During tranquil sleep the brain continues to demonstrate bustling activity, and brain cells produce bursts of electrical pulses that cumulate into rhythmic waves—a sign of heightened brain cell function. But the question remains why is the brain active when we are resting? Slow brain waves are associated with restful, refreshing sleep, and a study in mice, by scientists at the Washington University School of Medicine in St. Louis, has now found that brain waves help flush waste out of the brain during sleep. The results indicated that individual nerve cells coordinate to produce rhythmic waves that propel fluid through dense brain tissue, washing the tissue in the process.

The findings, the researchers suggested, could point to potential future therapeutics or preventive strategies against some neurological disorders. “These neurons are miniature pumps,” said Li-Feng Jiang-Xie, PhD, a postdoctoral research associate in the department of pathology & immunology. “Synchronized neural activity powers fluid flow and removal of debris from the brain. If we can build on this process, there is the possibility of delaying or even preventing neurological diseases, including Alzheimer’s and Parkinson’s disease, in which excess waste—such as metabolic waste and junk proteins—accumulate in the brain and lead to neurodegeneration.”

Jiang-Xie is lead author of the team’s published paper in Nature, titled “Neuronal dynamics direct cerebrospinal fluid perfusion and brain clearance,” in which they concluded, “Our study demonstrates that neurons serve as master organizers for brain clearance. This fundamental principle introduces a new theoretical framework for the functioning of macroscopic brain waves.”

Brain cells orchestrate thoughts, feelings and body movements, and form dynamic networks essential for memory formation and problem-solving. But to perform such energy-demanding tasks, brain cells require fuel. Their consumption of nutrients from the diet creates metabolic waste in the process.

Senior author Jonathan Kipnis, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of pathology & immunology and a BJC investigator, commented, “It is critical that the brain disposes of metabolic waste that can build up and contribute to neurodegenerative diseases.” But as the authors noted, “The accumulation of metabolic waste is a leading cause of numerous neurological disorders, yet we still have only limited knowledge of how the brain performs self-cleansing.”

Cleaning the dense brain is no simple task. Cerebrospinal fluid (CSF) surrounding the brain enters and weaves through intricate cellular webs, collecting toxic waste as it travels. Upon exiting the brain, contaminated fluid must pass through a barrier before spilling into the lymphatic vessels in the dura mater—the outer tissue layer enveloping the brain underneath the skull. But what powers the movement of fluid into, through, and out of the brain? As the authors pointed out, the blood-brain barrier, and evolutionary adaptations that help to protect the brain, also create the problem of how the brain can dispose of its metabolic waste. “Within the brain, billions of neurons form complicated networks for cognitive processing. How the interstitial fluid (ISF) navigates this maze and efficiently removes brain waste is a fundamental question in neuroscience,” they stated. Insights into what the team called the “biological dilemma” have been provided by discovery of the glymphatic system, which is involved in transporting cerebrospinal fluid, but while the team said “substantial knowledge” has been acquired regarding bulk flow in perivascular spaces, “… fluid dynamics within the high-resistance parenchyma (neurons, glial cells and the surrounding interstitial space together account for around 95% of the brain volume in vivo) remain largely a mystery.”

Studying the brains of sleeping mice, the researchers have now found that neurons drive cleaning efforts by firing electrical signals in a coordinated fashion to generate rhythmic waves in the brain, Jiang-Xie said. They determined that such waves propel the fluid movement. The team further explained, “Firing of neurons in a highly desynchronized fashion maximizes the information complexity for diverse cognitive tasks during wakefulness,” the team explained, but this activity produces only small fluctuations in ISF. In contrast, they wrote, during sleep, neural networks synchronize individual action potentials to create large-amplitude, rhythmic and self-perpetuating ionic waves in the interstitial fluid of the brain. “In essence, neurons are the most ideal cell type that coordinate the dynamics of paravascular flow, brain interstitial fluid and the blood–brain barrier to optimize metabolic waste clearance,” they wrote. “… neurons coordinate their actions to generate large-amplitude, rhythmic ionic oscillations in the ISF during sleep (or ketamine anaesthesia). These high-energy ionic waves facilitate the perfusion of fresh CSF through the parenchyma and the removal of metabolic waste products. In essence, neurons that fire together ‘shower’ together.”

The research team silenced specific brain regions so that neurons in those regions didn’t create rhythmic waves. Without these waves, fresh cerebrospinal fluid could not flow through the silenced brain regions and trapped waste couldn’t leave the brain tissue.

“One of the reasons that we sleep is to cleanse the brain,” Kipnis said. “And if we can enhance this cleansing process, perhaps it’s possible to sleep less and remain healthy. Not everyone has the benefit of eight hours of sleep each night, and loss of sleep has an impact on health. Other studies have shown that mice that are genetically wired to sleep less have healthy brains. Could it be because they clean waste from their brains more efficiently? Could we help people living with insomnia by enhancing their brain’s cleaning abilities so they can get by on less sleep?”

Brain wave patterns change throughout sleep cycles. Of note, taller brain waves with larger amplitude move fluid with more force. The researchers are now interested in understanding why neurons fire waves with varying rhythmicity during sleep and which regions of the brain are most vulnerable to waste accumulation.

“We think the brain-cleaning process is similar to washing dishes,” neurobiologist Jiang-Xie explained. “You start, for example, with a large, slow, rhythmic wiping motion to clean soluble wastes splattered across the plate. Then you decrease the range of the motion and increase the speed of these movements to remove particularly sticky food waste on the plate. Despite the varying amplitude and rhythm of your hand movements, the overarching objective remains consistent: to remove different types of waste from dishes. Maybe the brain adjusts its cleaning method depending on the type and amount of waste.”

The authors concluded, “To sustain and automate waste clearance during sleep, we propose that multiple loops of recurrent circuits are designed to generate self-perpetuating oscillations. Together, our findings pinpoint neurons as important drivers of brain clearance and offer a new avenue to investigate how neural circuits are shaped by the demand of self-cleaning throughout the evolution of sleep.”

Kipnis added, “We knew that sleep is a time when the brain initiates a cleaning process to flush out waste and toxins it accumulates during wakefulness. But we didn’t know how that happens. These findings might be able to point us toward strategies and potential therapies to speed up the removal of damaging waste and to remove it before it can lead to dire consequences.”

Previous articleScouring Nature for Better Biopharmaceuticals
Next articleColon Cancer Traced to Cells That Activate Immune-Escape Genes