Effects of Altitude-like Cognition Training on Neuroplasticity and Cognitive Functions

ALTIBRAIN aims to test a novel model, linking altitude-like oxygen manipulations, endogenous erythropoietin (EPO) in the brain, neuroplasticity and cognition. Specifically, ALTIBRAIN will determine whether upregulation of endogenous brain EPO by altitude-like hypoxia cognition training is a fundamental mechanism of enduring neuroplasticity and long-lasting cognitive improvement in humans. This will be investigated in healthy individuals (substudy 1) and symptomatically stable patients with mood disorders (depression or bipolar disorder; substudy 2).

Substudy 1 involves four intervention groups: (1) altitude-like hypoxia (12%) combined with cognitive training, (2) hypoxia with no training, (3) cognitive training under normoxia (20%), and (4) normoxia with no training. Participants are randomised in blocks of four and undergo interventions in these groups for practical reasons. During the 3-weeks treatment, participants breathe 12% ambient oxygen (≈4400 meters altitude) or normal sea-level oxygen (20%) in a treatment room, 3.5 hours daily, six days per week. On iPads, they perform cognitive training or matched control games without cognitive benefits. Cognitive training is interleaved by short breaks, during which the participants can relax or walk on a treadmill inside the room. Participants undergo cognition assessments in weeks 1 (baseline), 4 and 8 and functional and structural MRI in weeks 1 and 8, when red blood cells are comparable between groups. A subgroup will also undergo PET scanning in week 4.

In substudy 2, patients are randomized to either (1) altitude-like hypoxia (12%) combined with cognitive training, 3.5 hours daily, five-six days per week for three weeks or (2) treatment as usual (TAU). After completed testing, patients in the TAU group undergo the 3-week active intervention, followed by an additional session of neurocognitive testing in the week after treatment completion. All remaining study procedures are identical to substudy 1.

The power calculation was based on the primary hypothesis that altitude-like hypoxia combined with cognitive training produces robust sustained cognitive improvement compared with normoxia and no training. To accommodate for up to a 15% drop-out, we will include 30 participants per group; i.e., 120 healthy individuals and 60 patients to obtain complete data for minimum 26 participants per group, i.e., 104 healthy individuals and 52 patients.

Inclusion criteria

(substudy 1):

• 18-50 years
• No psychiatric history
• Fluency in Danish

Inclusion criteria

(substudy 2):

• 18-65 years
• International Classification of Diseases (ICD)-10 diagnosis of Bipolar Disorder or depression confirmed with the Schedules for Clinical Assessment in Neuropsychiatry (SCAN)
• Fluency in Danish
• Partial or full remission (defined as a score of ≤14 on the Hamilton Depression Rating Scale 17-items (HDRS-17) and the Young Mania Rating Scale (YMRS)
• Objectively-verified cognitive impairment according to Screen for Cognitive Impairment in Psychiatry (SCIP) and/or self-reported cognitive impairment measured with Cognitive Complaints in Bipolar disorder Rating Assessment (COBRA). For SCIP, their performance must be ≥0.5 standard deviations (SD) below their demographically adjusted expected total SCIP score or on minimum 2 SCIP subtest scores. For COBRA, patients must report substantial cognitive impairment defined as a score ≥14.

Common Exclusion Criteria:

• Schizophrenia or schizoaffective disorder
• Neurological disorder
• Alcohol or substance abuse
• History of serious head trauma
• Previous altitude sickness
• Heart disease
• Diabetes
• Renal failure
• Untreated/insufficiently treated hypertension
• Thromboses or thromboembolic events
• First-degree family with thromboembolic events before age 60
• Pregnancy
• Breastfeeding
• Smoking or use other nicotine products regularly
• BMI>30
• Electroconvulsive therapy (ECT) 3 months prior to participation
• Dyslexia
• Claustrophobia (MRI scans)
• Pacemaker and/or other MRI incompatible metal implants (MRI scans)
• Participation in experiments with radioactivity (>10 mSv) within the last year (PET scans)
• Significant occupational exposure to radioactivity (PET scans)
• Medication incompatible with study aims (e.g., SV2A binding agents; PET scans)