Effects of Sleep Deprivation and Adrenergic Inhibition on Glymphatic Flow in Humans
Condition: Sleep Deprivation; Sleep Wake Disorders; Sleep
MeSH terms: Sleep Deprivation; Sleep Wake Disorders
Study type: Interventional
Phase: Early Phase 1

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.
    

Intervention name(s): Carvedilol 25mg; Placebo oral capsule
Intervention type(s): Drug; Drug
Intervention description(s): Cross-over, randomized, placebo-controlled study.; Cross-over, randomized, placebo-controlled study.
Other intervention name(s): Coreg
Intervention MeSH terms: Carvedilol
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: Randomized, cross-over, placebo-controlled study
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: carvedilol; adrenergic antagonists; glymphatic system; volunteers; Molecular Mechanisms of Pharmacological