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The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor\u2010cognitive tasks, provoking a relative decrease in O<jats:sub>2<\/jats:sub> in relation to the acutely augmented requirement. We termed this fundamental, demand\u2010dependent drop in O<jats:sub>2<\/jats:sub> availability \u201cfunctional hypoxia.\u201d\u00a0Major players in the hypoxia response are hypoxia\u2010inducible factors (HIFs) and associated prolyl\u2010hydroxylases. HIFs are transcription factors, stabilized by low O<jats:sub>2<\/jats:sub> accessibility, and control expression of a multitude of genes. Changes in oxygen, however, can also be sensed via other pathways, among them the thiol\u2010oxidase (2\u2010aminoethanethiol) dioxygenase. Considering the far\u2010reaching biological response to hypoxia, hitherto mostly observed in rodents, we initiated a translational project, combining mild to moderate inspiratory with functional hypoxia. We had identified this combination earlier to benefit motor\u2010cognitive attainment in mice. A total of 20 subjects were included: 13 healthy individuals\u00a0and 7 patients with depression and\/or autism spectrum disorder. Here, we show that motor\u2010cognitive training under inspiratory hypoxia (12% O<jats:sub>2<\/jats:sub>) for 3.5\u2009h daily over 3\u2009weeks is optimally tolerated. We present first signals of beneficial effects on general well\u2010being, cognitive performance, physical fitness and psychopathology. Erythropoietin in serum increases under hypoxia and flow cytometry analysis of blood reveals several immune cell types to be mildly modulated by hypoxia. To obtain reliable information regarding the \u201cadd\u2010on\u201d value of inspiratory on top of functional hypoxia, induced by motor\u2010cognitive training, a single\u2010blind study\u2014with versus without inspiratory hypoxia\u2014is essential and outlined here.<\/jats:p>","DOI":"10.1002\/nep3.47","type":"journal-article","created":{"date-parts":[[2024,6,4]],"date-time":"2024-06-04T08:43:13Z","timestamp":1717490593000},"page":"228-242","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Tolerability and first hints for potential efficacy of motor\u2010cognitive training under inspiratory hypoxia in health and neuropsychiatric disorders:\u00a0A translational viewpoint"],"prefix":"10.1002","volume":"2","author":[{"given":"Svea\u2010Solveig","family":"Mennen","sequence":"first","affiliation":[{"name":"Clinical Neuroscience Max Planck Institute for Multidisciplinary Sciences City Campus G\u00f6ttingen Germany"},{"name":"Georg\u2010August\u2010University G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maren","family":"Franta","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Max Planck Institute for Multidisciplinary Sciences City Campus G\u00f6ttingen Germany"},{"name":"Georg\u2010August\u2010University G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Begemann","sequence":"additional","affiliation":[{"name":"Clinical Neuroscience Max Planck Institute for Multidisciplinary Sciences City Campus G\u00f6ttingen Germany"},{"name":"Georg\u2010August\u2010University G\u00f6ttingen Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justus B. 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