In Search of New Therapies, Studying the Neurobiology of Brain Development in Pediatric Anxiety
In Search of New Therapies, Studying the Neurobiology of Brain Development in Pediatric Anxiety
Anxiety disorders are the most common class of pediatric psychiatric illness,” notes Dr. Chad Sylvester. They affect up to 30% of all youths under 18 years of age and severely impair an estimated 10%, he says. In the U.S. alone, that means impairment due to anxiety in some 7 million children.
Just as worrisome, pediatric anxiety disorders “can place affected children at significantly elevated risk for anxiety, depression, and substance-use disorders later in life,” Dr. Sylvester noted in a 2018 editorial published in the Journal of the American Academy of Child & Adolescent Psychiatry.
Perhaps in part this is because as many as 50% of anxious children remain symptomatic “even with the best available treatment,” Dr. Sylvester has also pointed out. This, he stresses, “makes pediatric anxiety disorders a major public health problem.”
Another factor possibly contributing to the levels of impairment and difficulty in successfully treating childhood anxiety disorders is the time lag that often occurs between the time when symptoms or their precursors are thought to first manifest and the time, often years later, when a young person receives a diagnosis.
This helps explain the focus of research conducted by Dr. Sylvester and his team at Washington University. They are trying to establish a base of scientific evidence that would link pediatric anxiety disorders with specific forms of atypical brain development—processes that likely begin very early in life, even in infancy.
Dr. Sylvester is called “a star” by BBRF Scientific Council member Daniel S. Pine, M.D., a National Institutes of Health Distinguished Investigator and Chief of the Section on Development and Affective Neuroscience, who praises him for his abilities as both a doctor and researcher. The two have collaborated on several published papers. For his part, Dr. Sylvester humbly states that “I really like being a child psychiatrist.” Being a medical doctor is part of the story, but it is linked to the fact that he also has a doctorate in neuroscience. His young and rising career is an example of how medical training with a focus on psychiatry plus training in the sciences can combine to motivate and shape a career.
Dr. Sylvester finds being a doctor immensely satisfying. “I really enjoy working with children and families. I like hearing people’s stories and thinking about how they think and feel—and thinking about these things in the context of how the brain develops.”
The salient point is this, he says: “If we can intervene during the early years in life when anxiety or other pediatric psychiatric disorders develop, then we may be able to prevent lifelong morbidity associated with those illnesses. This kind of research could have the highest impact, from a human and public-health point of view.”
FINALLY RECOGNIZING CHILDHOOD ILLNESSES
Research programs like that of Dr. Sylvester mark the great distance science has come in very recent times. Less than 20 years ago, the notion of a child, particularly a preschooler, having a diagnosable depression or anxiety disorder was not taken seriously by many in medicine.
Asked about this, Dr. Sylvester speaks about one of the senior members of the faculty at Washington University, Dr. Joan Luby. Dr. Luby is a BBRF Scientific Council member, three-time recipient of BBRF grants, and winner of BBRF’s Ruane and Klerman prizes in 2020 and 2004, respectively.
“You have to give great credit to Joan,” Dr. Sylvester says. “She really had to fight tooth-and-nail to get people to believe that someone so young could be depressed.” Dr. Luby’s pathbreaking research has focused on the characterization of early childhood psychopathology, early behavioral and biological markers of risk, and associated alterations in brain and emotional development in early childhood. Her contributions include establishing criteria for identification, validation, and early intervention in depressive syndromes in preschoolers. She also conducted studies, some with Dr. Deanna Barch, a Washington University colleague, BBRF Scientific Council member and four-time BBRF grantee, showing the effect of parental nurturance and early experiences of poverty on brain development. Dr. Luby has also developed and tested an early psychotherapeutic intervention for preschool depression called Parent- Child Interactive Therapy.
