Dynamic neurovascular adaptation of the retina during high-altitude hypoxia: integrated analysis of ERG and OCTA changes in healthy subjects.

Acute hypobaric hypoxia induces rapid neurovascular adjustments in the central nervous system, yet the specific spatiotemporal dynamics of these responses remain incompletely understood. The retina, with its high metabolic demand and direct accessibility, provides a unique noninvasive model to investigate neurovascular coupling dynamics under simulated high-altitude hypoxia. Twenty-one healthy adults underwent ophthalmic evaluations at sea level, during a stepwise ascent to 4,500 m in a hypobaric chamber (simulated altitudes: 3,500 m, 4,000 m, 4,500 m), and during a subsequent recovery phase. Images were acquired 10 min after reaching each plateau. Optical coherence tomography angiography (OCTA) was used to quantify vessel density (VD), perfusion area (PA), and small-vessel density (SVD). Full-field electroretinogram (ERG) was recorded under dark- and light-adapted conditions. Linear mixed-effects models and correlation analyses were used to assess altitude-related changes. The superficial vascular plexus (SVP) exhibited a sustained compensatory vasodilation (increased VD and PA) across all altitudes. In contrast, ERG amplitudes declined significantly at 4,500 m, revealing a functional supply-demand mismatch. Strict statistical analysis revealed a loss of linear neurovascular correlation during hypoxia, while strong correlations re-emerged during the recovery-phase. In addition, physiological parameters did not immediately return to baseline during recovery, indicating a distinct physiological hysteresis. The retina displays differential neurovascular responses during progressive hypoxia. Although the superficial microvasculature mounts a sustained compensatory response, neuronal function decompensates under severe stress. These results suggest that retinal vascular dilation reaches a functional ceiling, leading to neurovascular uncoupling, and that the system exhibits a metabolic lag during recovery.NEW & NOTEWORTHY This study identifies a critical "functional mismatch" in retinal neurovascular adaptation to acute hypoxia. We demonstrate that while superficial microvasculature sustains compensatory dilation up to simulated 4,500 m, neuronal function significantly declines. This dissociation suggests that vascular autoregulation reaches a functional ceiling, failing to sustain neural activity under severe stress. These findings establish the retina as a sensitive noninvasive model for determining the physiological limits of cerebral oxygen regulation.