Every year, one in ten babies worldwide are born too early. That’s roughly 15 million children, according to the World Health Organization. When children are born too soon, they are at higher risk of mental and physical disabilities, especially if they weigh less than 1500 grams at birth.

While three-quarters of these preterm births are thought to be preventable, sometimes it’s simply not possible. That last fact has researchers like Alexander Olsen, an associate professor at the Norwegian University of Science and Technology (NTNU), working to better understand the consequences of very low birth weights on cognitive development.

Olsen is director of the Clinical Neuroscience Laboratory at the university, which focuses on investigating the consequences of brain injury and disease, in part by using advanced neuroimaging. Olsen is also a specialist in clinical neuropsychology and holds a position at St. Olavs Hospital, where he works with assessments and clinical follow-ups of patients with acquired brain injuries.

While Olsen’s primary research interest is traumatic brain injury, his research using fMRI on this topic attracted the attention of colleagues in Trondheim who had been working with very low birth weight individuals and brain development.

Long-term study offers new insights

When Olsen was a research fellow at NTNU’s Medical Imaging Laboratory, he worked closely with the head of the Trondheim fMRI Group, Asta Håberg, to expand his research to include a collaboration with the Centre for Early Brain Development, which is conducting a long-term study of individuals with low birth weight. The collaboration also grew to include researchers from the University of Southern California’s Imaging Genetics Center at the Stevens Institute for Neuroimaging and Informatics.

“The idea emerged that a lot could potentially be learned through studying these groups in parallel, because they are both typically characterized by alterations in the white matter of the brain, although for different reasons,” he said. The white matter is important because it helps provide connectivity between different areas of the brain.

“Comparing how brain function adapts differently to pre- and perinatal injuries and those acquired as adults could provide important information on how the brain works in general,” he added.

Cognitive control a problem

Olsen and his colleagues wanted to see how the brains of very low birth weight individuals differed from their normal birth weight cohorts when it came to cognitive control, and the ability to think proactively or reactively about different tasks. That’s because cognitive control dysfunction is one of the biggest problems facing very low birth weight individuals, Olsen said.

“Cognitive control is related to the goal-directed regulation of thoughts, actions and emotions,” Olsen said. “You have to effectively organize and quickly use your mental capacities in a flexible way to cope with the world. A lot of individuals born with very low birth weight have problems with that.”

To study this question, the researchers relied on a group of very low birth weight individuals who were born between 1986 and 1988 in Trondheim, Norway. These individuals had already participated in MRI studies in Trondheim when they were 1, 5, 14 and 20 years old. Thirty-two individuals between 22 and 24 years of age from this group participated in Olsen’s study and were matched with same-aged controls that had normal birth weights.

For the first time in this cohort, the researchers used fMRI imagery to conduct their work, which allows them to see activation in different parts of the brain as study subjects are engaged in a task.

In this study, participants looked at a computer screen while in the scanner and were shown a series of random letters. Their task was to press a button as quickly as possible when they saw a new letter pop up on the computer screen, except when the letter was “x”. The most common response was to press the button, because the letter “x” was only presented 10% of the time.

“You need two different types of cognitive control to complete this assignment,” Olsen said. “So that simple task gave us a lot of information.”

Proactive and reactive systems

The brain is constantly working to create meaning out of the flood of information that comes at us every waking minute of our day, Olsen says. Researchers have identified two different processes the brain relies on to achieve this task: a proactive cognitive control function, and a reactive function.

Proactive cognitive control relates to proactively working on a task — like the task given to study participants in the MRI scanner. They knew that most of the time they had to press the button, and they mentally prepared, in a proactive way, to identify new letters as each letter popped up, and to find a balance so that they could respond as quickly and accurate as possible.

But the appearance of the “x” on the screen required a different reaction, Olsen said. “The reactive system kicks in when something happens that is not expected,” he said. “Then you need to adapt your behaviour and react to the new information. You have to throw away your old plan and come up with a new plan.”

The difference between the two different cognitive systems turned out to be important in explaining other behavior in the very low birth weight individuals, the researchers found.

More reactive, less proactive

The very low birth weight study participants completed the tasks as well as the normal birth weight participants, the researchers found. But they used different cognitive functions to do so, Olsen said.

“What we found was that the preterm group had less proactive brain activation and were more reactive compared to the normal birth weight control group,” Olsen said.

This hyper-reactive brain activation signature was accompanied with poorer white matter organization in the brain, and was associated with lower fluid intelligence and anxiety problems. Researchers define fluid intelligence as the ability to think abstractly, identify relationships and solve novel problems.

This difference meant “their brains reacted as if they were encountering something new each time,” he said. “It suggests their brains are hypervigilant due to suboptimal organization of the central nervous system. One interpretation is that they are less prepared and more surprised each time, which might create more anxiety problems.”

Making sense of anxiety

As both a researcher and a clinical neuropsychologist, Olsen thinks about the potential applications of his research findings.

“As a clinician, this is particularly interesting,” he said. “It makes sense as to why, when you meet some of these individuals as patients, they are experiencing problems with cognitive control function, and having this tied to other emotional problems.”

Although the fMRI isn’t a practical tool for a clinical setting, the researchers’ findings can provide a backdrop for better understanding patients in this group, he said.

“When we work with people with cognitive dysfunction or anxiety problems, we are trying to help them be more proactive in how they prepare for certain situations, so they don’t have to rely on reactive problem solving as much,” Olsen said. “When you work with cognitive behavioral therapy or cognitive rehabilitation, you work on getting structure into people’s lives so they don’t have to rely too much on their online cognitive control processing. Creating structure and routine in your life frees up cognitive control resources that can instead be more effectively used for dealing with those things that can’t be planned for.”

Reference: Alexander Olsen, Emily L. Dennis, Kari Anne I. Evensen, Ingrid Marie Husby Hollund, Gro C.C. Løhaugen, Paul M. Thompson, Ann-Mari Brubakk, Live Eikenes, Asta K. Håberg, Preterm birth leads to hyper-reactive cognitive control processing and poor white matter organization in adulthood, NeuroImage, Volume 167, 2018, Pages 419-428.