Neuroprotective Effects of Moderate Hypoxia: A Systematic Review

Damgaard, Viktoria; Mariegaard, Johanna; Lindhardsen, Julie Marie; Ehrenreich, Hannelore; Miskowiak, Kamilla Woznica

doi:10.3390/brainsci13121648

Cited by 4 publications

References 87 publications

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Tolerability and first hints for potential efficacy of motor‐cognitive training under inspiratory hypoxia in health and neuropsychiatric disorders: A translational viewpoint

Mennen,

Franta,

Begemann

et al. 2024

Neuroprotection

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Hypoxia is more and more perceived as pivotal physiological driving force, allowing cells in the brain and elsewhere to acclimate to lowered oxygen (O2), and abridged metabolism. The mediating transcription program is induced by inspiratory hypoxia but also by intensive motor‐cognitive tasks, provoking a relative decrease in O2 in relation to the acutely augmented requirement. We termed this fundamental, demand‐dependent drop in O2 availability “functional hypoxia.” Major players in the hypoxia response are hypoxia‐inducible factors (HIFs) and associated prolyl‐hydroxylases. HIFs are transcription factors, stabilized by low O2 accessibility, and control expression of a multitude of genes. Changes in oxygen, however, can also be sensed via other pathways, among them the thiol‐oxidase (2‐aminoethanethiol) dioxygenase. Considering the far‐reaching 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‐cognitive attainment in mice. A total of 20 subjects were included: 13 healthy individuals and 7 patients with depression and/or autism spectrum disorder. Here, we show that motor‐cognitive training under inspiratory hypoxia (12% O2) for 3.5 h daily over 3 weeks is optimally tolerated. We present first signals of beneficial effects on general well‐being, 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 “add‐on” value of inspiratory on top of functional hypoxia, induced by motor‐cognitive training, a single‐blind study—with versus without inspiratory hypoxia—is essential and outlined here.

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Tolerability and first hints for potential efficacy of motor‐cognitive training under inspiratory hypoxia in health and neuropsychiatric disorders: A translational viewpoint

Mennen,

Franta,

Begemann

et al. 2024

Neuroprotection

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Variable Cerebral Blood Flow Responsiveness to Acute Hypoxic Hypoxia

Johnson,

Wang,

Stickland

et al. 2024

Preprint

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Cerebrovascular reactivity (CVR) to changes in blood carbon dioxide and oxygen levels is a robust indicator of vascular health. Although CVR is typically assessed with hypercapnia, the interplay between carbon dioxide and oxygen, and their ultimate roles in dictating vascular tone, can vary with pathology. Methods to characterize vasoreactivity to oxygen changes, particularly hypoxia, would provide important complementary information to established hypercapnia techniques. However, existing methods to study hypoxic CVR, typically with arterial spin labeling (ASL) MRI, demonstrate high variability and paradoxical responses. To understand whether these responses are real or due to methodological confounds of ASL, we used phase-contrast MRI to quantify whole-brain blood flow in 21 participants during baseline, hypoxic, and hypercapnic respiratory states in three scan sessions. Hypoxic CVR reliability was poor-to-moderate (ICC=0.42 for CVR relative to PETO2 changes, ICC=0.56 relative to SpO2 changes) and was less reliable than hypercapnic CVR (ICC=0.67). Without the uncertainty from ASL-related confounds, we still observed paradoxical responses at each timepoint. Concurrent changes in blood carbon dioxide levels did not account for paradoxical responses. Hypoxic CVR and hypercapnic CVR shared approximately 40% of variance across the dataset, indicating that the two effects may indeed reflect distinct, complementary elements of vascular regulation.

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Effects of cognitive training under hypoxia on cognitive proficiency and neuroplasticity in remitted patients with mood disorders and healthy individuals: ALTIBRAIN study protocol for a randomized controlled trial

Miskowiak,

Damgaard,

Schandorff

et al. 2024

Trials

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Background Cognitive impairment is prevalent across neuropsychiatric disorders but there is a lack of treatment strategies with robust, enduring effects. Emerging evidence indicates that altitude-like hypoxia cognition training may induce long-lasting neuroplasticity and improve cognition. We will investigate whether repeated cognition training under normobaric hypoxia can improve cognitive functions in healthy individuals and patients with affective disorders and the neurobiological underpinnings of such effects. Methods In sub-study 1, 120 healthy participants are randomized to one of four treatment arms in a double-blind manner, allowing for examination of separate and combined effects of three-week repeated moderate hypoxia and cognitive training, respectively. In sub-study 2, 60 remitted patients with major depressive disorder or bipolar disorder are randomized to hypoxia with cognition training or treatment as usual. Assessments of cognition, psychosocial functioning, and quality of life are performed at baseline, end-of-treatment, and at 1-month follow-up. Functional magnetic resonance imaging (fMRI) scans are conducted at baseline and 1-month follow-up, and [11C]UCB-J positron emission tomography (PET) scans are performed at end-of-treatment to quantify the synaptic vesicle glycoprotein 2A (SV2A). The primary outcome is a cognitive composite score of attention, verbal memory, and executive functions. Statistical power of ≥ 80% is reached to detect a clinically relevant between-group difference with minimum n = 26 per treatment arm. Behavioral data are analyzed with an intention-to-treat approach using mixed models. fMRI data is analyzed with the FMRIB Software Library, while PET data is quantified using the simplified reference tissue model (SRTM) with centrum semiovale as reference region. Discussion The results will provide novel insights into whether repeated hypoxia cognition training increases cognition and brain plasticity, which can aid future treatment development strategies. Trial registration ClinicalTrials.gov, NCT06121206. Registered on 31 October 2023.

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Neuroprotective Effects of Moderate Hypoxia: A Systematic Review

Cited by 4 publications

References 87 publications

Tolerability and first hints for potential efficacy of motor‐cognitive training under inspiratory hypoxia in health and neuropsychiatric disorders: A translational viewpoint

Tolerability and first hints for potential efficacy of motor‐cognitive training under inspiratory hypoxia in health and neuropsychiatric disorders: A translational viewpoint

Variable Cerebral Blood Flow Responsiveness to Acute Hypoxic Hypoxia

Effects of cognitive training under hypoxia on cognitive proficiency and neuroplasticity in remitted patients with mood disorders and healthy individuals: ALTIBRAIN study protocol for a randomized controlled trial

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