Molecular and micro-architectural mapping of abnormal gray matter developmental trajectories in psychosis

Abstract

ABSTRACTThe psychosis spectrum encompasses a heterogeneous range of clinical conditions associated with abnormal brain development. The molecular and micro-architectural attributes that account for structural deviations from typical neurodevelopment are still unknown. Here, we aggregate magnetic resonance imaging data from 38,696 healthy controls and 1,256 psychosis-related cases, including first-degree relatives, psychotic experiences, first-episodes, and chronic conditions. Using normative modeling, we generated centile scores for cortical gray matter phenotypes, identifying deviations in regional volumes below the expected trajectory for all conditions. Additionally, we mapped 46 neurobiological features from healthy individuals (including neurotransmitters, cell types, layer thickness, microstructure, cortical expansion, and metabolism) to these centiles using a multivariate approach. Results revealed that neurobiological features were highly co-localized with centile deviations, where metabolism and neurotransmitter concentrations showed the most consistent spatial overlap with abnormal developmental trajectories. These findings shed light on the vulnerability factors that may underlie atypical brain maturation during different stages of psychosis.