The Science of Childhood Anxiety

Anxiety disorders are the most common mental health challenges in youth. Left untreated, they can disrupt the lives of both children and their families.

The good news is that with intervention, most children will overcome these conditions. Across Yale School of Medicine, scientists are working to understand anxiety at every level, from common anxious behaviors to molecular biomarkers in the brain. They are using their findings to develop and disseminate new evidence-based treatments for childhood anxiety.

Today, the go-to treatment for childhood anxiety disorders is cognitive behavioral therapy (CBT). This is a form of psychotherapy that teaches children skills for confronting anxious thoughts and helps them practice managing situations that cause anxiety. While it is the gold-standard treatment backed by considerable scientific evidence, up to 50% of children will not see sufficient benefit from CBT alone.

Wendy Silverman, PhD, Alfred A. Messer Professor in the Child Study Center, co-directs the Anxiety and Mood Disorders Program alongside Eli Lebowitz, PhD, associate professor in the Child Study Center. One of their main interests is learning how to improve outcomes beyond CBT.

“We’re developing cutting-edge, research-based knowledge that can reduce the suffering that anxiety causes children and their families,” says Silverman.

YSM experts are investigating how to improve CBT outcomes for children by involving the parents. Silverman’s research has uncovered two main components of parent intervention that improve childhood anxiety: not enabling children to completely avoid the things that make them anxious and taking steps to enhance their autonomy.

Parents may unintentionally reinforce their child’s anxiety by allowing them to avoid what makes them anxious. They also may unintentionally limit the children’s sense of autonomy by being overly intrusive. “One of the things that we take pride in is that we’ve focused on trying to understand what parents need to do, and to test our ideas and see if changing the parents’ behaviors is enhancing the effects of CBT,” Silverman says. “Our findings thus far suggest that they do."

As much as CBT can be helpful, it can also be challenging to get one’s child to do the necessary steps for CBT to work. This is one important reason why Lebowitz created a novel intervention program for parents named Supportive Parenting for Anxious Childhood Emotions (SPACE). Existing intervention programs often teach parents to act as therapists for their child, such as training them on how to practice breathing exercises.

“It makes sense, but this doesn’t work very well in practice,” says Lebowitz. “And part of the reason, I think, is that it’s not easy to get your kid to do things, especially if they’re not excited about doing it.”

SPACE is unique because it focuses entirely on parent involvement and changing parental behavior—children are not involved in the sessions. For example, parents learn how to use supportive messages that convey confidence that their child can tolerate and manage distress. “It might sound like a parent saying to a child, ‘I get that this is really hard for you, but I know that you can handle it,’” Lebowitz says.

The program also works with parents to identify the ways in which they are accommodating anxious behaviors. “We’ll pick one thing that parents are doing that is an accommodation and help them make a detailed plan for how they’re going to change that,” Lebowitz explains.

Much of the existing research on SPACE has focused on parents of children under age 14. Ongoing studies are now exploring its use with parents of older teens.

“Both anxiety and accommodation can interfere with normative developmental shifts during the teen years, including increased autonomy and individuation from parents,” says Rebecca Etkin, PhD, associate research scientist in the Child Study Center. “In this sense, SPACE may be particularly well-suited for anxious teens and their parents. We want to see whether it is effective during this distinct developmental window.”

Unfortunately, many families in need of CBT face barriers, including limited availability of services and geographic constraints. One way to improve access is digital interventions. Silverman and her team are developing an evidence-based digitized intervention program for parents that they can access directly from their computer or smart phone.

“The work we’re doing will be one of the very few parent interventions that is digitized and importantly tested for effectiveness,” she says.

Silverman and Lebowitz recently received a generous gift to develop and test other interventions that help parents reduce other child anxiety-related behavioral and emotional difficulties, such as restrictive eating and unexplained somatic symptoms. One of these projects in particular focuses on understanding the risks of social media and its potential benefits, including offering a sense of connection.

“A lot of research has focused on the idea that social media is harmful and the less of it the better,” says Lebowitz. “But we actually see is that this is not quite right—there are negatives, but there are also positives. So, we’re trying to get a little bit more nuanced of a picture.”

