How will your competent? doctor use this to help your memory and glymphatic clearance post stroke? Oh sorry, DOING NOTHING LIKE ALL RESEARCH IS TREATED?
A Common Smartphone Metric May Be Brain Health’s Next Frontier
Memory researcher Sara Mednick, PhD, had been chasing a mysterious signal for years when she came across a paper that changed everything.
As a cognitive scientist at the University of California, Irvine, Mednick had been studying how the brain creates memories during sleep. Her research kept pointing to the autonomic nervous system: In 2016, she reported that autonomic activity — as measured by heart rate variability (HRV), the variation in time between heartbeats — enhances brain plasticity during REM sleep, improving memory consolidation. Her 2019 study showed that autonomic and central nervous system activity together benefit memory.
“I kept saying, there’s this autonomic signal that’s really, really important, and I don’t know what it is,” Mednick said.
Things started to click when she found a 2022 study revealing a pattern in the brains of sleeping mice. Every 50 seconds, the locus coeruleus — a small nucleus in the pons of the brainstem — generated an infraslow oscillation of norepinephrine, the key neurotransmitter of the locus coeruleus. A drop in norepinephrine followed, creating spindles (bursts of brain wave activity). The rhythm determined effective memory consolidation.
- Very low-frequency HRV may index locus coeruleus norepinephrine activity during sleep.
- HRV correlated with sleep spindle timing and memory consolidation in humans and mice.
- Non-REM norepinephrine oscillation frequency predicted glymphatic clearance in mice.
- Sleep disruption, aging, stress, depression, CV disease may impair glymphatic waste removal.
- Smartphone/smartwatch HRV could become a noninvasive biomarker for neurodegeneration risk.
Mednick realized, “Oh, it’s the locus coeruleus. That’s what this signal that I’ve been measuring is.”
One of the study authors was Maiken Nedergaard, MD, DMSc, a neuroscientist at the University of Rochester Medicine in Rochester, New York, who in 2012 discovered the glymphatic system, the brain mechanism that clears away waste while we sleep. Nedergaard and her colleagues had put biosensors in the rodents’ prefrontal cortex, allowing them to measure norepinephrine. “If you couldn’t measure norepinephrine activity, it just looked like the locus coeruleus was kind of dead” during sleep, Mednick said. This study showed that it’s not.
In 2025, the same researchers discovered a new insight: The frequency of norepinephrine oscillation during non-REM sleep predicted glymphatic clearance in mice. “You could see that the amount of waste clearance correlated to this infraslow rhythm,” said co-author Celia Kjaerby, PhD, an associate professor of neuroscience at the University of Copenhagen in Copenhagen, Denmark.
Since then, Kjaerby, Nedergaard, and Mednick have teamed up on new research — a reviewed preprint published in eLife in March — connecting HRV to glymphatic clearance. The finding suggests HRV could be used to measure how well the glymphatic system is working.
That would be a “massive breakthrough,” Mednick said. Such an accessible biomarker (standard on smartwatches and smartphones) could help identify patients at risk for neurodegenerative disease and give researchers a powerful tool to test treatments aimed at repairing a broken glymphatic system and slowing cognitive decline.
Making the Connection
Of course, none of this was on Mednick’s radar as she immersed herself in that paper in 2022. Determined to collaborate with the neuroscientists, she packed her bags for a 6-month sabbatical in Copenhagen. It was clear to her that they were all working on the same thing: “Me in my human models, and Celia Kjaerby and Maiken Nedergaard in their rodent models,” she said.
She and Kjaerby, who was starting her own research group within Nedergaard’s international lab, gradually learned the ins and outs of each other’s work.
“None of this was really related to [HRV] until I came,” Mednick said. “They had heart rate in their signals, but nobody was measuring it.”
In her lab, Mednick had been recording a very slow frequency heart rhythm in humans that changed whenever memory-consolidating “big infraslow spindles” appeared on their EEGs. It looked like an exact match to the rodent rhythm.
“We were sort of like, no way. This fits perfectly together,” Kjaerby said. “What you’re seeing must be what we are seeing.”
When Mednick applied her HRV algorithms to Kjaerby and Nedergaard’s rodent data, the connection was undeniable: The tiny fluctuations occurring every 50 seconds corresponded exactly to the rodents’ locus coeruleus and norepinephrine activity and predicted the same sleep spindles she’d seen in humans.
Why HRV Reflects Glymphatic Clearance
While you sleep, cerebrospinal fluid is being pumped through perivascular channels in your brain, flushing out metabolic waste. The process accelerates the longer you slumber and slows as you wake up.
When sleep is disrupted or the system falters, it increases the risk for neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia. Stress, depression, cardiovascular disease, and aging can all disrupt sleep — potentially interrupting the process and raising risk for cognitive decline, as noted in a May review conducted by Nedergaard and published in Science.
The vascular movement helping to pump out waste is closely tied to heart rate fluctuations, explaining why HRV may provide a window into the process.
“It’s a very important observation, that it’s locus coeruleus and norepinephrine that drives [HRV],” Nedergaard said. “We know that locus coeruleus and norepinephrine is a major driver, or basically pump, of the glymphatic system.”
Measuring glymphatic flow has previously been invasive and expensive, requiring a lumbar drain and contrast MRI scans. Noninvasive glymphatic imaging platforms have seen “an explosion of studies” in recent years, Nedergaard said, but these still require specialized equipment.
HRV is already tracked on most smartwatches. If the right algorithm applied to a smartwatch could pick up the very low frequency HRV range, it could potentially provide consumers with a measure of glymphatic clearance — right from their smartphones, Mednick said.
Limitations and What’s Next
The research leaves open questions about the relationship between HRV and the autonomic nervous system.
“Our study has just done a rough correlation between the heart rate and the arousal system,” Kjaerby said. “It seems there is a link — and we have not fully characterized the link.”
Previous research suggests a strong link between the locus coeruleus and parasympathetic nervous system activity, which could explain why the heart slows when the locus coeruleus is suppressed. Or locus coeruleus activity could be coupled to the sympathetic nervous system, leading to heart rate acceleration with locus coeruleus arousal. But “these are speculations based on our paper,” Kjaerby said.
The next step is developing a robust HRV biomarker to noninvasively measure what the brainstem is doing, Mednick said. Meanwhile, all those emerging glymphatic imaging platforms could provide more evidence. “What I’m most excited about is to use it as a way to see whether treatment actually improves glymphatic function,” Nedergaard said.
For example, reduced HRV in the very low frequency range could hint at memory consolidation problems. But Kjaerby wonders if vagus nerve stimulation could restore an optimal rhythm — and an HRV measure could reveal how well that manipulation works.
For Mednick, knowing that the locus coeruleus drives HRV represents a starting point for a much deeper dive. “Every single thing that our body and minds need requires some amount of recruitment from the heart,” she said. “If we did a really good analysis of the HRV, I think we could find a lot more information.”
Nedergaard reported serving as a consultant for CNS2 Inc. for unrelated work. Kjaerby and Mednick reported having no relevant disclosures.
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