Identifying Neural Signatures Mediating Behavioral Symptoms and Psychosis Onset: High-Dimensional Whole Brain Functional Mediation Analysis

ABSTRACT Along the pathway from behavioral symptoms to the development of psychotic disorders sits the multivariate mediating brain. The functional organization and structural topography of large-scale neural mediators among patients with brain disorders, however, are not well understood. Here, we design a high-dimensional brain-wide functional mediation framework to investigate brain regions that intermediate between baseline behavioral symptoms and future conversion to full psychosis among individuals at clinical high risk (CHR). Using resting-state functional magnetic resonance imaging (fMRI) data from 263 CHR subjects, we extract an α brain atlas and a β brain atlas: the former underlines brain areas associated with prodromal symptoms and the latter highlights brain areas associated with disease onset. In parallel, we identify the P mediators and the N mediators that respectively facilitate or protect against developing brain disorders among subjects with more severe behavioral symptoms and quantify the effect of each neural mediator on disease development. Taken together, the α - β atlases and the P - N mediators paint a brain-wide picture of neural markers that are potentially regulating behavioral symptoms and the development of psychotic disorders and highlight a statistical framework that is useful to uncover large-scale intermediating variables in a regulatory biological organization.