INTRODUCTION: Gender dysphoria (GD) causes distress from gender-sex incongruence with elevated suicide risk, yet its neuropathology remains unclear. The thalamic-cortical functional connectivity (FC) in transgender women (TW) is unexplored. We investigated thalamo-cortical FC and its mediating role in TW's symptom-cognition relationships. METHODS: We retrospectively analysed resting-state fMRI from 44 TW, 40 cisgender men (CM), and 42 cisgender women (CW), between October 2021 and January 2024. Clinical symptoms (GIDYQ-AA) and cognition (MCCB) were assessed. Seed-based thalamic subregion FC and mediation analyses were performed. RESULTS: Relative to CW, TW and CM exhibited increased FC in multiple thalamo-prefrontal circuits. Compared to CM, TW showed decreased left mPFtha-left DLPFC FC (p = 0.026), and right rTtha-left DLPFC FC (p = 0.025). Compared to CM, right PPtha-right MOG FC (p = 0.023; p < 0.001), and right cTtha-right SOG FC (p = 0.008; p < 0.001) were increased in TW and CW. In TW, left rTtha-bilateral MPFC FC correlated with GIDYQ-AA scores, attention/vigilance, and composite. This FC fully mediated relationships between GD symptoms and both attention/vigilance (bootstrapped 95% CI = 1.861-11.688) and composite (bootstrapped 95% CI = 1.025-12.283). CONCLUSIONS: TW exhibit thalamo-cortical FC abnormalities and cognitive dysfunction. Critically, thalamus-MPFC dysconnectivity mediates GD symptom-related cognitive dysfunction, revealing a novel neural pathway. Validation in larger, diverse samples is needed.
Chen et al. (Wed,) studied this question.