The team is working with teens with social anxiety and their parents over an extended period to better understand their social media habits and how their anxiety levels affect engagement with different platforms. The teens will answer questions sent to an app on their phones about mood and social media usage in an effort to capture emotional responses as they unfold.

“We hope to develop interventions that can help make the best of social media while protecting against the more problematic effects,” Lebowitz says.

Researchers are also testing therapies to address anxiety at the neurological and molecular levels. In collaboration with Dylan Gee, PhD, professor of psychology in Yale's Faculty of Arts and Sciences, and Hilary Blumberg, MD, John and Hope Furth Professor of Psychiatric Neuroscience at Yale School of Medicine, Lebowitz and Silverman are using brain imaging to identify changes in a child’s brain before and after parents enroll in SPACE.

In one study, children viewed anxiety-inducing images while undergoing magnetic resonance imaging (MRI); the researchers conducted scans with and without the children’s parents nearby. Before SPACE, children’s brains were better able to activate the regulatory circuitry needed to turn off an anxious response when their parents were nearby. But after SPACE, children could activate this circuitry even without the parent around.

“As parents work on gradually reducing some of their accommodations, you can see a child get better at regulating their own fear system in the brain,” Lebowitz says. “It’s remarkable.”

Research into the molecular underpinnings of anxiety can also inform new childhood anxiety treatments. In a recent study, Lebowitz, Silverman, and Flora Vaccarino, MD, Harris Professor in the Child Study Center, discovered that a protein known as fibroblast growth factor 2 (FGF2) could be protective from the toxic effects of stress. FGF2 levels in children and their parents were linked to the children’s risk of developing anxiety and depression, the study showed.

The findings could help explain why some children who are exposed to early life trauma such as poverty or abuse are more prone to developing mental health disorders. And FGF2 could be a target for treatment.

“This is very novel because it starts to give a clue to what is the molecular chain that connects those lived experiences to the actual psychological outcomes,” Lebowitz says.

Michael Crowley, PhD, associate professor in the Child Study Center, collaborates with Silverman and Lebowitz to study the role that attention plays in development and maintenance of childhood anxiety. There is a large body of research that shows that anxious children, like anxious adults, are prone to focus on threatening stimuli such as angry faces compared with neutral faces. This has led to innovative interventions that involve attention retraining.

The idea is that if experts train children to look away from threatening stimuli, it may reduce their anxiety—especially children with social anxiety who are most prone to attend to threats. The researchers have just completed a clinical trial for attention retraining with 10- to 14-year-olds with social anxiety disorders and are currently analyzing the findings.

Besides this innovative attention retraining research, as Crowly notes, “I like to design tasks that are engaging to kids,” Crowley says. “My goal is to assess something without the kids knowing what we are assessing.”

With this goal in mind, Crowley has created a virtual game, named Boom, to study threat processing in children with anxiety disorders. The game is similar to that of hot potato—the child and three digital players take turns virtually passing a ball to each other’s gloves. At some point, the ball turns into a bomb, and as the bomb lands in each player’s glove, the outline of the glove turns yellow. The goal is to avoid having the bomb go off in your glove.

What isn’t obvious is that the game is designed to measure different types of threatening stimuli, both ambiguous and direct. In the game, the direct threat occurs as the bomb is traveling towards your glove. The ambiguous threat is the yellow outlined glove as it is unknown where the bomb will travel next.

While children play the game, Crowley’s team measures their brain activity using electroencephalography (EEG). The researchers have discovered that in kids with anxiety, the brain reacts more strongly to ambiguous threats than it does in their peers, but less strongly to direct threats. They believe that the initial abnormally large brain response to not knowing where the bomb is going impairs the brain's ability to properly respond when the threat is actually traveling the child’s way.

“The brains of children with anxiety are unable to differentiate between threats you need to do something about and those that are not your problem.”

Based on these insights, Crowley hopes to study whether interventions like attention training could restore appropriate threat processing.

Crowley’s team is also working on a test called the Balloon Risk Avoidance Task, which evaluates risk-taking and avoidance behaviors. It features a digital balloon that is full of air and about to burst. Kids have six seconds to let air out of the balloon. The more air they let out, the less risk they face that the balloon will pop. But at the same time, the balloon becomes less valuable as it deflates. “The more air you keep in the balloon, the more points you get,” Crowley explains.