Dr. Sylvester points out that the research of Drs. Luby, Barch, and others did much to change minds of the skeptics. “It showed that preschoolers have depressive symptoms, that they can exhibit low mood, lack of interest, irritability, etc. For many kids like this, it’s not a momentary phenomenon. And these symptoms really do predict that kids with these emotional problems when they’re younger also have emotional problems when they’re older. I think these findings are part of what has forced people to take these symptoms in preschool and childhood more seriously.”
NORMAL VS. ABNORMAL FEAR
When is fear or anxiety abnormal? Every parent knows that every child expresses fears. Anxiety about strangers is common to see within half a year of birth, and can continue until about age 2. It’s part of the normal process of the child learning to be at home in the environment that extends beyond the parent-child dyad. There’s an even deeper reason that traces to evolution. “Even single-cell organisms have avoidance responses to things that are dangerous,” Dr. Sylvester points out. “There’s a long evolutionary history of response to threat. Of course it’s fundamentally important that people have fear in particular instances. It’s when fear gets hijacked in situations where a person is actually safe that problems arise.” There are several reasons. For one thing, the fear response can generalize to other situations, without warrant; or it can be too intense, given the level of threat; or, it can get to the point of impairing a person’s ability to function.
“In the first couple of years of life, your brain is learning what you can expect from the environment; what you have to do for yourself versus wheat you can depend on from others; whether or not the environment is safe versus dangerous. And there’s evidence that the plasticity of the brain when these things are being learned is especially sensitive to the environment.”
Developmental plasticity can be thought of in two very different ways. On the one hand, malleability of connections between neurons is what enables us to learn and remember— to instinctually recoil from perceived threats, but also to learn to know that some novel exposures pose no threat. At the same time, if a very young child has stressful or otherwise unusual exposures, unusual challenges in their environment, or if their brain circuitry underlying the response to novelty, for example, is following an atypical trajectory, there is the possibility patterns will be established that not only generate psychiatric symptoms in early life, but patterns that may be increasingly difficult to modify as the child ages.
But Dr. Sylvester stresses: “’Difficult to change’ does not necessarily mean it will be impossible to modify a particular brain circuit” underlying, for example, an inordinate feeling of threat or anxiety about unfamiliar things in the environment. “It just may take some work to change it.”
“This prospect is one of the reasons I went into child psychiatry,” he explains. It’s where the observation of early childhood anxiety intersects with research the team is performing on how brain circuits develop.
“One thing our lab is focusing on is to examine different brain circuits that respond to things related to attention, paying attention to things that are unexpected or new or different. We refer to the ‘oddball response’— the brain’s response to novelty. How does that circuit develop? How does variation among individuals affect how that circuit responds? And how does this relate to different levels of individual risk?”
The lab’s studies of attention and brain responses to novelty span a wide range of ages—from infancy to ages 10-12. This has led to the development and testing of methods to train the attention of young people. The general idea is that “we test how readily attention in children is grabbed involuntarily by things that are unexpected or different,” Dr. Sylvester explains. “In older kids we measure that by showing flashes of light on a screen and measuring how those flashes distract kids from a task that we instruct them to perform. We’ve found that anxious kids have increased distractibility—their attention network in the brain responds more strongly to the flashes on the screen than that of kids who are not anxious. The attention-training program we’re working on teaches kids to stay focused on the task, even when flashes come up all the time.“
To the extent young people can be trained to “get used” to the flashes and persist in their assigned task, the question is how this relates to activity levels in parts of the brain that process the distracting flashes. “We hope to leverage what we’re finding out about how these brain circuits function differently at higher and lower levels of attention paid to the ‘distractions.’ We hope that can become a basis for developing new treatments,” Dr. Sylvester says.
EARLY WINDOW OF SENSITIVITY
It all relates to the window of great environmental sensitivity that opens in brain development in the early years of life—and trying to find ways to take advantage of the plasticity that underlies that sensitivity in kids who are overreacting to distractions or novelty. “We’re trying to see if we can retrain them.”
