Altitude-like hypoxia cognition training to target brain erythropoietin as a novel mechanism of long-lasting enhancement of neuroplasticity and cognitive functions

Informazioni relative al progetto

ALTIBRAIN

ID dell’accordo di sovvenzione: 101043416

DOI

10.3030/101043416

Data della firma CE 18 Luglio 2022

Data di avvio 1 Dicembre 2022

Data di completamento 30 Novembre 2027

Finanziato da

• European Research Council (ERC)

Costo totale

€ 1 999 944,00

Contributo UE

€ 1 999 944,00

Coordinato da

KOBENHAVNS UNIVERSITET
Denmark

Periodic Reporting for period 1 - ALTIBRAIN (Altitude-like hypoxia cognition training to target brain erythropoietin as a novel mechanism of long-lasting enhancement of neuroplasticity and cognitive functions)

Periodo di rendicontazione: 2022-12-01 al 2025-05-31

Sintesi del contesto e degli obiettivi generali del progetto

Cognitive impairment in memory, attention, and executive functioning is a persistent and disabling symptom domain across a range of neuropsychiatric disorders, including unipolar depression, bipolar disorder, and schizophrenia. These deficits often continue even after remission of mood or psychotic symptoms, hindering recovery, impairing daily functioning, and contributing to the largest portion of these disorders’ socio-economic burden. Despite the ur-gent clinical need, there are currently no effective pharmacological treatments for cognitive impairment in bipolar or unipolar depression, and none approved for use in schizophrenia. While cognitive remediation offers modest bene-fits, the lack of robust, enduring interventions underscores the need for a new treatment paradigm—one that targets the underlying biological mechanisms of cognitive dysfunction.
ALTIBRAIN addresses this critical gap by testing a novel theoretical model linking mild oxygen deprivation (hypox-ia), the brain’s production of erythropoietin (EPO), and long-lasting neuroplasticity. Drawing on preclinical findings, the central hypothesis is that intermittent exposure to moderate, altitude-like hypoxia (12% oxygen), with or without cognitive training, may stimulate the brain’s natural production of EPO—a protein that promotes neuronal survival, growth, and synaptic plasticity—thereby enhancing cognitive performance.
To test this hypothesis, ALTIBRAIN employs a unique translational design, with parallel experimental protocols in humans and mice. Both models undergo three weeks of daily hypoxia exposure, with and without cognitive training, enabling insights at both behavioural and mechanistic levels. While human studies allow assessment of real-world cognitive outcomes, animal studies provide access to cellular and molecular mechanisms—including hippocampal volume, progenitor cell differentiation, and EPO signalling—via methods not possible in humans.
In mice, cognitive changes are evaluated using the IntelliCage system for high-throughput, automated testing of learning and memory in group-housed animals. In humans, randomized controlled trials assess cognitive outcomes and brain changes via comprehensive neuropsychological testing, MRI, PET, and blood-based biomarkers in healthy individuals and patients with mood disorders.
If successful, ALTIBRAIN could offer a conceptual and therapeutic breakthrough. The findings may lay the ground-work for non-drug-based treatments that improve cognitive function not only in psychiatric disorders, but also in neurodegenerative conditions and aging populations. Ultimately, the project seeks to redefine how cognitive health can be enhanced—by activating the brain’s own regenerative potential through natural, physiologically grounded interventions.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

Since its launch in December 2022, ALTIBRAIN has made substantial scientific progress in line with its objectives. The project comprises two ongoing randomized controlled trials (RCTs): one in healthy individuals and one in pa-tients with mood disorders. Both trials investigate whether three weeks of daily exposure to moderate hypoxia (with or without cognitive training) can enhance cognition, neuroplasticity, and EPO expression. Recruitment is well ad-vanced, with over 80% of participants enrolled across both trials. Safety assessments show good tolerability, with only mild and transient side effects such as headache and fatigue.

Seven peer-reviewed scientific publications have already been produced, documenting the trial protocols, validation of a novel ecologically valid fMRI task, and a systematic review on the neuroplastic effects of moderate hypoxia.
The main outcomes of the clinical trials will remain blinded until late 2025, but the project is on track to deliver new insights into the cognitive and neural effects of altitude-like hypoxia combined with training. Notably, preliminary fMRI findings suggest the potential for hypoxia-cognition training to enhance working memory-related brain activa-tion in patients and to modulate neural efficiency in healthy individuals. These results, while still early, are promis-ing.
On the preclinical side, infrastructure and training are in place for the animal studies, now relocated to the University of Copenhagen in 2025. A key methodological advancement includes the development of IntelliR—a standardized, automated system for assessing higher-order cognition in mice—which will enable precise investigation of how hy-poxia influences neuroplasticity at the molecular and cellular levels.
Altogether, these achievements lay the foundation for the next stages of the project, including the unblinding and primary outcome analyses in late 2025. While final results are still pending, ALTIBRAIN is already providing promis-ing early insights into how oxygen-based interventions may one day be used to promote cognitive health and resili-ence.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

ALTIBRAIN is pioneering a new approach to cognitive enhancement by investigating whether short-term, moderate hypoxia—on its own or combined with cognitive training—can activate the brain’s natural neuroplastic processes. The model builds on prior preclinical findings and proposes that this combination may stimulate endogenous produc-tion of erythropoietin (EPO), a protein known to support neuronal survival, synaptic plasticity, and cognitive perfor-mance.
While results from the ALTIBRAIN trials remain blinded until autumn 2025, the project has already contributed im-portant advances beyond the current state of the art. These include validated neuroimaging tools for real-world cog-nition, the development of a novel cognitive testing platform for mice (IntelliR), and the establishment of a transla-tional framework linking behavioural data to underlying biological mechanisms.
After completion of ALTIBRAIN, several critical steps are needed to ensure future uptake and impact. These include further studies in ageing populations and clinical groups with cognitive impairment, demonstration studies using more accessible delivery systems (e.g. oxygen masks), and dose-response trials to determine optimal treatment parameters. Future implementation will also depend on support for regulatory alignment, integration into healthcare pathways, and potential public–private partnerships for scale-up.
If successful, ALTIBRAIN could redefine how we approach cognitive enhancement in psychiatry—shifting focus from symptom management to regeneration and cognitive resilience—offering a new frontier in brain health across psychiatric and ageing populations.