Sex-specific associations of episode type in bipolar I disorder with neuro-metabolic lateralization of the cortico-striatal-cerebellar (CSC) circuit.

OBJECTIVE: This study aims to examine whether neuro-metabolic lateralization of the cortico-striatal-cerebellar (CSC) circuit is associated with sex-specific mechanisms underlying episode types in bipolar I disorder (BD-I). METHODS: A total of 109 patients in the acute phase of BD-I were included in the analysis. For comparisons of general clinical characteristics, CSC circuit structural volumes, metabolic features, and laterality indices (LI), analyses were conducted between the male group (n = 49) and the female group (n = 60). For predictive modeling, sex-stratified XGBoost models were built separately: the male cohort (n = 49) was subdivided into mania (n = 31) and depression (n = 18), and the female cohort (n = 60) was subdivided into mania (n = 17) and depression (n = 43). Structural MRI and MRS were utilized to obtain volumetric and metabolic features within the CSC circuit. Key sex-related features were identified through inter-group consistency analysis, Mann-Whitney U tests, and LASSO regression, followed by the calculation of laterality indices (LI). Sex-stratified XGBoost models were constructed to evaluate the predictive performance of CSC circuit features and LI for symptom onset, with SHAP analysis used to determine feature contributions. RESULTS: LI analysis demonstrated that males had significantly higher LI for ACC-sV, ACC-NAA, BG-Cho, and ACC-Glx (all P < 0.007), whereas females exhibited significantly higher LI for BG-sV (P < 0.007). In the sex-stratified XGBoost models, the LI-based models significantly outperformed the absolute-value-based models in predicting manic episodes in males (AUC = 0.803) and depressive episodes in females (AUC = 0.824) (Delong test: P < 0.05). However, the cross-sex prediction performance remained limited. Additionally, SHAP analysis indicated that ACC-Glx LI contributed most to manic episode prediction in males, while ACC-NAA LI and BG-Cho LI had the highest contributions to depressive episode prediction in females. CONCLUSION: In patients with BD-I, significant sex differences are evident in the structural and metabolic characteristics of the CSC circuit. Neuro-metabolic lateralization alterations in the ACC and BG regions may be involved in sex-specific mechanisms underlying different symptom onset types. CLINICAL TRIAL NUMBER: Not applicable.