Three brain biotypes found in Stanford Medicine-led study of kids with ADHD, anxiety

Three distinct brain biotypes exist in children who have attention-deficit/hyperactivity disorder, anxiety disorder or both, a new Stanford Medicine-led study has shown.

The discovery could help clarify a confusing picture for two of the most common mental health conditions of childhood, which often overlap. Each biotype is characterized by malfunctions in a specific set of brain circuits, according to the study, published Oct. 16 in Nature Mental Health.

The biotypes, which were identified through an analysis of thousands of fMRI scans of children’s brains, correspond to three sets of symptoms. The biotypes could aid early diagnoses, provide new therapeutic targets and make it easier to match patients to effective treatments, the research team said.

“The high overlap between ADHD and anxiety actually hinders our understanding of the neurobiology underlying traditional, symptom-based diagnoses,” said co-senior study author Yu Zhang, PhD, assistant professor of psychiatry and behavioral sciences. ADHD and anxiety are diagnosed using symptom checklists, but children with one condition often have several symptoms of the other, he noted.

The study’s lead author is Yong Jiao, PhD, a postdoctoral scholar at the University of Iowa. Zhang shares senior authorship of the study with Jing Jiang, PhD, assistant professor of pediatric neurology at the University of Iowa.

“We wanted to know whether the biological differences among children with ADHD and anxiety follow the diagnostic labels used in the clinic,” Zhang said.

The answer: Not exactly. Kids with ADHD, anxiety or a mix of the two conditions can all have any of the three biotypes, although certain types are more common in each diagnosis. The findings bring more granularity to traditional diagnostic categories and could be a helpful addition to future research and clinical care, the researchers said.

Using AI to parse thousands of brain scans

The researchers analyzed data from the Adolescent Brain Cognitive Development study, a long-term look at brain development that includes more than 11,000 U.S. children who were enrolled in the project when they were 9 or 10 years old.

From the ABCD data, the researchers studied 3,508 kids who, when they joined the study, had a diagnosis of ADHD, anxiety or a combination of the two conditions; 693 kids who were undiagnosed when they enrolled in the study but were later diagnosed with one or both conditions; and 1,947 controls, children who never received either diagnosis. All children had fMRI brain scans, and all completed several cognitive and behavioral tests. The researchers used brain scans from an additional 224 children from a second study, the Healthy Brain Network, to validate the results. All the children in the validation group had a diagnosis of ADHD or anxiety disorder.

The researchers built an artificial intelligence-powered model to analyze functional connectivity — how different brain regions work together — on the children’s brain scans. The model incorporated information about children’s diagnoses and behavioral assessments to figure out which functional connectivity patterns were more prominent in the brains of kids with ADHD and/or anxiety than in children who never received these diagnoses.

From the combination of the brain scans and the children’s behavioral data, the model identified two brain-behavior dimensions contributing to ADHD and anxiety: cognitive-behavioral dysfunction and emotion-attention dysfunction. These two facets of brain dysfunction are each driven by different brain networks. They combine in different ways to form the three brain biotypes uncovered by the model, which are the externalizing-disinhibited biotype, the internalizing-distressed biotype and the mixed biotype.

New way to characterize the brain

Although the biotypes did not overlap (each child was in only one biotype), all biotypes occurred in all the traditional, symptom-based diagnostic categories.

Kids with the externalizing-disinhibited biotype showed more hostility, defiance and impulsivity, as well as more aggression and rule-breaking, and were more likely to have an ADHD diagnosis. Those with the internalizing-distressed biotype had more guilt, tension and perfectionism, as well as more anxious-depressed symptoms, and more often had anxiety diagnoses. Children with the mixed biotype had more attention problems, irritability and self-injury, and were more likely to have ADHD diagnoses — although, again, all combinations of biotypes and diagnoses were seen among kids in the study.

Interestingly, the biotypes could be detected in the baseline brain scans of children who had no diagnoses when they enrolled in the study but who were later diagnosed with ADHD, anxiety or a mix of both.

“We think this means we may be able to use the biotypes as an early indicator of these conditions,” Zhang said, adding that the ability to spot the biotypes early was the aspect of the study’s findings that surprised him most. “It could help us provide more timely intervention for these conditions and slow down or, we hope, even reverse their progression.”

Biomarkers to inform treatment

Symptom-based ADHD and anxiety diagnoses probably won’t be replaced by brain biotypes, Zhang said.

Rather, he thinks the two techniques could complement each other, possibly making it easier to help patients find the right treatments. At present, matching kids to the treatments that will work best can take a lot of trial and error.

“When doctors prescribe a new medication, it can take quite a long time — a couple of weeks or months — to see a response,” Zhang said. “If the first medication doesn’t work, they switch to a different one” — a slow, costly and frustrating process.

Zhang envisions using information from the new study in future clinical trials to see which treatments improve which specific patterns of brain activity, and to match treatments to each of the three brain biotypes.

“We want to find biomarkers that can really inform the right treatment at the right time,” he said.

Researchers on the study are affiliated with the Wu Tsai Neurosciences Institute at Stanford University and the Stanford Institute for Human-Centered AI.

Researchers also contributed to the study from the University of Iowa, the University of Texas at Austin and the University of Pennsylvania Perelman School of Medicine.

The research was supported by grants from the National Institutes of Health (grant numbers R01MH129694, R01MH136197, R01MH145082, R01MH140425, U24AA021697, R01DA057567, R37MH101495 and R01MH132784), the Eagles Autism Foundation, the Stanford Knight Initiative for Brain Resilience, the Rosenkranz Foundation, the Brain and Behavior Research Foundation, and the Effie and Wofford Cain Foundation.

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