Three past recipients of NARSAD grant awards and their colleagues at Washington University, St. Louis have reported the first-ever structural brain biomarker to predict a small child’s risk of having recurrent major depressive disorder (MDD).

The researchers used MRI scans to measure a brain area called the anterior insula (AI). In children at high risk for recurrent MDD, the volume of the AI was smaller than normal. The effect was especially notable in children who, before reaching school age, had experienced feelings of what psychiatrists call “pathological”––or abnormal¬¬––guilt.

The results of the study appeared online November 12th in JAMA Psychiatry.

The team, including Joan Luby, M.D., Deanna Barch, Ph.D., and Kelly Botteron, M.D., all recipients of multiple NARSAD grants,* studied certain children over time. Initially, more than 300 youngsters aged three to five were recruited. After doctors examined that group, 145 were found to have already suffered a depressive episode or were at risk of becoming depressed. These children were followed for 10 years.

The researchers knew that “one of the most consistent and robust correlates of preschool-onset depression has been the tendency for pathological guilt. Toddlers under three years of age experiencing such feelings of guilt have been estimated to be 10 times more likely than their same-age peers to have MDD at age five. Examples of pathological guilt include a child fixating on feeling badly about a minor misbehavior; feeling like “a bad kid” without objective reason to have this feeling; blaming himself or herself for things that are not their fault.

The AI is a portion of the brain involved in processing feelings of self-conscious emotions, especially guilt. Past studies have shown it to be structurally and functionally abnormal in adults with MDD, obsessive-compulsive disorder, and eating and anxiety disorders. Decreased AI volume has been seen in acutely depressed adults, including those who have gotten better. The study by Drs. Luby, Barch, Botteron, and colleagues now expands this work to the very young.

Brain scans and diagnostic interviews, made during a 10-year period in the original sample of affected children, confirmed that shrinkage of the AI is associated with MDD by age five. The study also shows that a child, who at age three has experienced pathological guilt, has a high risk of having a smaller-than-normal AI by school age and is likely to suffer recurrent MDD.  

In the current study, brain scans were not begun until the children reached school age. For this reason a question remains about causality. Does the AI shrink or fail to grow to normal size because of the effects brought on by feelings of pathological guilt very early in life? Or might a child with a smaller-than-normal AI be disposed to experience abnormal guilt feelings and later become prone to chronic severe depression? Future studies will explore these questions.     

* NARSAD Grants awarded to members of the research team



Deanna M. Barch, Ph.D., Washington University School of Medicine, St. Louis: Young Investigator, 1995, 2000; Independent Investigator, 2006; Distinguished Investigator, 2013

Kelly N. Botteron, M.D., Washington University School of Medicine, St. Louis: Young Investigator, 1997; Independent Investigator, 2005

Joan L. Luby, M.D., Washington University School of Medicine, St. Louis: Young Investigator, 1999; Independent Investigator, 2004, 2008

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