Refining the Connections

In the New York Times bestselling novel I Know This Much Is True, author Wally Lamb chronicles Thomas Birdsey’s descent into schizophrenia through the eyes of his twin brother, Dominick. In the book, Thomas starts to exhibit the hallmark symptoms of the disease, including paranoia, disordered thinking, and hallucinations, during adolescence, and suffers his first full psychotic break when he goes off to college. The timeline of his illness mimics the trajectory observed in real-life schizophrenia, as well as that seen in other neuropsychiatric disorders. Why so many mental illnesses manifest themselves during the teenage years is an open question. A new study from the University of Cambridge tracking the distribution of myelin across important association hubs in the cortex, enabling refinement of critical communication networks necessary for adulthood, may offer a clue.

What is normal development?

About half of all lifetime cases of mental illness, including disorders like schizophrenia, depression, and bipolar disorder, begin in early adolescence, and nearly three-quarters take hold before the age of 24, according to the National Institute of Mental Health (NIMH).

“Most psychiatric disorders, schizophrenia in particular, have their initial incidences during late adolescent and early adulthood,” says Edward Bullmore, head of psychiatry at the University of Cambridge. “People have often argued that these disorders reflect some sort of developmental process going awry in the brain. But historically we haven’t had a good understanding of the process of brain development during the course of normal adolescence. We haven’t had good benchmarks of those normal processes nailed down. Without an understanding of typical development, we can’t say much about the atypical.”

Many scientists have theorized that synaptic pruning, a developmental remodeling process that “snips” unnecessary synaptic connections in the brain—thereby allowing other connections, thought to be critical to the development of the healthy adult brain, to strengthen—may play a role in the origin of neuropsychiatric disorders. But Kirstie Whitaker, a researcher in Bullmore’s laboratory at Cambridge, says that it’s unlikely that such pruning explains all of the brain differences observed between normal adolescents and those who go on to develop mental illness.

Bullmore agrees. “In schizophrenic brains, you see evidence that synaptic density is abnormal—but you can’t quite say there is evidence that the developmental process of synaptic pruning is the explanation for that. Partly, that’s because that we don’t have a very good imaging marker for pruning,” he says. What may be a more likely explanation, he suggests, is a developmental process that is reorganizing cortical circuits and networks—not just accounting for those differences in synaptic density, but also common schizophrenic symptoms like disordered thinking and speech. But, once again, to test the theory, researchers would have to be able to map normal structural development in the adolescent brain.

Refinement through myelin

To better measure that normal development, Bullmore, Whitaker, and colleagues used magnetic resonance imaging (MRI) to examine the brain structure of nearly 300 people aged 14-24 years. Instead of looking at blood flow or cortical volume, the group measured levels of myelin, the fatty insulation that helps speed neural signaling in the cortex.

“There’s been a lot of nice work showing how important myelin is to insulating signals, especially in the long-range connections we have in the brain,” says Whitaker. “It makes sense that you’d need to be able to send signals far and quickly and send them in a way that they wouldn’t degrade over time to develop a healthy adult brain. And that’s myelin’s job.”

While historically myelin has been thought of as residing in the brain’s white matter tracts, it is also found in the gray matter, or cortex—the same areas that tend to shrink during adolescent development. When the researchers investigated those changes in the cortex, they discovered that while the cortex became thinner, its levels of myelin actually increased during the teenage years. And they did so particularly in the brain’s association areas, parts of the brain that act as major communication hubs for cortical networks.

“We saw that the brain was very developmentally active, especially in areas of the brain we know are important for higher order cognitive function,” says Bullmore. “You can think of these adolescent brain changes as wiring the hubs of the cortical network so it’s able to support the higher order cognitive functions required to become a successful, independent adult.”

The group also compared the MRI myelination levels to the Allen Brain Atlas (which maps known gene expression in brain areas) and found that the brain areas that showed the greatest changes in myelination were also those that had the strongest expression of genes linked to risk of developing schizophrenia.

“One of the biggest problems with being schizophrenic is that your thoughts are disorganized,” says Abigail Baird, a neuroscientist at Vassar College and a member of the Dana Alliance for Brain Initiatives. “And this paper speaks very nicely to that. It confirms a lot of converging evidence that there are areas of the brain that are supposed to be having really good back-and-forth conversations. And when they can’t do that, when those networks aren’t streamlined and communication is hindered, it’s likely you will probably end up with some serious issues.”

A question of timing?

Whitaker says that the results suggest that adolescence is a time of synaptic “refinement.” By looking at differences in the refinement of cortical networks during the teenage years, we might be able to glean more insights into how different neuropsychiatric diseases develop.

“It may be there’s a difference in timing of this synaptic reorganization. We know that many areas of the brain change during development but, we hypothesize, some of them may be getting there faster than others and that may be the problem,” she says. “We know that myelin limits plasticity—so it limits your ability to adjust to new experiences. And we believe that people who are at risk for mental health disorders may be developing too quickly, getting these connections fixed too early, and end up with connections that are slightly out of sync. It may sound counterintuitive, but a slow brain development is very important. It allows your brain to choose the very best connections, the very best ways of interacting with your environment, and the very best way of responding to what you experience in that environment.”

Bullmore agrees, and says it makes sense that if the different communication hubs in the brain can’t properly sync up, they won’t be able to appropriately signal to one another. Moreover, he suggests that such problems with network refinement may also be linked to neuropsychiatric disorders beyond schizophrenia. He and his colleagues are currently investigating myelination levels as a potential link to depression in the teenage brain. Still, he says, there’s much work to do to understand the trajectory of standard adolescent brain development before anyone goes too far down that path.

“To the extent that normal intracortical myelin is part of the story of normal brain development, it could very well be part of the story for how other psychiatric disorders arise with high incidence during adolescence. It could provide us with some new and very interesting insights,” he says. “I think it will be very interesting to see how this myelin signal stands up, not just as a marker of normal development, but also potentially as a marker of a developmental disorder. But we’re not quite there yet.”