Altered cortical-striatal circuits connectivity is associated with psychotic symptoms in patients with first-episode, drug-naïve early-onset schizophrenia

Background: Schizophrenia is recognized as a connectivity disorder. Although functional connectivity (FC) abnormalities are frequently reported in schizophrenia patients, findings remain inconsistent. Additionally, causal connectivity in early-onset schizophrenia (EOS) is underexplored, and the association between aberrant brain measures and psychotic symptoms remains unclear. Methods: Resting-state fMRI data were collected from 21 first-episode, drug-naïve EOS patients and 21 matched healthy controls (HCs). A voxel-wise meta-analysis was first used to identify the consistent brain regions with altered spontaneous functional activity in EOS. These regions served as seeds for subsequent FC analysis and Granger causality analysis (GCA), and the obtained functional brain measures were examined for their associations with psychotic symptoms. Results: Relative to HCs, EOS patients exhibited reduced FC between the left middle frontal gyrus (MFG) and right Cerebellum_8 as well as left Cerebellum_7b, while the connectivity between the right caudate nucleus (CAU) and right precuneus (PCUN) was increased. The increased FC between the right CAU and right PCUN was positively correlated with PSYRATS-delusion scores. Additionally, GCA revealed increased causal flow from the right CAU to right amygdala, while effective connectivity (EC) from the triangular part of the right inferior frontal gyrus to left MFG was inhibited, but no significant association was detected between these functional changes and psychotic symptoms. Conclusions: EOS not only showed aberrant FC in cortico-striato-cerebellar circuits, but also exhibited disrupted causal connectivity in striatal-amygdala circuits and within prefrontal cortex. Importantly, hyperconnectivity within the cortical-striatal circuits may represent a key neural mechanism underlying the psychotic symptoms of EOS.