So far, the researchers have found that when the balloons pop unexpectedly, teens with social anxiety show distinct brain responses. Studying these responses can help psychologists understand the underlying pathways driving the various manifestations of anxiety.

When Thomas Fernandez, MD, associate professor in the Child Study Center and of psychiatry, was still in training, there was a lot of excitement about understanding the genetics associated with autism spectrum disorder. Since then, scientists have identified around 250 genes associated with autism.

The genetic contribution to anxiety disorders, on the other hand, has historically received less attention. Anxiety is less heritable than autism, but the genetic contribution for anxiety disorders that emerge in childhood may be higher than for anxiety disorders overall. While scientists estimate the heritability of anxiety disorders in general to be around 30% to 50%, some studies suggest higher heritability for certain childhood-onset anxiety presentations.

“I saw firsthand how researchers in the field went about finding vulnerability genes for autism,” Fernandez says. “So, we’re using a very similar playbook for childhood anxiety.”

Now, Fernandez and Emily Olfson, MD, PhD, assistant professor in the Child Study Center, are studying children and their parents to identify genetic changes that are present in the child but not the parents, known as “de novo mutations.”

“All of us have some de novo mutations—maybe about 50 to 100 sprinkled throughout the genome,” Olfson says. “But when they occur within the coding regions of genes, they can be really disruptive.”

Previous research shows that people with autism have higher rates of damaging de novo mutations than the general population. In 2022, Olfson, Lebowitz, Silverman, and Fernandez published a study on 68 children and their families that found that children with anxiety had similarly high levels of these mutations.

Studying de novo mutations can help point the researchers to where they should be looking for genes associated with anxiety. “The end game is using the genes to steer us toward the right part of biology that we can then target to come up with better treatments,” Fernandez says.

Building on those findings, the team is now studying more families to better understand how these de novo mutations, along with other genetic and environmental factors, shape pediatric anxiety disorders. They recently received a National Institutes of Health grant to enroll 750 new families over the next five years. Olfson is the principal investigator, with co-investigators Lebowitz, Fernandez, Silverman, and Shuangge Steven Ma, PhD, department chair and professor of biostatistics at Yale School of Public Health.

Joel Gelernter, MD, Foundations Fund Professor of Psychiatry, is interested in how different anxiety disorders differ genomically. “We are studying social phobia, panic disorder, and generalized anxiety disorder, working to understand why people differ in their risk to these specific anxiety disorders and evaluating various risk factors,” he says.

Gelernter was recently involved in one of the largest studies to date of the genomics underlying anxiety disorder. The study included around 122,000 people with anxiety disorders and around 730,000 without. It found that some genetic differences associated with anxiety were linked to signaling that helps reduce overactivity in the nervous system. Many anxiety medications available today work by targeting this process.

“It’s nice when the biology that you get out of a large genome-wide study ratifies things that we already know because that can help increase confidence in further findings from the study,” Gelernter says.

John Krystal, MD, Robert L. McNeil, Jr. Professor of Translational Research and chair of the Department of Psychiatry, is interested in the neurobiology of psychiatric disorders, including post-traumatic stress disorder (PTSD), of which anxiety is a major symptom.

In the late 1980s, Krystal’s team discovered that the drug yohimbine activated symptoms in patients with PTSD. “This was the first time we could link a specific biological mechanism to the symptoms of PTSD,” Krystal says. At the time, he adds, this finding was highly controversial. “A lot of people felt that PTSD was a purely psychological syndrome that didn’t have an underlying biology.”

Since then, Krystal has dived deep into understanding the neurobiology of PTSD to learn how to better treat it. His team is evaluating the use of ketamine and psychedelics. These would be among the first treatments to be developed specifically for PTSD. They may also be applicable for other disorders including anxiety disorders, Krystal adds.

An important gap in PTSD treatment is the absence of biological tests that inform how to best help patients manage their PTSD symptoms. A doctor doesn’t diagnose cancer based on how they feel. Rather, they use tests of the biology of the cancer to determine the best course of treatment.

“And we can’t do that in any psychiatric disorder other than Alzheimer’s disease,” Krystal says. “But now we are building a foundation for this approach to the treatment of anxiety disorders for the first time.”