Identifying psychosis subtypes use individualized covariance structural differential networks and multi-site clustering

Background: Similarities among schizophrenia (SZ), schizoaffective disorder (SAD) and bipolar disorder (BP) including clinical phenotypes, brain alterations and risk genes, make it challenging to perform reliable separation among them. However, previous subtype identification that transcend traditional diagnostic boundaries were based on group-level neuroimaging features, ignoring individual-level inferences. Methods: 455 psychoses (178 SZs, 134 SADs and 143 BPs), their first-degree relatives (N = 453) and healthy controls (HCs, N = 220) were collected from Bipolar-Schizophrenia Network on Intermediate Phenotypes (B -SNIP I) consortium. Individualized covariance structural differential networks (ICSDNs) were constructed for each patient and multi-site clustering was used to identify psychosis subtypes. Group differences between sub-types in clinical phenotypes and voxel-wise fractional amplitude of low frequency fluctuation (fALFF) were calculated, as well as between the corresponding relatives. Results: Two psychosis subtypes were identified with increased whole brain structural covariance, with decreased connectivity between amygdala-hippocampus and temporal-occipital cortex in subtype I (S-I) compared to subtype II (S-II), which was replicated under different clustering methods, number of edges and across datasets (B-SNIP II) and different brain atlases. S-I had higher emotional-related symptoms than S-II and showed sig-nificant fALFF decrease in temporal and occipital cortex, while S-II was more similar to HC. This pattern was consistently validated on relatives of S-I and S-II in both fALFF and clinical symptoms. Conclusions: These findings reconcile categorical and dimensional perspectives of psychosis neurobiological heterogeneity, indicating that relatives of S-I might have greater predisposition in developing psychosis, while relatives of S-II are more likely to be healthy. This study contributes to the development of neuroimaging informed diagnostic classifications within psychosis spectrum.