Strong collaboration has transformed research in neuroimaging, epilepsy and migraines

by Tom O’Neill

They came for the tea and cookies, but stayed for the main course: insights into reducing the neurological “noise” that complicates the science of brain imaging.

On a recent Tuesday afternoon, members of the Pediatric Neuroimaging Research Consortium (PNRC) and their guests gathered over sips of Twining’s Earl Grey.

Inspired by a gathering format established at Princeton University, “team neuroscience” is equal parts informative and informal. The group’s core includes 10 researchers from five divisions, but its work impacts research throughout Cincinnati Children’s and institutions across the U.S. 

This strong sense of collaboration is fueling major developments in many areas of neuroscience. From migraines and language processing to epilepsy and hydrocephalus. From the behavioral to the structural. 

Simply put, the brain is a complicated place. Image is everything.

 “To ask and answer all the questions of the 21st century, we need all the different specialties at the table,” says Tracy Glauser, MD, Director of the Comprehensive Epilepsy Center.

 “The questions of the brain and mind are so complex,” he says, “so we rely on technology to look at the function and structure.”

Glauser, who also serves as Associate Director of the Cincinnati Children’s Research Foundation, says that multi-institutional research and the sharing of data are essential to the future of personalized medicine. He has considerable direct experience in collaboration as principal investigator of a major ongoing clinical trial to study treatments for absence epilepsy.

The double-blind, random trial is a monument to the power of multi-institutional cooperation. It involves 32 medical centers, 150 trial members and 446 patients.

The first two cycles of the trial established a baseline for medication strategies, and show promise that researchers can improve the genetic predictors of individual children’s outcomes.  

Collaboration fits Cincinnati Children’s to a tea

The PNRC tea-hour might seem symbolic, but it works.

“It puts people more at ease, and that’s the culture we want to have,” says PNRC Director Jennifer Vannest, PhD, Division of Neurology. “Some might think we’re a tough crowd, but really, it’s about constructive feedback. We all benefit from that.”

Meetings typically include scientists from all five core PNRC divisions (Radiology, Neurology, Neurosurgery, Anesthesia and Biostatistics). One recent gathering also included a neonatologist, a data analyst, and three first-year graduate students in neuroscience.

“We couldn’t do what we do without being interdisciplinary,” says Vannest, whose research focuses on neurological disorders and language impairments. “In order to develop better techniques for MRI, we need engineers and physicists.”

Enter Gowtham Atluri, PhD, an assistant professor of electrical engineering and computer systems at University of Cincinnati. His presentation to the group focused on reducing the “noise” in data from functional magnetic resonance imaging (fMRI).

He says he only began to understand the nuances of neuroimaging once he realized “there was a good bit of noise” in the scans. fMRI captures brain activity in time segments. 
The key, he says, is to understand how these images (say, one taken every two seconds for 10 minutes and then layered through various algorithms) can reveal patterns of connections between different brain regions.

Vannest is optimistic. “We’re beginning to better understand how the brain is organized, that it’s subdivided, and that its function happens with network interactions,” she says. “That’s the focus of new imaging techniques. It is changing how we look at learning and the acquisition of skills.”

Not just where, but when, neurons fire off. A single image cannot capture that. But a tall stack of images, organized for maximum “noise reduction,” might.

“This is, I think, exemplary about what’s going in neuroimaging,” says Scott Holland, PhD, a physicist who founded the consortium in 2005. He directs both Research in Patient Services and the Reading and Literacy Discovery Center at Cincinnati Children’s.

“Neuroimaging has gotten so complicated that no one of us has all the pieces,” he says. “I know how to make wonderful images of children’s brains. But I’d say more than half the job now is the analysis of that data.”   

fMRI data shows the importance of reading to children

Holland and Vannest.

Scott Holland, PhD, and Jennifer Vannest, PhD, are leading efforts to capture brain activity with fMRI techniques while reducing data “noise.”

In a study published in September 2015 in Pediatrics, a team led by Holland and John S. Hutton, MD, MS, Division of General and Community Pediatrics, demonstrates that reading to preschool children at home is associated with the activation of brain areas that support mental imagery and narrative.

Furthermore, higher reading exposure showed up on scans as neural stimulation in the left-sided parietal-temporal-occipital association cortex. This is the “hub” region for semantic language processing.

The following month, the journal Brain Research published a study by six PNRC members, including Holland and Vannest, showing that narrative comprehension at age 6 accurately predicted a child’s performance on the ACT college-entrance test at age 18. The data came from fMRI in a longitudinal study that included measures of academic achievement 10 to 12 years later. 

