Sex differences in brain structure among adolescents with bipolar disorder

Objectives: Bipolar disorder (BD) is twice as prevalent amongst female as amongst male adolescents. Thus far, little is known regarding the neurostructural substrates underlying this disparity. We therefore examined sex differences in neurostructural magnetic resonane imaging (MRI) phenotypes amongst adolescents with BD.

Methods: T1-weighted structural MRI was acquired from 44 BD (25 female [F] and 19 male [M]) and 58 (28 F and 30 M) healthy control (HC) adolescents (13-21 years old). Whole-brain and region-of-interest (ROI) analyses examined structural volume and cortical thickness using FreeSurfer. ROIs included the ventrolateral prefrontal cortex (vlPFC), anterior cingulate cortex (ACC), amygdala and hippocampus. General linear models evaluated sex-by-diagnosis interactions, controlling for age and intracranial volume.

Results: Whole-brain analysis revealed sex-by-diagnosis interactions in the left supramarginal gyrus (SMG) (P = .02, η² = 0.02) and right inferior parietal lobule (IPL) volumes (P = .04, η² = 0.01). Sex differences in HCs were found in the SMG (M > F) and IPL (F > M). In BD, sex differences were reversed and of smaller magnitude in the SMG (M < F) and of greater magnitude in the IPL (F > M), driven by trends towards smaller SMG and IPL in BD vs HC male participants (P = .05 and .14). Whole-brain analyses for cortical thickness, and ROI analyses for volume and cortical thickness, were not significant.

Conclusions: Normative sex differences may be disrupted in adolescent BD in the SMG and IPL, heteromodal association network hubs responsible for higher order integration of cognitive and emotional processing. Unexpectedly, these findings may inform our understanding of aberrant brain structure in adolescent BD male patients, rather than female patients. Future work should focus on replication, as well as the impact of puberty status and sex hormones on measures of brain structure and function.