Altered Brain Activity in Preschoolers a Depression Biomarker

Kathleen Louden

July 08, 2013

A new imaging study believed to be the first to compare preschool-aged children who have major depressive disorder (MDD) with healthy control individuals shows "the earliest known findings of disrupted brain function in depression."

When processing facial expressions of emotion during functional magnetic resonance imaging (fMRI), the depressed group of 4- to 6-year-olds had significantly altered reactivity of the amygdala, the brain region implicated in the pathogenesis of depression.

This increased amygdala activity, seen previously in older children, teenagers, and adults with depression, reportedly correlated with disruptions in parent-reported emotion regulation and negative affect.

The findings suggest that disrupted amygdala function is a depression-related biomarker that spans development, according to lead author Michael Gaffrey, PhD, a clinical psychologist and assistant professor of psychiatry at Washington University in St. Louis, Missouri.

"We hope this study gives a better understanding of depression in young children and validates that depression in preschoolers is a relevant clinical disorder," Dr. Gaffrey told Medscape Medical News.

The study was published in the July issue of the Journal of the American Academy of Child and Adolescent Psychiatry.

"Breakthrough" Information

Asked by Medscape Medical News to comment on the study, Diane Misch, MD, assistant professor of clinical psychiatry, University of Illinois at Chicago College of Medicine, said the study is a "breakthrough...that hopefully will allow us to help patients, parents, and clinicians. Watchful waiting is no longer going to be the gold standard for young children with depression."

Dr. Misch was not involved in the study but said she knows study coauthor Joan Luby, MD, and considers her a mentor.

Earlier work by Dr. Luby and other pioneers in the field of preschool-onset MDD "has dispelled the 'they'll grow out of it' myth," said Dr. Misch, a child psychiatrist who has encountered preschool-onset depression in a small number of her own patients.

In 2009, Dr. Luby and her team found that preschool depression is a strong predictor of later depression ( Arch Gen Psychiatry 2009;66:897-905).

"Often, people with depression have it their whole life," Dr. Misch said. "Early identification and treatment of depression could change the trajectory of a child's life."

The estimated prevalence of preschool-onset MDD is 2.1%, the same as for school-aged children, said Dr. Gaffrey.

"It gives people pause that children this young can lack the happiness we would expect at this age," he said. "But there is a good amount of evidence that it does indeed occur, and they have the same symptoms as in older children with depression."

Increased Amygdala Activity

For the current study, Dr. Gaffrey and colleagues recruited 54 children, aged 4 to 6 years, from the St. Louis metropolitan area. Of these children, 31 were healthy and not depressed, and 23 children had MDD, as identified with the Preschool Age Psychiatric Assessment. None of the children had received antidepressant medication.

The children's parents completed the Emotion Regulation Checklist, which rated their perception of their child's ability to self-regulate emotions and the child's expression of negative affect.

The 2 groups did not differ in demographic and clinical characteristics evaluated, according to the authors, except that the depressed group had worse scores on the Emotion Regulation Checklist: higher scores on the Negativity subscale and lower scores on the Emotion Regulation subscale (P < .001 for both).

After a mock neuroimaging session to ensure that the children moved less than 1 mm on average, the participants underwent fMRI while viewing images of faces showing happy, sad, fearful, and neutral expressions.

Previously, Dr. Gaffrey and colleagues showed in a study involving 11 preschoolers with depression in which this test was employed that greater severity of depression was associated with greater activity in the right amygdala, especially with regard to the viewing of sad images, but that study lacked a comparison group ( J Affect Disord 2011;129:464-370).

In the new study, regardless of the type of facial expression viewed, depressed children reportedly experienced a significantly higher elevation in activity in the right amygdala compared with the comparison group (P < .05).

After quantifying the imaging data, the investigators found a correlation with the parent-reported scores from the Emotion Regulation Checklist in the entire sample. Specifically, the higher the amygdala activity, the lower the scores were on the Emotion Regulation subscale and the higher the scores were on the Negativity subscale, Dr. Gaffrey said.

Table. Correlation of Emotion Regulation Checklist Scores and Right Amygdala Activity During Face Processing

Emotion Regulation Checklist Subscale r 95% Confidence Interval P-Value (1-tailed)
Emotion regulation (n = 53) -0.52 -0.29 to -0.69 .001
Negativity (n = 52) 0.42 0.17 - 0.63 .001


When the researchers analyzed the data by patient subgroup (depressed vs healthy), the relationship was no longer statistically significant. Dr. Gaffrey said that small subgroup sizes might explain the lack of significance or that possibly in depressed children, the increased amygdala activity is an exaggeration of a normal developmental response in the brain.

Marker of Lifelong Depression?

"We believe this study demonstrates that there are differences in the brains of these very young children and that they may mark the beginnings of a lifelong problem [with depression]," Dr. Gaffrey said in a statement.

It is unclear whether the changes in the brain are a precursor or a consequence of very early childhood depression, he noted.

Although it is too early to say that disrupted brain activity can help in the accurate diagnosis of depression in young children, Dr. Gaffrey said in an interview, "If we can identify the regions of the brain that are affected by depression, it may give us an indication of what we need to focus on therapeutically or preventively."

He stressed that the researchers are not suggesting that antidepressant medications be prescribed for preschoolers. Interventions being tested in preschool-aged children at Washington University include therapy that helps parents practice different ways of parenting to help their child gain coping skills, Dr. Gaffrey and Dr. Misch said.

Dr. Misch said that a larger study is needed to confirm the new study findings, but that their findings give more insight into the dysregulation of brain activity that occurs in depression.

"Increasing evidence shows the same changes happen in the brain of depressed people whether the person is 50, 15, or 5 years old," she added.

This study was funded by the National Institute of Mental Health, Bethesda, Maryland; the Klingenstein Third Generation Foundation, New York City; and the CHADS (Communities Healing Adolescent Depression and Suicide) Coalition, St. Louis, Missouri. Dr. Gaffrey and Dr. Misch have reported no relevant financial relationships. Dr. Misch has disclosed that study coauthor Dr. Luby is a mentor.

J Am Acad Child Adolesc Psychiatry. 2013;52:737-745. Abstract


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