Clinical trial NCT06121206: Effects of Altitude-like Cognition Training on Neuroplasticity and Cognitive Functions
Official title: Altitude-like Cognition Training to Target Brain Erythropoietin as a Novel Mechanism of Long-lasting Neuroplasticity and Cognitive Functions
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Cognitive Impairment
Bipolar Disorder
Depression
Keywords: Cognition
Neuroplasticity
Hypoxia
Cognitive training
Depression
Bipolar Disorder
Cognitive Impairment
Lead sponsor: Mental Health Services in the Capital Region, Denmark
Sponsor class: OTHER
Collaborators: name: European Research Council
name: University of Copenhagen
name: Rigshospitalet, Denmark
First posted: 2023-11-07
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to investigate the effects of a three-week altitude-like cognition training intervention in healthy individuals (substudy 1) and symptomatically stable patients with mood disorders (depression or bipolar disorder; substudy 2). This multi-modal intervention consists of an adaptive cognitive training programme that participants complete while they're inside an altitude-training room with 12% O2, corresponding to 4400 meters altitude.

Across substudy 1 and 2, the investigators hypothesize that altitude-like cognition training has a beneficial effect on cognition after three-weeks treatment completion measured with a global cognition composite score (primary outcome measure). Further, the investigators hypothesize that hypoxia and cognition training will yield improved executive functioning after treatment completion and changes in brain activity during working memory in the dorsal prefrontal cortex 4 weeks after treatment completion (secondary outcome measures). In the patient study, the investigators further hypothesize that the intervention will have beneficial effects on daily-life cognition measured in virtual reality (VR) 4 weeks after treatment completion (secondary outcome measure in substudy 2). For exploratory purposes, the study will examine effects on additional measures of cognition, functioning and self-ratings scales (tertiary outcomes).

The investigators will compare the combination of altitude-like hypoxia (12%) and cognitive training with (1) hypoxia with no training, (2) cognitive training under normal oxygen levels (normoxia; 20%), and (3) normoxia with no training in healthy individuals (substudy 1). For patients with mood disorders (substudy 2) the effects of altitude-like hypoxia (12%) and cognitive training are compared to treatment as usual (TAU).

Detailed description: 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.

Eligibility criteria: 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)

Primary outcomes:
measure: Cognitive composite score
timeFrame: Baseline, week 4 (end of treatment. Primary outcome assessement time point), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
Secondary outcomes:
measure: "Problems solved on first choice" in One Touch Stockings of Cambridge (OTS) from Cambridge Cognition (CANTAB)
timeFrame: Baseline, week 4 (end of treatment. Secondary outcome assessement time point), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Dorsal prefrontal cortex activity during spatial N-back
timeFrame: Baseline, week 8
measure: ONLY IN PATIENTS (SUBSTUDY 2): Cognition Assessement in Virtual Reality (CAVIR) test: Composite score
timeFrame: Baseline, week 8 (secondary outcome assessment time point) (+end of treatment follow-up for patients in treatment as usual group)
Other outcomes:
measure: Rey Auditory Verbal Learning Test
timeFrame: Baseline, week 4 (end of treatment), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Trail Making Test Part A
timeFrame: Baseline, week 4 (end of treatment), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Trail Making Test Part B
timeFrame: Baseline, week 4 (end of treatment), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Coding
timeFrame: Baseline, week 4 (end of treatment), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Digit Span
timeFrame: Baseline, week 4 (end of treatment), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Wechsler Adult Intelligence Scale (WAIS)-III Letter-Number Sequencing
timeFrame: Baseline, week 4 (end of treatment), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Verbal fluency with the letter "D" and 'S"
timeFrame: Baseline, week 4 (end of treatment), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Rapid Visual Information Processing (RVP) from Cambridge Cognition (CANTAB)
timeFrame: Baseline, week 4 (end of treatment) and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Spatial Working Memory (SWM) from Cambridge Cognition (CANTAB)
timeFrame: Baseline, week 4 (end of treatment) and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: One Touch Stockings of Cambridge (OTS) from Cambridge Cognition (CANTAB)
timeFrame: Baseline, week 4 (end of treatment) and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Emotion Recognition Task (ERT) from Cambridge Cognition (CANTAB)
timeFrame: Baseline, week 4 (end of treatment) and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Wisconsin Card Sorting Task (WCST)
timeFrame: Baseline, week 4 (end of treatment) and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Cognition Assessement in Virtual Reality (CAVIR) test
timeFrame: Baseline and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: The Assessment of Quality of Life (AQoL)
timeFrame: Baseline, week 4 (end of treatment), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: World Health Organization Quality of Life (WHOQoL-BREF)
timeFrame: Baseline, week 4 (end of treatment), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA)
timeFrame: Baseline, week 4 (end of treatment), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Work and Social Adjustment Scale (WSAS)
timeFrame: Baseline, week 4 (end of treatment), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Sheehan Disability Scale (SDS)
timeFrame: Baseline, week 4 (end of treatment), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: Pittsburgh Sleep Quality Index (PSQI)
timeFrame: Baseline, week 4 (end of treatment), and week 8 (+end of treatment follow-up for patients in treatment as usual group)
measure: ONLY IN PATIENTS (SUBSTUDY 2): Functional Assessment Short Test (FAST)
timeFrame: Baseline and week 8
Locations:
city: Copenhagen
country: Denmark
facility: Neurocognition and Emotion in Affective Disorders (NEAD) Centre, University of Copenhagen and Psychiatric Centre Copenhagen, Frederiksberg hospital
state: Capital Region Of Copenhagen
Study officials:
affiliation: Mental Health Services in the Capital Region, Denmark
name: Kamilla W Miskowiak, DMSc, DPhil
role: PRINCIPAL_INVESTIGATOR
References: