Popular sleeping pill shown to block brain's critical cleaning cycle

Each night, our brains execute a "wash and rinse" routine that clears away harmful protein waste linked to neurodegenerative diseases like Alzheimer's. Now, new research shows that a common prescription sleep aid can disrupt this essential process.

In 2012, neuroscientist Maiken Nedergaard from the University of Rochester Medical Center (URMC) described a unique system used by the brain to rid itself of waste. Termed the "glymphatic system," it acts like a series of pipes surrounding the blood vessels in the brain through which cerebrospinal fluid (CSF) moves. As the CSF flows through these channels it picks up and carries waste away.
Since its discovery just over a decade ago, the glymphatic system has been linked to the development of Parkinson's disease and shown to be important in clearing away toxic proteins during sleep, potentially warding off the development of Alzheimer's disease. In fact, a study in 2021 showed how the glymphatic system could be activated by ultrasound in Alzheimer's patients to potentially clear away amyloid and tau, two types of protein waste associated with the disease.

Now, Nedergaard has carried out another study at URMC to investigate how the glymphatic system is powered, and how the common sleep aid Ambien (zolpidem) might affect the process.

“As the brain transitions from wakefulness to sleep, processing of external information diminishes while processes such as glymphatic removal of waste products are activated,” said Nedergaard. “The motivation for this research was to better understand what drives glymphatic flow during sleep, and the insights from this study have broad implications for understanding the components of restorative sleep.”

Coming through in waves

Working with mice, Nedergaard and her team used an optical imaging technique combined with EEG and EMG monitors to monitor the rodents as they moved freely and went through their normal phases of sleep and wakefulness.

They found that during a phase of sleep when the brain is relatively calm, known as non-REM sleep, the neurotransmitter norepinephrine was released in slow waves. These waves caused what the researchers have termed "micro-arousals," which in turn caused the rhythmic constriction of blood vessels independent of the heart's beating. These constrictions are what pumped the CSF through the glymphatic system, essentially powering its waste-draining process.

“These findings, combined with what we know about the glymphatic system, paint the whole picture of the dynamics inside the brain, and these slow waves, micro-arousals, and the norepinephrine were the missing link,” said Natalie Hauglund, first author of the study and currently a postdoctoral fellow at the University of Oxford.

The Ambien effect

Next the study authors decided to look at how the popular sleep aid Ambien, or zolpidem, affects the brain's cleaning process. After administering it to the mice, they found that it blocked the waves of norepinephrine that are normally released, which disrupted the glymphatic system and kept it from carrying out its waste-removal task. This could mean that the drug could prevent toxic waste proteins like tau and amyloid from being cleared away, which could cause them to build up – a hallmark of neurodegenerative diseases like Alzheimer's.

“The research provides a mechanistic link between norepinephrine dynamics, vascular activity, and glymphatic clearance, advancing understanding of sleep’s restorative functions,” said Nedergaard. “It also calls attention to the potentially detrimental effects of certain pharmacological sleep aids on brain health, highlighting the necessity of preserving natural sleep architecture for optimal brain function.”

New Atlas