Graded normobaric hypoxia alters cerebral oxygenation and cognition in middle-aged adults: a single-blind counterbalanced randomized crossover trial

Aging is associated with reduced cerebrovascular reactivity and impaired neurovascular coupling, limiting the brain's ability to maintain adequate oxygen delivery during physiological stressors such as hypoxia. These vascular changes may heighten middle-aged adults' vulnerability to hypoxia-induced neural and cognitive impairments, yet dose-response data integrating cerebral oxygenation and cognition remain scarce. In a single-blind, randomized crossover trial, 16 participants completed four normobaric sessions (45-65 min each) at different FiO₂ levels (20.9%, 17.4%, 14.5%, and 12.5%), including 35-55 min of hypoxic exposure. Executive function and memory were assessed using a modified Stroop (inhibition, flexibility), N-back (1-, 2-back), Corsi (forward/backward), and Operation Span (OST). Pulse oxygen saturation (SpO₂), heart rate, blood pressure, and prefrontal oxygenation (ΔHbO₂, ΔHHb, ΔtHb, ΔTSI) were recorded continuously. SpO₂ declined with decreasing FiO₂ (p < 0.001), while heart rate rose and blood pressure remained stable. ΔHbO₂ fell progressively (p = 0.002), while ΔHHb increased only at 12.5% FiO₂ (p = 0.011); ΔtHb and ΔTSI remained unchanged. Cognitive effects paralleled these physiological changes: from 14.5% FiO₂, reaction time slowed (p < 0.001), and accuracy declined on the flexibility task (p < 0.001). Moreover, working memory showed load dependence-N1-back remained stable, N2-back declined only at 12.5% FiO₂ (p = 0.014), and OST worsened from 14.5% FiO₂ onward (p < 0.001). Corsi's performance was unaffected. Acute hypoxia thus impairs prefrontal oxygenation and executive function in middle-aged individuals beginning at FiO₂ ≈ 14.5%, with cerebral blood volume preserved but limited compensatory reserve. These findings highlight age as a critical factor in hypoxia tolerance and risk mitigation. KEY POINTS: • Aging is associated with reduced cerebrovascular reactivity and neurovascular coupling, which may limit the brain's ability to maintain oxygen delivery during hypoxia. • This randomized crossover study examined the effects of graded normobaric hypoxia (20.9%, 17.4%, 14.5%, and 12.5% inspired oxygen) on cerebral oxygenation and cognition in healthy middle-aged adults. • Cerebral oxygenation (oxyhemoglobin concentration) declined progressively with decreasing FiO₂, while executive and working memory performance deteriorated from 14.5% FiO₂ onward, indicating a threshold for hypoxia-induced cognitive impairment. • Reaction times slowed and accuracy decreased in cognitive flexibility and complex working memory tasks, whereas visuospatial memory remained stable across all conditions. • These findings show that middle-aged adults experience earlier and more pronounced cognitive and cerebral oxygenation declines than younger adults under comparable hypoxic stress, underscoring age as a key factor in hypoxia tolerance and a potential target for preventive interventions.