Moderate hypoxia and cognitive training for cognitive impairment in mood disorders: a randomized controlled trial

Cognitive impairment is a debilitating feature of mood disorders (MD) linked to decreased neuroplasticity. Moderate hypoxia upregulates neuroplasticity and may improve cognition when combined with cognitive training. In this outcome assessor-blinded randomized controlled trial, we investigate the effects of three weeks of repeated hypoxia (12% O ₂ ) with concurrent cognitive training (H-CT) for 3.5 hours, 5-6 days per week compared with treatment as usual (TAU). Cognitively impaired individuals with remitted MD were randomized to H-CT or TAU and assessed at baseline, treatment completion, and one-month follow-up. The primary outcome was a broad cognitive composite measure. Additional cognitive, functioning, blood-based, and neuroimaging (SV2A as a presynaptic marker with [ ¹¹ C]UCB-J positron emission tomography (PET) and neural activity during working memory functional magnetic resonance imaging (fMRI)) outcomes were assessed. Sixty-four participants were randomized to H-CT ( n =34) or TAU ( n =30), and 26 H-CT and 29 TAU completed the intervention and assessments. There was no effect of H-CT on the primary outcome ( ps≥ 0.24) but H-CT induced improvements in the secondary executive function outcome (treatment effect=0.76, 95% CI=[0.23;1.28], adj. p =0.02) that prevailed at follow-up (treatment effect=1.07, 95% CI=[0.36;1.77], adj. p =0.02). Executive function improvement was accompanied by H-CT-related lower presynaptic [ ¹¹ C]UCB-J binding in the nucleus accumbens ( p =0.03). H-CT also produced sustained improvements in everyday functioning (adj. ps ≤0.049). No effects were observed on dorsolateral prefrontal cortex activity or real-life cognitive skills ( p s≥0.54). Two serious but treatment-unrelated adverse events occurred. In conclusion, H-CT produces robust effects on executive functions, but not broader cognition, in MD, and H-CT may thus be particularly promising for targeting executive dysfunction in this population.