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ABSTRACT BACKGROUND: According to cognitive theories of depression, more negative and less positive self-schemas are thought to play a causal role in the disorder. Existing evidence speaks to the neural substrates of self-referential processes in both healthy and depressed individuals, but little is known about how the brain relates to selfreferential processing in the context of depression risk in children. We therefore studied the neural substrates of self-referential processing in never-depressed preadolescent children at high and low risk for depression based on maternal depression history. METHODS: A total of 87 never-depressed 10–12-year-old children (29 with maternal depression) completed a selfreferential encoding task during a functional magnetic resonance imaging session, in which they were presented a series of positive and negative trait adjectives and endorsed whether each word was self-descriptive. Small volume correction analyses were conducted within 7 regions of interest that are important for self-referential and emotion-related processes. RESULTS: Analyses of small volume correction indicated that high-risk children showed greater activation in the ventrolateral prefrontal cortex and ventromedial prefrontal cortex during the positive-word self-referential encoding task condition than low-risk children. Ventrolateral prefrontal cortex activation mediated the association between maternal depression and child depressive symptoms only when children had lower positive self-schemas, indicating that more positive self-schemas may protect at-risk children from developing depressive symptoms. CONCLUSIONS: Cortical midline and prefrontal regions are important to self-, emotion-, and regulation-related processes. Heightened activation within these regions in never-depressed high-risk children indicates that these neurobiological substrates

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