Pubertal maturation and sex effects on the default-mode network connectivity implicated in mood dysregulation

Abstract

This study examines the effects of puberty and sex on the intrinsic functional connectivity (iFC) of brain networks, with a focus on the default-mode network (DMN). Consistently implicated in depressive disorders, the DMN's function may interact with puberty and sex in the development of these disorders, whose onsets peak in adolescence, and which show strong sex disproportionality (females > males). The main question concerns how the DMN evolves with puberty as a function of sex. These effects are expected to involve within- and between-network iFC, particularly, the salience and the central-executive networks, consistent with the Triple-Network Model. Resting-state scans of an adolescent community sample (n = 304, male/female: 157/147; mean/std age: 14.6/0.41 years), from the IMAGEN database, were analyzed using the AFNI software suite and a data reduction strategy for the effects of puberty and sex. Three midline regions (medial prefrontal, pregenual anterior cingulate, and posterior cingulate), within the DMN and consistently implicated in mood disorders, were selected as seeds. Within- and between-network clusters of the DMN iFC changed with pubertal maturation differently in boys and girls (puberty-X-sex). Specifically, pubertal maturation predicted weaker iFC in girls and stronger iFC in boys. Finally, iFC was stronger in boys than girls independently of puberty. Brain-behavior associations indicated that lower connectivity of the anterior cingulate seed predicted higher internalizing symptoms at 2-year follow-up. In conclusion, weaker iFC of the anterior DMN may signal disconnections among circuits supporting mood regulation, conferring risk for internalizing disorders.

Fig. 1. Scatterplot illustrating a representative relationship between puberty and the iFC of the central-executive network (central-executive network), as a function of sex

Specifically, pubertal development (x axis) is positively associated with the mPFC iFC with dmPFC (y axis) in boys, but negatively associated with the iFC between these regions in girls

Fig. 2. Pubertal development is associated with the iFC of the central-executive network (central-executive network), as a function of sex

Upper panel: interactions between puberty and gender characterizing the iFC between the mPFC seed ROI (1a), clusters within the dmPFC (1b), and dlPFC (1c). Not depicted, is the right middle temporal cortex. Bottom panel: interactions between puberty and sex characterizing the iFC between the pCC seed ROI (2a), the dmPFC (2b), and the bilateral precentral gyrus (2c). Not depicted are the right middle temporal and left inferior parietal cortex

Fig. 3. Sex is associated with the iFC of the DMN (default-mode network), the central-executive network (central-executive network), and the salience network (salience network)

Upper panel: boys exhibited higher iFC than girls between the lpgACC seed ROI (1a) and clusters within the dmPFC (1b), dlPFC (1c), cuneus (1d), and thalamus (1e). Bottom panel: boys exhibited higher iFC than girls between the lpCC seed ROI (2a), the bilateral insula (2b), regions of the anterior (2c), and middle temporal cortex (2d)