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

NCT03576664 | Completed Early Phase 1

• 2 other identifiers: sleepgfH-16045933
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 1

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.

Conditions

Sleep Deprivation; Sleep Wake Disorders; Sleep

Keywords

carvedilol; adrenergic antagonists; glymphatic system; volunteers; Molecular Mechanisms of Pharmacological

Outcome Measures

Primary Outcomes (10)

• Measure the change in functional Magnetic Resonance Imaging (fMRI)-detected glymphatic flow in wakefulness and sleep at baseline

  Baseline compared to baseline - within same 1 day

• Measure and compare functional Magnetic Resonance Imaging (fMRI)-detected glymphatic flow in baseline sleep and in sleep-deprived sleep

  Baseline to follow-up 5±3 days

• Measure and compare fMRI-detected glymphatic flow in placebo and carvedilol condition

  Placebo compared to treatment 5±3 days apart.

• Correlate fMRI-detected glymphatic flow with simultaneous detected EEG sleep slow wave activity

  Nocturnal sleep compared to sleep during Magnetic Resonance scans within same 1 day.

• Measure EEG slow wave activity during Magnetic Resonance imaging and compare Carvedilol with placebo to see how sleep is affected by the treatment

  Placebo compared to treatment 5±3 days apart.

• Measure if fMRI-detected glymphatic flow correlates with subjective sleepiness ratings

  Measurements collected within the same 1 day

• Measure fMRI-detected glymphatic flow and whether it correlates with cognitive performance before and after MR imaging

  Measurements collected within the same 1 day

• Measure fMRI-detected glymphatic flow and whether correlates with changes in cognitive performance from before to after MR imaging

  Measurements collected within the same 1 day

• Measure whether Carvedilol improves sleepiness after the MR scan compared to placebo

  Measurements collected within the same 1 day

• Measure whether Carvedilol improves cognitive performance (measurement: psychomotor vigilance test) after the MR scan compared to placebo

  Measurements collected within the same 1 day

Secondary Outcomes (9)

• Measure whether fMRI-detected glymphatic flow is spatially correlated with simultaneous EEG NREM slow wave activity

  Measurements collected within the same 1 day

• Measure whether fMRI-detected glymphatic flow correlates with simultaneous NREM EEG activity

  Measurements collected within the same 1 day

• Measure whether fMRI-detected glymphatic flow is positively correlated with sleep driven structural changes in T2 and diffusion weighted (DWI) images

  Measurements collected within the same 1 day

• Measure whether Carvedilol modulates nocturnal recovery sleep (measurement: EEG slow wave activity) after sleep deprivation

  Baseline to follow-up 5±3 days

• Measure whether the psychomotor vigilance test is modulated by carvedilol

  Placebo compared to treatment 5±3 days apart.

Study Arms (2)

Carvedilol first

EXPERIMENTAL

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

Drug: Carvedilol 25mg; Drug: Placebo oral capsule

Placebo first

EXPERIMENTAL

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

Drug: Carvedilol 25mg; Drug: Placebo oral capsule

Interventions

Carvedilol 25mg DRUG

Cross-over, randomized, placebo-controlled study.

Also known as: Coreg

Carvedilol first; Placebo first

Placebo oral capsule DRUG

Cross-over, randomized, placebo-controlled study.

Carvedilol first; Placebo first

Eligibility Criteria

• Age: 18 Years - 35 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

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

You may not qualify if:

• 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).

Sponsors & Collaborators

• Gitte Moos Knudsen: lead
• University of Copenhagen: collaborator
• Danish Center for Sleep Medicine: collaborator

Study Sites (1)

Neurobiology Research Unit, Rigshospitalet

Copenhagen, 2100, Denmark

Location

MeSH Terms

Conditions

Sleep Deprivation; Sleep Wake Disorders

Interventions

Carvedilol

Condition Hierarchy (Ancestors)

Dyssomnias; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Mental Disorders

Intervention Hierarchy (Ancestors)

Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 3-Ring

Study Officials

• Sebastian C Sebastian, PhD

  Neurobiology Research Unit, Rigshospitalet

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Center director of Center for Integrated Molecular Brain Imaging

Model Details: Randomized, cross-over, placebo-controlled study

Study Record Dates

• First Submitted: March 8, 2018
• First Posted: July 3, 2018
• Study Start: August 28, 2018
• Primary Completion: September 1, 2019
• Study Completion: October 1, 2019
• Last Updated: November 23, 2022

Record last verified: 2022-11

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: Data will be made available upon data-analyses completion, about year: 2020.
• Access Criteria: Data can be accessed via website or by contacting the NRU lab. Mainly research teams in Europe are granted access.

Locations

DK (1)