Sex-specific habenular dysconnectivity in patients with late-life depression

There are significant sex differences in the prevalence, symptom presentation, treatment response and brain abnormalities of patients with late-life depression (LLD). The functional connectivity of the habenula has been associated with depressive symptoms and cognitive impairments in patients with LLD. However, sex differences in habenular functional connectivity patterns among LLD patients remain unclear. One hundred and fourteen patients with LLD and 75 healthy controls (HCs) were included in the present study. Resting-state functional magnetic resonance imaging was used to analyse the static and dynamic functional connectivity (sFC and dFC) of the habenula. There were significant interactions between diagnosis (LLD vs. HCs) and sex for the dFC of the left habenula with the left insula, precentral gyrus, angular gyrus, and middle frontal gyrus and for the right habenula with the right middle temporal gyrus. Pairwise comparisons revealed a trend of HC males > HC females and LLD males < HC males for the connections between the left habenula and the left precentral gyrus, angular gyrus and middle frontal gyrus. Conversely, a trend of HC males < HC females and LLD males > HC males was found for the connections between the right habenula and right middle temporal pole. Furthermore, there was a significant interaction for the sFC of the right habenula with the right fusiform gyrus, with trends of HC males > HC females, LLD males < HC males, and LLD females > HC females. Regression analysis revealed that left habenular-left insular dFC was associated with long-delay memory in females and working memory in males; right habenular-right middle temporal pole dFC was associated with information processing speed in females. Sex moderated the relationships between cognitive function (global cognition, delay-recalled memory and working memory) and dFC between the left habenula and left insula. In conclusions, this study revealed sex-specific alterations in the functional connectivity patterns of the habenula in LLD patients, and these alterations were associated with various cognitive functions in a sex-specific manner. These findings provide a neurobiological basis for understanding sex differences in LLD patients.