New research from Boston University suggests that tonight while you sleep, something amazing will happen within your brain. Your neurons will go quiet.
A few seconds later, blood will flow out of your head.
Then, a watery liquid called cerebrospinal fluid (CSF) will flow in, washing through your brain in rhythmic, pulsing waves.
The study, published on October 31 in Science, is the first to illustrate that the brain’s CSF pulses during sleep, and that these motions are closely tied with brain wave activity and blood flow.
“We’ve known for a while that there are these electrical waves of activity in the neurons,” says study coauthor Laura Lewis, a BU College of Engineering assistant professor of biomedical engineering and a Center for Systems Neuroscience faculty member. “But before now, we didn’t realize that there are actually waves in the CSF, too.”
This research may also be the first-ever study to take images of CSF during sleep.
And Lewis hopes that it will one day lead to insights about a variety of neurological and psychological disorders that are frequently associated with disrupted sleep patterns, including autism and Alzheimer’s disease.
The coupling of brain waves with the flow of blood and CSF could provide insights about normal age-related impairments as well.
Earlier studies have suggested that CSF flow and slow-wave activity both help flush toxic, memory-impairing proteins from the brain. As people age, their brains often generate fewer slow waves.
In turn, this could affect the blood flow in the brain and reduce the pulsing of CSF during sleep, leading to a buildup of toxic proteins and a decline in memory abilities. Although researchers have tended to evaluate these processes separately, it now appears that they are very closely linked.
To further explore how aging might affect sleep’s flow of blood and CSF in the brain, Lewis and her team plan to recruit older adults for their next study, as the 13 subjects in the current study were all between the ages of 23 and 33.
Lewis says they also hope to come up with a more sleep-conducive method of imaging CSF. Wearing EEG caps to measure their brain waves, these initial 13 subjects were tasked with dozing off inside an extremely noisy MRI machine, which, as anyone who has had an MRI can imagine, is no easy feat.
“We have so many people who are really excited to participate because they want to get paid to sleep,” Lewis says with a laugh.
“But it turns out that their job is actually–secretly–almost the hardest part of our study. We have all this fancy equipment and complicated technologies, and often a big problem is that people can’t fall asleep because they’re in a really loud metal tube, and it’s just a weird environment.”
But for now, she is glad to have the opportunity to take images of CSF at all. One of the most fascinating yields of this research, Lewis says, is that they can tell if a person is sleeping simply by examining a little bit of CSF on a brain scan.
“It’s such a dramatic effect,” she says.
“[CSF pulsing during sleep] was something we didn’t know happened at all, and now we can just glance at one brain region and immediately have a readout of the brain state someone’s in.”
As their research continues to move forward, Lewis’ team has another puzzle they want to solve: How exactly are our brain waves, blood flow, and CSF coordinating so perfectly with one another? “We do see that the neural change always seems to happen first, and then it’s followed by a flow of blood out of the head, and then a wave of CSF into the head,” says Lewis.
During sleep, the brain exhibits large-scale waves: waves of blood oxygenation (red) are followed by waves of cerebrospinal fluid (blue), as reported in Fultz et al., Science, 2019. The image is credited to Laura Lewis, Boston University.
One explanation may be that when the neurons shut off, they don’t require as much oxygen, so blood leaves the area. As the blood leaves, pressure in the brain drops, and CSF quickly flows in to maintain pressure at a safe level.
“But that’s just one possibility,” Lewis says. “What are the causal links? Is one of these processes causing the others? Or is there some hidden force that is driving all of them?”
Intracranial fluid homeostasis during sleep plays an important role in pathophysiology of neurodegenerative diseases such as Alzheimer’s. However, there is no direct, noninvasive method to easily and continuously measure cerebrospinal fluid (CSF) or cerebral blood flow (CBF) during sleep. Currently the most common non-invasive technique in measuring CBF in clinical practice is Transcranial Doppler sonography (TCD)  which measures CBF velocity .
TCD is not practical for sleep studies because the required equipment physically restricts sleep position. In addition, it requires a highly skilled operator onsite to both conduct the procedure and interpret the results.
In this paper, we describe the design and development of an inexpensive, non-invasive, portable, and wireless Rheoencephalography (REG) system and its use in monitoring CBF changes and fluid dynamics during sleep. REG is an impedance plethysmography technique (–,) that indirectly measures the CBF changes by measuring the component of the transcranial impedance that corresponds to volume oscillations in intracranial arteries elicited by the cardiac cycle.
The direct correlation between impedance and CBF is explained by the classical Nyboer model ( and references therein),  which states that the change in volume of the arterial blood pulse is directly proportional to the accompanying change of electrical impedance . Moreover, at the same temperature and frequency, CSF has higher conductivity than blood .
Therefore, an increase in CBF (which will accompany a decrease in CSF) increases the resistivity and hence the intracranial impedance.
REG technology was first introduced in 1959 , , but its clinical applications remained limited, possibly due to its high sensitivity to movement artifacts or its potential for contamination by extracranial blood flow .
However, recent studies in animals and humans have convincingly demonstrated that the morphology of the REG waveform is sensitive to changes in CBF and stiffness of the cerebral arteries and arterioles –,. Therefore, REG could also be used in monitoring autoregulation of CBF which is very critical in neurointensive care and prevention of stroke.
The experimental and clinical conditions in which REG proved useful include CO2-inhalation, carotid clamping, controlled hemorrhage, and drug-induced vasospasm in animals ; hydrocephalus , trauma, intracranial hemorrhages, and cerebral atherosclerosis (e.g. , –,) in patients.
The contribution of this paper is twofold. First, we used simultaneous REG and EEG recording of healthy volunteers to further establish the utility of REG in monitoring intracranial fluid homeostasis during sleep.
We designed and implemented a REG system and validated it via controlled breathing maneuvers. Second, we conducted a study to measure CBF during sleep in order to better understand overall fluid homeostasis alterations during different stages of sleep.
The significance of this study is in expanding our understanding of the role of sleep in the pathophysiology of neurodegenerative diseases.
II. Related Work
Recent sleep studies have described how cerebrospinal fluid (CSF) circulation during sleep can facilitate the fluid exchange between CSF and interstitial fluid (ISF) for the clearance of waste metabolites  such as -amyloid  and Tau . -amyloid levels fluctuate during wake and sleep with higher levels reported during wake and lower levels during sleep . In addition, it has been shown that sleep disruption can increase overall -amyloid levels . H
owever, in order to better understand these mechanisms it is necessary to measure the dynamics of intracranial fluids during sleep. There is an inverse relationship between changes in CSF and CBF, described by the revised Monroe Kellie hypothesis (i.e. the sum of the volumes of brain tissue, CSF, ISF and intracranial blood remains nearly constant) .
Therefore, any decrease/increase in one component should be compensated by an increase/decrease in another, respectively.
However, the picture is more complex when local blood flows are investigated across different brain regions during Non-REM sleep, with both increases and decreases reported for various brain structures in animals –,.
A substantial increase in ISF volume during slow-wave sleep and a decrease during REM sleep has also been reported in mice.
The increase in ISF volume has been linked to the clearance of waste metabolites from the brain , , which, in turn is relevant to understanding the pathogenesis of Alzheimer’s disease , , . Therefore further studies are needed in order to fully understand the dynamics of intracranial fluids during sleep in humans.
Hilary Katulak – Boston University
The image is credited to Laura Lewis, Boston University.
Original Research: Closed access
“Coupled electrophysiological, hemodynamic, and cerebrospinal fluid oscillations in human sleep”. Laura Lewis et al.