Brain functional connectivity initiates structured reorganization at a critical oxygen threshold during hypoxia.

The human brain dynamically adapts to hypoxia, a reduction in oxygen essential for metabolism. The brain's adaptive response to hypoxia, however, remains unclear. We investigated dynamic functional connectivity (FC) in healthy adults under acute hypoxia (FiO2 = 7.7%, 11.8%) using BOLD fMRI, physiological monitoring (PetO2, PetCO2, SpO2), and a Go/No-Go task. Principal component analysis identified a hypoxia-responsive FC component involving 400 cerebral parcels. This component emerged with a critical drop in PetO2 (~53 mmHg), preceding changes in SpO2, BOLD signals, and behavior. These FC changes were network-specific and centered on the default mode network (DMN), which selectively synchronized with other high-level cognitive networks. In contrast, visual networks remained stable and segregated from the DMN. These results suggest that the brain proactively reorganizes its functional architecture in anticipation of oxygen decline, rather than in response to it. FC-based markers may offer early indicators of vulnerability in neurological or neurodegenerative conditions.