Sex-specific amygdala connectivity alterations in medication-naïve major depressive disorder: A static and dynamic analysis.

Background: Major depressive disorder (MDD) represents a leading contributor to the global disease burden, characterized by pronounced sex differences in prevalence and symptom expression. The amygdala, as a critical node within the brain's affective circuitry, has been implicated in MDD pathophysiology. However, the neurobiological mechanisms underlying sex-specific vulnerability and clinical heterogeneity in MDD remain incompletely understood. This study aimed to investigate sex-stratified alterations in amygdala functional connectivity (FC) using both static and dynamic connectivity frameworks in medication-naïve MDD patients.

Methods: We employed seed-based FC analyses anchored in the amygdala to examine static FC (sFC) and dynamic FC (dFC) in 61 age- and sex-matched MDD patients and 61 healthy controls (HCs).

Results: Significant sex-by-diagnosis interactions were identified in amygdala-striatal circuitry connectivity. Female MDD patients exhibited aberrant dFC patterns involving the visual network and sensorimotor network, characterized by heightened dynamic coupling compared to male patients. Conversely, reduced dFC was observed between the right amygdala and right superior cerebellum in female MDD patients relative to male counterparts. Notably, static and dynamic FC demonstrated divergent directional effects within the same sex, suggesting dissociable neurobiological mechanisms across temporal scales.

Limitation: The cross-sectional design and relatively small sample size may limit the generalizability of findings.

Conclusions: These findings elucidate sex-differentiated amygdala connectivity phenotypes in MDD, highlighting sexually dimorphic neurocircuitry mechanisms that may underlie differential disease manifestation. These data advance our understanding of MDD's neurobiological substrates and may inform the development of sex-specific diagnostic criteria and personalized treatment strategies.