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

The human brain, one of the most energy-demanding organs, continuously adapts to internal and external challenges. Hypoxia, a reduction in oxygen availability, poses a substantial threat to brain function. Despite its importance, the nature of the brain's adaptive response to hypoxia remains poorly understood. In this study, we investigated dynamic functional connectivity (FC) under acute hypoxic conditions (FiO₂ = 7.7 % and 11.8 %) in healthy adults using blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) and concurrent advanced physiological monitoring, including partial pressures of end-tidal oxygen (PetO₂) and carbon dioxide (PetCO₂) and peripheral oxygen saturation (SpO₂), and a Go/No-Go cognitive task to assess behavioral performance. Principal component analysis identified a hypoxia-responsive component in dynamic FCs across 400 cerebral parcels. This component captured hypoxia-specific FC changes that coincided with a critical drop in PetO₂ (∼53 mmHg), preceding subsequent changes in SpO₂, bulk BOLD signals, and behavioral performance. These FC changes were network-specific, with a marked increase primarily centered on the default mode network (DMN), which selectively synchronized with other high-level cognitive networks. In contrast, hypoxia-responsive connectivity showed limited involvement of visual networks, including connectivity with the DMN. These findings suggest that the brain engages in proactive and structured FC adaptations in anticipation of oxygen decline, rather than in response to it. FC-based metrics offer new insights into the temporal dynamics of brain resilience and may hold translational value for the early detection of vulnerability in neurological or neurodegenerative disorders.