Still, for all the advancements in capturing the brain’s activity, some things remain elusive. Holland recalled a dispiriting moment about 15 years ago, while giving a presentation to the American Association of Child and Adolescent Psychiatry.

Hershy and Powers

A team led by Andrew Hershey, MD, PhD, (left) and Scott Powers, PhD, published surprising findings about the effectiveness of migraine medications in the Oct. 27, 2016, issue of The New England Journal of Medicine.

One of the 300 doctors there stood up and expressed concern about a bipolar patient he feared might develop schizophrenia. Can you image him and tell if that’s going to happen, he asked Holland.   

“And I had to say, ‘No. Our technology isn’t there yet. Maybe one day.’ ”

A 2015 University of Minnesota study that Atluri was a part of, however, did reveal abnormalities in the connections of different brain regions in people with schizophrenia. So in terms of large cohorts, that day is here. In terms of individual patients, no. 

You can’t see schizophrenia on an fMRI scan, in much the same way neuroimaging can’t capture psychological disorders or why children are compelled to certain behaviors.  

Or why some children develop debilitating migraine headaches. 

Andrew Hershey, MD, PhD, Director, Division of Neurology, and Scott Powers, PhD, Division of Behavioral Medicine and Clinical Psychology, are Co-Directors of the Headache Center at Cincinnati Children’s.

Study reveals the power of suggestion & anticipation

In a study published Oct. 27, 2016, in The New England Journal of Medicine, a team led by Hershey and Powers set out to compare the effectiveness of the two leading migraine medications for children, amitriptyline and topiramate.

Both drugs have adverse side-effects, most commonly paresthesia (typically a pins and needles sensation), fatigue, dry mouth and weight loss.

Findings showed that a placebo, a mere sugar pill, proved just as effective at limiting the frequency and severity of children’s migraines. 

The Childhood and Adolescent Migraine Prevention (CHAMP) study was conducted at 31 sites in the U.S., with Cincinnati Children’s responsible for all clinical oversight activities. Researchers at the University of Iowa provided the statistical data management.

The 24-week clinical trial included 328 eligible patients. Sixty-one percent of those on a placebo saw the days they had a headache reduced by 50 percent or more. Topiramate hit that mark 55 percent of the time; amitriptyline 52 percent. 

“We did find it surprising,” says senior author Hershey. 

“Not that we could get a placebo response rate that was equally as high,” he explains, “but because we required that all the children receive acute therapy, healthy habit discussions and adherence management. That may be why they improved across the country.”   

Hershey and Powers believe the likely cause of the placebo’s effectiveness is the expectation of relieving the migraine, and yet the impact on the brain was physiological—not imagined. In much the same way, children who anticipate getting a migraine are more likely to get one than they otherwise would. Stress is a factor. 

This means that, for some children, the stress-reducing experience of taking medication—any medication—might be stronger than the actual biochemical effects of the medicine. It suggests a vital role for other forms of therapy.

“Our national team was hoping to develop evidence to drive the choice by medical providers of the first-line prevention medication for helping youth with migraine, but the data showed otherwise,” says first author Powers. “We see this as an important opportunity for health care providers, scientists, children, and families because our findings suggest a paradigm shift. 

“First-line prevention treatment will involve a multidisciplinary team approach and focus on non-pharmacological aspects of care,” he says. “The good news is we can help children with migraines get better.” 

Balancing brain & mind

The migraine medication findings underscore the potential value of cognitive behavioral therapy as a tool for controlling pain. They also show that the complexities of the brain and the mind are essentially inseparable. 

No other organ of the body is like that. 

Glauser says non-invasive imaging will continue to be crucial in unlocking the brain’s mysteries. The big challenge is a simple function of anatomy. “The brain is not an easily accessible organ, like the heart or liver or kidney,” he says. “You can’t take someone’s brain out.”

So it takes a neuroimaging team focused on collaboration in all its tea-sipping forms. 

At the recent meeting of the PNRC, most of the 24 researchers in attendance thanked Atluri for his insights and filed away to the elevators. Left were just a few stragglers. A minute later, there was a sound of wheels rolling down the hallway. 

For a guy with three degrees in Engineering and Applied Science from Yale, Holland might seem like an unlikely guy to be pushing the cart of tea supplies back to storage for another week. But there he was, yet another example of teamwork in action.