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This is the first study to date to examine volumetric alterations in the anterior insula (AI) as a potential biomarker for the course of childhood major depressive disorder (MDD).To examine whether children with a history of preschool-onset (PO) MDD show reduced AI volume, whether a specific symptom of PO MDD (pathological guilt) is related to AI volume reduction (given the known relationship between AI and guilt processing), and whether AI volumes predict subsequent likelihood of having an episode of MDD.In a prospective longitudinal study, 306 children (age range, 3.00-5.11 years) and caregivers completed DSM diagnostic assessments at 6 annual time points during 10 years as part of the Preschool Depression Study. Magnetic resonance imaging was completed on a subset of 145 school-age children (age range, 6.11-12.11 years).Whole-brain–adjusted AI volume measured using magnetic resonance imaging at school age and children's diagnosis of MDD any time after their imaging.Compared with children without a history of PO MDD, school-age children previously diagnosed as having PO MDD had smaller left and right AI volumes (Wilks Λ = 0.94, F2,124 = 3.37, P = .04, Cohen d = 0.23). However, the effect of PO MDD on reduced AI volumes was better explained by children's experience of pathological guilt during preschool (Λ = 0.91, F2,120 = 6.17, P = .003, d = .30). When covarying for children's lifetime history of MDD episodes, their experience of pathological guilt during preschool, as well as their sex and age at the time of imaging, schoolchildren's right-side AI volume was a significant predictor of being diagnosed as having an MDD episode after imaging (odds ratio, 0.96; 95% CI, 0.01-0.75; P = .03).These results provide evidence that structural abnormalities in AI volume are related to the neurobiology of depressive disorders starting in early childhood. The present findings are consistent with mounting research in adult MDD suggesting that insula function and structure may be a target biomarker for major depression.