Decreased left brain specialization in bipolar disorder patients and its association with neurotransmitter and genetic profiles: A longitudinal study

Brain specialization plays a crucial role in human behavior and cognition. Previous studies have suggested abnormal specialization in psychiatric disorders; however, the specialization patterns of bipolar disorder (BD) and the effects of medication on these changes remain unclear. According to Crow’s hypothesis regarding the key role of language in the origin of psychoses, BD patients (BDPs) may exhibit abnormal language-related specialization. Here, we aimed to explore brain specialization alterations of BDPs before and after pharmacological treatment. The autonomy index, based on resting-state images, was used to assess brain specialization in 82 BDPs and 88 healthy controls (HCs). Among patients, 43 BDPs who underwent 3 months of pharmacological treatment completed the follow-up. Using autonomy index as input, support vector regression (SVR) analysis was conducted to predict treatment response. Additionally, we conducted cross-sample correlation analyses between autonomy index and genetic profiles or the densities of neurotransmitter receptors/transporters. At baseline, BDPs exhibited reduced autonomy index in the left middle temporal gyrus (MTG) relative to HCs. However, no significant alterations were observed following pharmacological treatment. Using autonomy index, the SVR model could predict treatment response for BDPs with a correlation coefficient of 0.705. Brain specialization patterns were correlated with six genes and neurotransmitters including dopaminergic (D1R, D2R, and DAT) and serotonergic (5-HT2A) transmission. In line with Crow’s hypothesis, we found reduced brain specialization in a key node of the language network (LN) in BDPs. We also provided potential genetic and biological mechanisms underlying BD.