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Slow Waves of CSF During Sleep Clear Toxins Linked to Neurodegenerative Conditions

Article In Brief

A new study shows for the first time that during non-REM sleep, neural activity coupled with changes in blood volume enables cerebrospinal fluid to flow in slow waves. These slow waves not only play a role in memory consolidation, but also could alter the physiological and fluid dynamics of the brain.


During sleep, waves of fluid surge into the brain and can be visualized with functional MRI. At an earlier timepoint (left), a wave of blood (red) is followed (right) by a pulse of cerebrospinal fluid (blue) into the fourth ventricle.

What role does sleep play in human brain health and cognition? A new study used accelerated neuroimaging of healthy adults to gain some insights and clues to better understand that dynamic.

The researchers observed that during non-rapid eye movement (REM) sleep, neural activity coupled with changes in blood volume, enables cerebrospinal fluid (CSF) to flow in slow waves; this process, they believe, may help clear toxins from the brain that have been linked to neurodegenerative disease, including Alzheimer's disease (AD).

The paper, published online November 1 in Science, shows for the first time that these slow waves not only play a role in memory consolidation, but also could alter the physiological and fluid dynamics of the brain.

“These brain fluid dynamics give us new insights into the biological mechanisms of CSF flow in healthy sleep and address a key missing link in the neurophysiology of sleep,” lead investigator Laura Lewis, PhD, assistant professor of biomedical engineering at Boston University, told Neurology Today.

The observations not only offer important insights into the physiological underpinnings of sleep, independent experts told Neurology Today; they underscore the importance of focusing on enhancing overall sleep quality and deep sleep, especially in patients who are older and have sleep or medical disorders.

Study Design, Findings

In the current study, the researchers focused on non-REM sleep because they knew from previous studies that it was associated with clearance of waste products and major changes in blood flow and neural activity.

Dr. Lewis and a team of researchers at A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital recruited 13 young healthy adults in 2017 to participate in the functional brain imaging study.

Most (11) were female with a median age of 28 years old. Volunteers were excluded if they had sleep disorders, smoked, consumed more than 300 mg caffeine daily, or were pregnant.

While the participants slept for about two hours, the researchers simultaneously measured intrinsic changes in blood oxygenation with BOLD fMRI, neural activity with EEG, and CSF flow detected with fast fMRI.

They first investigated whether non-REM sleep was associated with distinct CSF flow dynamics and observed a large wave in the CSF signal at 0.05 Hz. In contrast, wakefulness studies showed that the CSF signal exhibited a small-wave when participants breathed at approximately 0.25 Hz. They also found a significant (5.52-dB) increase in the CSF signal peaking at 0.05 Hz during sleep, suggesting that large waves of CSF inflow occur approximately every 20 seconds.

Dr. Lewis and her team then looked at whether these large slow CSF waves were linked to the blood flow signals. “We consistently found that when the blood oxygenation signal decreased, CSF flow increased,” said Dr. Lewis.

The researchers suggested that alternating blood flow with CSF flow would be consistent with a decrease in cerebral blood volume that allowed more CSF to flow into the brain.

They next examined whether slow neural activity was linked to the coupled blood flow and CSF waves during sleep. “Although electrophysiological slow waves are known to play important roles in cognition, our results suggest that they may also be linked to the physiologically restorative effects of sleep, as slow neural activity is followed by brain-wide pulsations in blood volume and CSF flow,” Dr. Lewis and her colleagues stated.

The main limitation was that the researchers didn't establish causation between what they measured and the outcomes. “Also, participants' sleep was somewhat disrupted by having to be in an MRI machine for testing rather than in bed,” said Dr. Lewis.

The researchers have started looking at whether the findings can be replicated in an older population with cognitive decline and whether CSF flow is associated with clearing waste products, which they didn't measure directly in their study.

Expert Commentary

“This study provides one more piece of evidence that sleep, particularly slow-wave sleep, is an important physiological process for the removal of toxic byproducts that accumulate in the brain and can lead to unhealthy neurons,” said Phyllis C. Zee, MD, PhD, professor of neurology and director of The Center for Sleep and Circadian Medicine at Northwestern University, who was not involved in the study.

Previous laboratory studies in humans have shown that when people were deprived of slow-wave sleep, they accumulated more amyloid-beta (Abeta) in their CSF. Also, larger population-based studies have found that fragmented sleep, which occurs more often as people age, may be an early biomarker for developing AD.

“Taken together, the data show that sleep is important for regulating the removal of amyloid- beta and tau, which are implicated in the pathology of Alzheimer's disease,” said Dr. Zee.

In addition, the slow waves in deep sleep may have other functions such as increased synaptic plasticity which may lead to improvements in learning and memory, Dr. Zee noted.

Dr. Zee said the findings suggest that clinicians should keep “looking at ways to enhance overall sleep quality and deep sleep, especially in patients who are older and have sleep or medical disorders.”

To make the findings more generalizable, they need to be validated in other age, gender, and clinical populations, said Dr. Zee. “Once that occurs, they could lead to developing technology that we could use clinically as an early biomarker for neurodegeneration.”

The findings show humans have a glymphatic system that is switched on during non-REM sleep, which has only been shown in mice before, said Maiken Nedergaard MD, DMSc, professor of neuroscience at the University of Rochester Medical Center.

“The analysis provides a mechanism for why non-REM increases glymphatic function [the waste-clearing system of the brain]. This is the first study that links changes in BOLD signal induced by neuronal activity to CSF transport. That is exciting because now we can start to understand that blood volume changes are mirrored by changes in CSF volume,” said Dr. Nedergaard.

She explained that within the brain's closed cavity, only the two fluid compartments—blood and CSF—are interchangeable.

Previous research also supports that the brain's cleaning process only occurs when people sleep. A laboratory study showed that people who had just slept had a low level of Abeta compared with people who had been awake for many hours.

However, other research looking at the role of aging in glymphatic clearance suggests that less CSF flow is produced in older people, which can result in less clearance of toxins from the brain.

“Emerging evidence from many groups suggest that glymphatic clearance and its decline in aging play a significant and perhaps key role in neurodegenerative diseases,” said Dr. Nedergaard.

Targeting brain CSF transport could be another way of looking at AD, given the recent failure of pharmaceutical trials that administered antibodies directed against Abeta, suggested Dr. Nedergaard.

For example, “measurements such as those introduced in the study might be used as an imaging platform to identify people at risk of Alzheimer's before their cognitive function is impaired. If we could treat these patients at an earlier stage, or before the irreversible loss of neurons, many new opportunities may arise,” said Dr. Nedergaard.


Drs. Lewis, Zee, and Nedergaard declared no competing interests.

Link Up for More Information

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