Identifying Neurobiological Psychosis Biotypes Using Multi-Scale Functional Network Connectivity and its Latent Independent Subspace

This study aims to identify Psychosis Imaging Neurosubtypes (PINs)-- homogeneous subgroups of individuals with psychosis characterized by distinct neurobiology derived from imaging features. Specifically, we utilized resting-state fMRI data from 2103 B-SNIP 1&2 participants (1127 with psychosis, 350 relatives, 626 controls) to compute subject-specific multiscale functional network connectivity (msFNC). We then derived a low-dimensional neurobiological subspace, termed Latent Network Connectivity (LNC), which captured system-wide interconnected multiscale information across three components (cognitive-related, typical, psychosis-related). Projections of psychosis participants msFNC onto this subspace revealed three PINs through unsupervised learning, each with distinct cognitive, clinical, and connectivity profiles, spanning all DSM diagnoses (Schizophrenia, Bipolar, Schizoaffective). PIN-1, the most cognitively impaired, showed Cerebellar-Subcortical and Visual-Sensorimotor hypoconnectivity, alongside Visual-Subcortical hyperconnectivity. Most cognitively preserved PIN-2 showed Visual-Subcortical, Subcortical-Sensorimotor, and Subcortical-Higher Cognition hypoconnectivity. PIN-3 exhibited intermediate cognitive function, showing Cerebellar-Subcortical hypoconnectivity alongside Cerebellar-Sensorimotor and Subcortical-Sensorimotor hyperconnectivity. Notably, 55% of relatives aligned with the same neurosubtype as their affected family members--a significantly higher rate than random chance (p-valueRelatives-to-PIN-1 < 0.001, p-valueRelatives-to-PIN-2 < 0.05, p-valueRelatives-to-PIN-3 < 0.001) compared to a non-significant 37% DSM-based classification, supporting a biological basis of these neurosubtypes. Cognitive performance reliably aligns with distinct brain connectivity patterns, which are also evident in relatives, supporting their construct validity. Our PINs differed from original B-SNIP Biotypes, which were determined from electrophysiological, cognitive, and oculomotor data. These findings underscore the limitations of DSM-based classifications in capturing the biological complexity of psychotic disorders and highlight the potential of imaging-based neurosubtypes to enhance our understanding of the psychosis spectrum.