In the current prospective study of neurodevelopmental predictors of depressive disorder onset in youth, age-related change in temporal, insula, and occipital cortical, and subcortical structure were associated with the onset of depressive disorder. Specifically, more positive age-related changes in thickness of temporal, occipital, and insula cortices, and amygdala volume, were associated with increased odds of disorder onset.
Notably, age-related change, but not current value (i.e., value at the time of depression onset), of cortical and subcortical grey matter was associated with the risk of depression onset. The lack of findings for the current value of cortical structure is inconsistent with some other studies of cross-sectional cortical structure in young people prior to depression onset12, 15, 17. However, some other studies have also found null effects (e.g., 10). Our findings suggest that during periods of marked brain development, such as adolescence, alterations to the trajectory of brain development are particularly important in the pathogenesis of depressive disorders.
Relatively increased age-related thickening of cortical regions predicting depression onset is consistent with some prior research11. In addition, several studies that have assessed brain structure in individuals early in the course of their disorder have reported increases in cortical grey matter30–32. As such, in contrast to consistent findings of structural decreases in individuals with established MDD, it may be that increases in cortical thickness are present prior to and early in the course of depressive disorder, reflecting a disturbance of normal brain development. Whether these structural changes reflect genetic mechanisms or occur as a result of early experience is unclear, although we note that our prior work has shown exposure to adverse environments is associated with similar patterns of relatively increased age-related change in cortical structure33.
Our findings may also be interpreted in relation to theories that propose protracted development of cortical (particularly prefrontal) regions, combined with accelerated development of subcortical regions during adolescence, to be associated with depression risk. Popular theories suggest that these changes may underlie reduced capacity for regulation of behavior and emotion, promoting risk for disorders such as depression34, 35. Our finding of increased age-related change in amygdala volume predicting depression onset may be partly consistent with these neurodevelopmental theories. This finding was also consistent with our prior investigation of early adolescent brain development changes predicting depression onset by late adolescence (although this prior finding was in females only). Increased age-related change in amygdala volume across adolescence may underlie alterations in emotion reactivity and stress regulation36, 37, predisposing adolescents and emerging adults to depression. Further research is needed to test this theory.
Findings of age-related change in temporal, occipital and insula regions associated with risk for depression onset, however, suggest that the aforementioned theories of neurodevelopmental risk for depression may be overly simplistic in their sole focus on prefrontal and subcortical regions3. Structural changes in the temporal, occipital and insula regions implicated here have been implicated in several prior studies of depression and depression risk7, 12, 17. All of these regions are implicated in social and emotional processing. The lingual and fusiform gyri are involved in the perceptual processing of facial emotion expressions38. The parahippocampal gyrus is involved in context appraisal39. The insula is suggested to be involved in visceral information processing, interoception and subjective emotional experience, including of social emotions such as shame and empathy40, 41. Alterations in the activity of these regions have been observed in several studies of depression42–45. As such, it is possible that altered developmental trajectories of these regions may underlie altered socio-emotional processing, which may create risk for depression onset46.
Cortical thickness, but not surface area changes were implicated in depression onset. The interpretation of this finding is unclear, although speculatively, it could indicate specific processes underlying depression risk. It has been suggested that the development of cortical thickness is dependent on local or intrinsic factors47, such as synaptic pruning48. As such, it may be that alterations in such processes are primarily implicated in the pathogenesis of depression. Further work, however, is needed to understand the mechanisms driving changes in thickness that influence vulnerability to depression.
Several limitations of this work should be considered when interpreting findings. First, gender was not found to moderate any associations; however, we may not have had adequate power to detect gender differences. Second, brain imaging was restricted to the adolescent period, and as such, brain development during emerging adulthood was interpolated. Future work is needed with parallel brain imaging and diagnostic assessments across the full developmental period. Third, it is possible that brain structural predictors of depression onset might change across development. While we did not address this possibility, it may be a valuable future direction of this work. Fourth, it is unclear whether the implicated brain changes are relevant to depressive disorder onset specifically, or may be associated with the development of psychopathology more generally. Further research is needed to address this question.
To conclude, in a fifteen-year longitudinal study of adolescent risk factors for mental disorder onset, we found that relative age-related increases in the thickness of temporal, insula and occipital brain regions, in addition to amygdala volume, were associated with risk for first onset of depressive disorder. Speculatively, these neurodevelopmental patterns may relate to alterations in social and emotional functioning that precede depression onset. Our findings suggest that increases in cortical thickness are present prior to the onset of depressive disorders, reflecting disturbances of normal brain development predisposing to depression. Decreases in structures commonly observed in extant studies of depression might occur subsequent to onset, because of disorder-related factors. Further research is needed to explore these hypotheses.