Mapping the functional connectome between grey matter and white matter

Brain white matter (WM) has traditionally been viewed as a passive conduit for neural transmission. However, evidence of blood oxygen level-dependent (BOLD) signals measured from the WM suggests its active participation in grey matter (GM) functional networks. Using 7-Tesla functional MRI (fMRI) data, we constructed a GM–WM functional connectome. We found that GM–WM functional architecture follows the unimodal–transmodal hierarchy of GM and is shaped by distributions of neurotransmitter receptors. Distinct WM networks exhibit unique connectivity profiles with GM, reflecting their roles in specific cognitive domains. Individual variations in this connectome correlated with cognitive performance. Notably, compared with the traditional GM–GM functional connectome, the GM–WM functional connectome shows stronger associations with brain disorders, suggesting greater diagnostic sensitivity as a neuromarker. These findings are replicated in a 3-Tesla fMRI cohort. Our work establishes WM as an integral component of the brain’s functional architecture, contributing to hierarchical architecture and supporting higher-order cognition. Mapping the functional connectome between grey and white matter reveals a hierarchical architecture shaped by neurotransmitter systems, predicts cognitive performance, and improves diagnostic classification of brain disorders.