Whole-Brain MRSI Metabolic Connectomics Reveals Network Disruptions and Altered Gradient Coherence in Psychosis Risk

Abstract

Brain network alterations preceding first-episode psychosis often escape connectomic approaches based on conventional neuroimaging, such as diffusion or functional magnetic resonance imaging (MRI). Whole-brain magnetic resonance spectroscopic imaging (MRSI) offers a potentially more sensitive alternative: by mapping neurometabolites across the brain, it enables the construction of metabolic connectomes that may capture very early and subtle disruptions of brain network properties. We combined whole-brain proton MRSI, diffusion MRI, and resting-state functional MRI in a sample of 29 individuals meeting DSM-5 criteria for Attenuated Psychosis Syndrome (APS) or Schizotypal Personality Disorder (SCZT), pooled into a single High Risk for Psychosis (HR) group, and 30 healthy controls (HC) to construct metabolic, structural, and functional connectomes. Network-based statistics identified a significant metabolic connectivity subnetwork with higher connectivity in HR than in HC, whereas no corresponding structural or functional connectivity differences were detected. Nodes of this subnetwork had modestly higher structural strength but were not consistently enriched among structural hubs, and no significant regional abnormalities in individual metabolite concentrations were detected. Eigenmode analysis of metabolic connectivity revealed a low-dimensional organization spanning a posterior unimodal-to-transmodal axis and a transmodal-to-limbic axis. Path analysis revealed higher bilateral energy in HR, indicating reduced coherence along a metabolic gradient that parallels the neurodevelopmental sensorimotor-to-association axis. These findings identify whole-brain metabolic network organization derived from MRSI as a systems-level phenotype of psychosis risk and raise the possibility that it captures altered development of large-scale cortical organization.