Published in clinical research journal, the study found that an intervention designed to strengthen circadian rhythms improved recovery in mice after a stroke. The improvements were accompanied by increased activity in the glymphatic system—the brain’s waste-removal network—and lower levels of inflammatory molecules that can persist after stroke.

How the Brain’s Glymphatic System Removes Waste

The findings build on more than a decade of research led by University of Rochester neuroscientist Maiken Nedergaard, MD, DMSc. Her laboratory discovered the glymphatic system in 2012.

The glymphatic system moves cerebrospinal fluid through brain tissue, helping remove waste products and other debris. Later research showed that glymphatic activity is particularly strong during sleep and plays an important role in maintaining brain health.

Neuroscientist Dr. Lauren Hublitz later helped demonstrate that glymphatic activity is influenced not only by sleep but also by circadian rhythms, the body’s 24-hour internal clock. In a 2020 study, Hublitz, Nedergaard and their colleagues found that glymphatic function follows daily cycles even when sleep is not involved. The findings established a direct link between circadian biology and the brain’s waste-removal system.

How Stroke Can Disrupt the Body Clock

“The discussion about recovery from stroke actually starts with the idea that stroke is not just a vascular event, but also a timing disorder,” said Hublitz, lead author of the new study.

Scientists have long known that strokes follow a time-of-day pattern. They often occur in the morning and can be more severe near the end of a person’s sleep period.

After a stroke, many patients develop disrupted sleep-wake cycles. These disorders are associated with poorer recovery, depression and a reduced quality of life.

“So we started asking simple questions,” Hublitz said. “If timing is disrupted after a stroke, can strengthening the body clock improve recovery?”

When the Brain’s Waste-Removal System Slows Down

In a healthy brain, the glymphatic system transports cerebrospinal fluid through brain tissue along blood vessels. This process delivers nutrients while helping remove waste products and inflammatory signals.

Previous studies have shown that glymphatic function is impaired after stroke. This disruption may reduce the brain’s ability to remove harmful molecules that accumulate during recovery.

Stroke research has traditionally focused on distinguishing beneficial inflammation from harmful inflammation and finding ways to suppress damaging inflammatory responses. Hublitz and her colleagues suggest that another part of the problem may be the brain’s reduced ability to filter out inflammatory signals.

“We think part of the problem may be a cleaning failure,” she said. “If the systems responsible for removing signaling molecules aren’t working properly, everything builds up.”

According to this model, a stroke damages both brain tissue and the pathways involved in clearing inflammatory signals. As these molecules accumulate, they may cause continued damage and slow recovery.

Can Strengthening Circadian Rhythms Improve Stroke Recovery?

To test whether stronger circadian rhythms could improve recovery, researchers examined several interventions known to influence the body’s internal clock. These included time-restricted light exposure, melatonin, a clock-targeting drug called KL001 and time-restricted breastfeeding.

The research team showed for the first time that each intervention could improve glymphatic function in healthy animals. Researchers then selected the most promising strategies—KL001 and time-restricted feeding—and tested them in a mouse model of stroke.

Treatment did not begin until three days after the stroke, well beyond the narrow treatment window for clot-busting drugs and other acute stroke interventions.

Despite the delay, mice that received either intervention showed better motor recovery, smaller lesion volumes, improved glymphatic flow and lower levels of inflammatory cytokines in the brain.

“All the cytokines moved in the same direction,” Hublitz said. “This suggests that we may not be targeting specific inflammatory pathways; instead, we may be helping the brain clear inflammatory signals more effectively.”

Why Time-Restricted Feeding Could Be a Convenient Approach

One of the most promising approaches was time-restricted feeding, a behavioral intervention already being studied for obesity, diabetes, cardiovascular disease and other conditions.

The findings may be particularly relevant to stroke rehabilitation because approaches that influence circadian rhythms could eventually be accessible outside specialized medical settings.

“One of the interesting things about this study is that we’re looking at an intervention that could potentially be implemented at home as well as in the hospital,” Hublitz said.

What Researchers Need to Study Next

The researchers emphasize that the findings are currently limited to animal models. Further research is needed to determine precisely how circadian rhythms, glymphatic function and inflammation interact after a stroke.

Future studies will also examine whether directly improving glymphatic flow leads to better recovery and whether circadian rhythm-based interventions could eventually be tested in clinical trials.

More broadly, the study reflects a growing view in neuroscience that sleep, circadian rhythms and the movement of fluids in the brain are central to brain health.

By learning more about how the brain’s internal clock regulates the glymphatic system, researchers hope to identify new ways to improve recovery not only after stroke but also in other neurological conditions involving inflammation and impaired waste removal.

“Understanding how circadian regulation shapes glymphatic clearance will help develop more targeted treatments,” Hublitz said. “Ultimately, our goal is to find ways to remove waste products, reduce inflammation and improve the brain’s ability to recover from injury.”