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.
