Effects of cognitive training under inspiratory hypoxia on cognition and neuroplasticity in healthy humans: a randomised, double-blind, controlled, four-arm trial

Abstract Moderate hypoxia is increasingly recognized as a physiological driver of neuroprotection and neuroregeneration. In this first randomised, double-blind, controlled, four-arm trial, we demonstrate the cognitive and neuroplastic effects of cognitive training under moderate inspiratory hypoxia in humans. Healthy volunteers underwent three weeks of either cognitive or sham training under normobaric hypoxia (12% O 2 ) or normoxia (20% O 2 ) for 3.5 hours daily, six days per week. Participants were assessed at baseline, treatment completion, and one-month follow-up. The primary outcome was change in a broad cognitive composite score. Additional cognitive, blood-based, and neuroimaging outcomes were assessed, including measurement of the presynaptic protein SV2A with [ 11 C]UCB-J positron emission tomography (PET) and neural activity through functional magnetic resonance imaging (fMRI). In total, 126 participants were randomised to hypoxia-cognitive training (H-CT: n =36), hypoxia-sham training (H-ST: n =30), normoxia- cognitive training (N-CT: n =30), or normoxia-sham training (N-ST: n =30). Intention-to-treat analyses showed no effect of H-CT relative to N-ST in the primary outcome at treatment completion (primary endpoint; treatment effect=0.11, 95% CI=[-0.06;0.28], p =0.19), but improvements emerged at follow-up (treatment effect=0.17, 95% CI=[0.01;0.34], p =0.04). N-CT induced transient improvement in the primary outcome at treatment completion (treatment effect=0.20, 95% CI=[0.02;0.38], p =0.03), which rendered non-significant at follow-up. Finally, H-ST showed no significant cognitive change relative to N-ST. Moderate hypoxia was safe and well-tolerated. Cognitive benefits were accompanied by decreased hippocampal presynaptic density measured with [ 11 C]UCB-J PET. In conclusion, three weeks of H-CT can enhance cognition with associated effects on neuroplasticity, although with a delayed onset of effects on cognition.