Effects of Sleep Deprivation and Adrenergic Inhibition on Glymphatic Flow in Humans

NCT ID: NCT03576664

Last Updated: 2022-11-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-08-28
• Study Completion Date: 2019-10-01

Brief Summary

The project is aimed at identifying how the adrenergic antagonist 'carvedilol' modulates the effects of sleep deprivation in healthy volunteers. The study is a double-blind, randomized, placebo-controlled, cross-over study. Investigators will include 20 healthy volunteers who will undergo three functional magnetic resonance (fMRI) imaging sessions, one at baseline, and two after sleep deprivation (one night without sleep). The two sleep-deprivation scans are performed in a randomized order where subjects receive placebo or carvedilol, in a within-subject, cross-over study design.

The following domains will be described: 1) fMRI imaging of cerebrospinal fluid (CSF) pulsations (glymphatic flow) in the human brain, performed by a combination of fMRI protocols that includes structural (T1, T2, diffusion weighted) and functional (multiband/fast imaging, spectroscopy) imaging. 2) fMRI imaging during wakefulness and sleep are determined by simultaneous electroencephalographic (EEG) recordings. 3) The effects of sleep deprivation on the fMRI derived glymphatic flow signal. 4) The effects of the adrenergic antagonist carvedilol on fMRI measurements and sleep intensity. 5) Quantification of cognitive performance before and after a nap in the MRI. Cognitive testing includes: assessments of visual attention, reaction time, paired-associative memory, working memory, emotional recognition and subjective ratings of sleepiness and mood.

Detailed Description

Aims and background:

Sleep is a universal biological process. Lack of, or insufficient sleep, has been associated with a range of diseases including obesity, cardiovascular disease, reduced cognition, impaired learning, and increased risk of motor vehicle accidents. Sleep is also associated with neuromolecular alterations in the brain, including reduced firing of arousal maintaining epinephrine and norepinephrine neurons.

A novel molecular function of sleep known as the glymphatic system has recently been described in rodents. This system is specifically activated during non-rapid eye movement (NREM) sleep, and glymphatic flow appear strongly enhanced during sleep when compared to wakefulness. Moreover, it has been shown that adrenergic antagonists enhance glymphatic clearance and flow in rodents. This study aims at applying newly developed functional magnetic resonance imaging (fMRI) protocols to investigate the extent of the glymphatic system non-invasively in humans.

In order for us to quantify the change in glymphatic clearance between sleep and wakefulness, it is necessary to measure the glymphatic process in both vigilance states, requiring that volunteers nap in the MRI scanner. Moreover, to clarify causal relationships, this study will challenge the glymphatic system via adrenergic inhibition. To do so, the investigators will administer the adrenergic antagonist Carvedilol, which can cross the blood-brain barrier. The drug will be perorally administered before a nap in the MRI, in a double blind, placebo controlled manner. To assess sleep quality and function, cognitive testing will be performed before and after the nap in the MRI scanner. Moreover, to distinguish sleep and wakefulness, electroencephalographic (EEG) recordings will be performed during magnetic resonance (MR)-imaging. Because sleep is a strong homeostatic regulated process, sleep quality, duration and timing will be controlled by EEG monitoring, immediately prior to and during the study to ensure that data is intra- and inter-individually comparable.

Hypotheses:

Investigators hypothesis that the fMRI data collected awake and during a nap will be altered by the adrenergic treatment. Specifically, investigator propose the following hypotheses: 1. Sleep promotes cerebrospinal fluid pulsations (glymphatic flow) in the human brain, as measured with fMRI. 2. Challenging the sleep-homeostat by sleep deprivation promotes the fMRI glymphatic flow signal further. 3. The rate of glymphatic flow is expected to be proportional to simultaneously measured non-rapid eye movement EEG slow wave activity. 4: The adrenergic antagonist carvedilol will enhance glymphatic clearance and sleep intensity. 5. The fMRI determined glymphatic flow is associated with improved cognitive performance following sleep. 6. Enhanced glymphatic flow is correlated with enhanced cognitive performance, including: assessments of visual attention, reaction time, paired-associative memory, working memory, emotional recognition and subjective ratings of sleepiness and mood.

Conditions

Sleep Deprivation; Sleep Wake Disorders; Sleep

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: DOUBLE

Study Groups

Carvedilol first

Carvedilol (25 mg) followed by Placebo oral capsule is administered in a crossover manner.

Group Type: EXPERIMENTAL

Carvedilol 25mg

Intervention Type: DRUG

Cross-over, randomized, placebo-controlled study.

Placebo oral capsule

Intervention Type: DRUG

Cross-over, randomized, placebo-controlled study.

Placebo first

Placebo oral capsule followed by Carvedilol (25 mg) is administered in a crossover manner.

Group Type: EXPERIMENTAL

Carvedilol 25mg

Intervention Type: DRUG

Cross-over, randomized, placebo-controlled study.

Placebo oral capsule

Intervention Type: DRUG

Cross-over, randomized, placebo-controlled study.

Interventions

Carvedilol 25mg

Cross-over, randomized, placebo-controlled study.

Intervention Type: DRUG

Placebo oral capsule

Cross-over, randomized, placebo-controlled study.

Intervention Type: DRUG

Other Intervention Names

Coreg

Eligibility Criteria

Inclusion Criteria

• Healthy volunteer (male or female) between 18 and 35 years.
• Good sleeper with sleep efficiency above 80%.

Exclusion Criteria

• Current or former primary psychiatric disorder in volunteer of first degree relatives (DSM IV Axis I or WHO ICD-10 diagnostic classification).
• Current or previous neurological disease, severe somatic disease, or the consumption of drugs likely to influence the test results.
• Claustrophobia or fear of being in an MR-scanner.
• Alcohol or drug abuse.
• Regular smoking or nicotine addiction
• Extreme morning or evening type, or extreme short or long sleeper.
• Disordered sleep, regular shift-work or extreme tiredness (e.g. Epworth Sleepiness Scale (ESS) > 10).
• Crossing of multiple time zones within the last 6 months.
• Extreme use of stimulants such as caffeine.
• Not adhering to the prescribed sleep-wake schedule before study initiation.
• Left handedness.
• Obesity (BMI > 27.5).
• Non-fluent in Danish or pronounced visual or auditory impairments.
• Current or past learning disability.
• Large head size (>59 cm in circumference).
• Pregnancy
• Contraindications for MRI (pacemaker, metal implants, etc.).
• Allergy to the ingredients in the administered drug.
• Abnormal ECG (e.g. prolonged QT syndrome, etc.)
• Dizzy when changing from supine to upright position (e.g. postural orthostatic tachycardia syndrome).
• Mild hypotension (blood pressure below 100/70 mmHg)
• Hypertension (blood pressure above 140/90 mmHg).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 35 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Center for translational Neuromedicine, University of Copenhagen, Denmark

UNKNOWN

Sponsor Role: collaborator

Danish Center for Sleep Medicine

OTHER

Sponsor Role: collaborator

Gitte Moos Knudsen

OTHER

Sponsor Role: lead

Responsible Party

Gitte Moos Knudsen

Center director of Center for Integrated Molecular Brain Imaging

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Sebastian C Sebastian, PhD

Role: PRINCIPAL_INVESTIGATOR

Neurobiology Research Unit, Rigshospitalet

Locations

Neurobiology Research Unit, Rigshospitalet

Copenhagen, , Denmark

Countries

Denmark

Other Identifiers

H-16045933

Identifier Type: OTHER

Identifier Source: secondary_id

sleepgf

Identifier Type: -

Identifier Source: org_study_id