is just slow and we are sort of slaves to brain development, or is there a piece of this that involves what we let people do when they’re that young?” he asks. 

From an evolutionary perspective, risk-taking among adolescents may in fact have benefits, says Giedd, because procreation typically entails leaving the home and venturing out into the world on one’s own.  “It’s hard to prove, but it makes sense that the upside of risk-taking may be that it has served us well as a species in terms of being able to change environments and adapt to new ones,” he says.

The question of how teenage brains balance risk with potential reward to make decisions in day-to-day life – whether it’s choosing salad vs. French fries or having sex without a condom – is a subject that is beginning to attract attention among scientists.  Limited data so far suggest that the brain pathways underlying adolescent decision-making are distinct from those in adults, with overactivation of reward circuits that favor short-term benefits, even when it’s clear there will be a price to pay in the long run.  More research is needed, and Rapoport’s team is planning to tackle the subject soon.

“There’s a huge void in the literature, particularly in teenagers under 19,” says Giedd.  “Imaging is a very exciting way to start asking questions about decision-making, because you can have adults and teens do the same thing and actually see if their brains are solving the problem in the same way.”

Sorting Out Nature/Nurture Interplays
NIMH researchers have also turned their attention to patterns of heritability in the developing brain, which are essential to understanding what influences the maturation of neural circuitry.  They have measured the expression patterns of hundreds of genes on all of the children in the study, and roughly 70 percent of the scans currently being done are in twins, Giedd says.  The goal is to understand “the nature/nurture aspect:  how much of the influence is genetic vs. nongenetic,” he says.

This effort has revealed some surprises, according to Giedd.  “The original idea was to look at all the different parts of the brain and ask which parts are very heritable and which parts are not – to get a sense of these maps of flat-out heritability.  Now, what we’re finding most intriguing is that the answer to that question changes with age.” 

Though not proven, the implication of that finding is that different genes are expressed depending on the stage of development, Giedd says.  He uses the example of a caterpillar that turns into a butterfly:  “They both have the same genes but they look quite different.  It’s not that the genes change, but that certain ones are turned on and off.”

The idea that various genes are differentially expressed in the brain throughout its development led researchers to ask whether this phenomenon could help explain any of the diseases that commonly appear around adolescence, including schizophrenia, ADHD, bipolar disorder, and anxiety disorders.  “Looking at these age-by-heritability interactions might help us understand which genes get turned on in healthy adolescents at the same time as say, schizophrenia is emerging in other people, which can help narrow the search a bit for the genes involved in such disorders,” Giedd says.

Clues to Childhood Diseases
In addition to helping identify new genes that might be involved in disease, the imaging studies are advancing our understanding of what role already recognized disease-associated genes might be playing.  In schizophrenia, for example, the scientists have found that neuregulin, a risk-conferring gene for the disease, is expressed in both normal and schizophrenic children, but its effects are exaggerated in schizophrenics, according to Rapoport.  This finding correlates with scan results that indicate that adolescent schizophrenia, like normal development, is characterized by a wave of gray matter loss that sweeps from the back to the front, but which is greatly exaggerated in ill children.  “It’s as if the regulatory process that’s controlling normal development is in high gear,” she says

Determining what kicks that system into high gear in schizophrenia could be the key to interrupting the disease process.  For clues, Nitin Gogtay in Rapoport’s laboratory has been studying healthy siblings of children with schizophrenia.  It turns out that in early childhood, many of the siblings have some version of the same brain abnormalities found in schizophrenia.  But as they get older, their brains look more and more normal, suggesting a degree of resiliency or, as Rapoport says, “a plastic response that keeps them healthy.”

Resilience may also play a role in the ability of some children with ADHD to eventually overcome the disorder and show normal attentional behaviors.  In studying a cohort of adolescents diagnosed with ADHD, Rapoport and her colleagues have found several specific areas of thinning in regions of the cortex related to attentional control and planning, particularly in children who have worse outcomes (defined as still having ADHD five years later).  Intriguingly, they also found two brain areas related to attention and working memory (right parietal cortex and hippocampus) that actually increase in volume in children who improved as they got older, as roughly half of kids with ADHD do.

“It’s as if the pruning process that normally thins down these parts of the brain during late adolescence is inhibited in the kids who do better, so they have a greater area of the brain dedicated to certain cognitive functions,” Rapoport says.  “This probably reflects the brain’s attempt to compensate for weaknesses in the attentional system in other places.”  The finding points to the possibility of therapeutic approaches that could intensely train these regions to harness the brain’s inherent plasticity and enhance these apparent compensatory mechanisms.

“Using brain scans to show at which age abnormalities occur is a new and fascinating field,” says Rapoport, one that will likely lead to treatments as well as better diagnostic tools in the future.  But, she cautions, the science isn’t there yet. To date, there is no scientific evidence that any scan is clinically useful in telling one disorder from another. 

Published in 2006