Adaptive behavior includes being able to act on new, salient stimuli that are appropriate under the circumstances, without over-reacting any time a new stimulus appears, but also not underreacting and ignoring new, important stimuli. Dr. Sylvester’s hypothesis is that anxiety, in terms of attention, can be thought of as at the opposite end of a spectrum whose other extreme is attention-deficit hyperactivity disorder (ADHD). The anxious child is hypervigilant, to the point of being thrown off by almost any new or unusual stimuli; the child with ADHD is under-vigilant, not paying attention even to important new stimuli (e.g., their name being called).
“The goal is to have an optimal balance between, ‘Yes, I need to detect new things as they happen’ and ‘no, I mustn’t get jumpy and overreact to any new stimulus,’“ Dr. Sylvester says.
Being overly vigilant is not just an inconvenience; it can really impair a child’s function. “If, every time they hear some sound, some noise, some movement, they become anxious, because they think it’s the signal of danger, that child is not going to be able to concentrate, won’t do as well on their test in school. Kids who are trying to sleep who react to every bump in the night—they are not going to get their sleep.
“On the one hand, we don’t want to take away vigilance—we all need to be able to detect danger. But hypervigilance is a problem. We want the child to strike the optimal balance.“
Hypervigilance is only one symptom of anxiety in young children. There are others—for example, anxiety about making a mistake, or overreacting when one has made an error. In children who develop anxiety, Dr. Sylvester hypothesizes it’s possible that symptoms won’t be apparent until there are disruptions in multiple relevant brain circuits. Oversensitivity to errors points to increased activity in brain areas that respond to errors, such as the dorsal anterior cingulate and the anterior insula, he notes. It may be that disruptions in multiple circuits—for example, those that are overactive in response to novelty in addition to those involved in error oversensitivity—may need to co-occur before anxiety symptoms become noticeable.
The challenge is to be able to detect anomalies in circuit development in those developmentally sensitive windows of time when they may be most amenable to therapeutic modification, say, via behavioral training.
“Each of these circuits that we think are perturbed in children on a path to anxiety is developing on its own schedule, and each has its own developmental widow. We propose that it’s the interaction among these developing circuits, each on its own trajectory, that is ultimately related to a child’s risk for anxiety as the brain develops,” Dr. Sylvester says. “It’s possible that each of the anomalies builds upon the others, ultimately leading to a disorder.”
With the earliest phases of circuit development in mind, Dr. Sylvester and colleagues have been performing remarkable brain-imaging studies of newborns. He credits their ability to gather important information to “our really amazing staff” who care for the infants and their mothers.
“The babies are fed immediately before we put them into the scanner. We have an ICU nurse there who wraps the babies up in blankets and rocks them to sleep. Then we put them in something that looks like a papoose that makes them feel snug. And then we put them in the scanner. We don’t give them any medicine or sedatives. They fall asleep and usually they’ll stay asleep for an hour or two. We have a success rate of about 95%—a testament to the staff. They’re just incredible at what they do.”
While the babies are being prepared, they are fitted with ear protector pads that block the sound of the scanner. They also wear noise-cancelling headphones. Those headphones also deliver the auditory stimulus that the team is trying to measure the brain’s response to. Unexpected little bits of static are piped through the headphones while the babies sleep and the brain’s response is recorded by the scanner. This data enables the team to gauge how circuits respond to novelty— in this case, unexpected sounds—in the youngest children.
It is laying the groundwork for attaining the therapeutic goals the team shares. “We don’t know as much as we’d like about the basic functional architecture and organization of the neonatal brain,” Dr. Sylvester says. “In order to be able to describe how a circuit develops and changes during development, and how that’s related to psychiatric risk, we begin by looking at the brain in newborns. What do the networks look like at this initial stage? Where are they? And then, thinking of psychiatric disorders, can we determine what’s the developmental norm?”
Knowing the normal pattern could provide a basis for being able to determine very early in life which children are already on a path to being at risk for developing anxiety or other early-childhood psychiatric disorders. “The younger we can intervene,” reasons Dr. Sylvester, “the larger the impact we can have.”
Written By Peter Tarr, Ph.D.