Neural energy metabolism encodes directed communication across the human cortex

Abstract

Complex cognition depends on directed communication between brain regions. Yet, resting functional MRI resolves only undirected associations, and inferring the direction of signalling has proven difficult across the whole brain. Because synaptic transmission is metabolically asymmetric, with the postsynaptic neuron bearing most of the energetic cost, regional energy demand carries a physical signature of the direction of communication. Here, we show that this signature organizes the human cortex into a reproducible directed hierarchy, in which sensory and attentional systems preferentially drive higher-order networks, while the default mode and control networks act as principal receivers. Critically, the inferred directionality is independently predicted by two cellular markers of neuronal energy demand, regional mitochondrial density and laminar cytoarchitecture, linking macroscale information flow to its cellular substrate. The directed architecture recapitulates the known feedforward and feedback organization of visual pathways and, using an average CMRGlc template, extends to functional MRI acquired without PET. By grounding communication direction in energy metabolism, Metabolic Connectivity Mapping bridges correlative and effective connectivity and offers a scalable, biologically interpretable framework for mapping directed communication across the human brain.