Differences in Functional Connectivity of the Insular Cortex in Adolescents with Schizophrenia Risk and Symptomatology

The insula is a key cortical region implicated in early-stage schizophrenia and prodromal symptomatology. This study sought to assess associations between insula functional connectivity (FC) and schizophrenia risk, as well as insula FC and prodromal symptom presence. Resting state FC data from 122 adolescents, aged 9-16 years, was utilized. FC differences between familial high-risk (FHR) participants (n=27) and controls (n=95) were assessed using second-level seed-based connectivity (SBC) and ROI-to-ROI connectivity (RRC) analyses. Associations between insula FC and symptom presence were assessed using first-level RRC analyses, followed by logistic regression using an elastic net model. SBC analyses found that FHR participants exhibited significantly lower FC between the left posterior insula (PI) and aspects of the visual system, as well as the left whole insula and aspects of the visual system, compared to healthy controls (voxel threshold: p<0.001, cluster threshold: p<0.05). Analyses of insula FC and prodromal symptoms found that decreased FC of the left PI and bilateral hippocampus (left: OR=0.0773, p=0.0458; right: OR=0.0971, p=0.0458), as well as increased FC between the right dorsal anterior insula (dAI) and right orbitofrontal cortex (OR=9.908, p=0.0229), is associated with positive symptom presence. Additionally, the presence of unusual thoughts was associated with decreased FC between the left dAI and left putamen (OR=0.00584, p=0.0350), increased FC between the left dAI and left dorsolateral prefrontal cortex (OR=65.196, p=0.0264), and increased FC between the left PI and right dorsolateral prefrontal cortex (OR=72.559, p=0.0264). These results indicate that discrete patterns of insula FC are associated with schizophrenia risk and prodromal symptomatology.