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New research has found that people with narcolepsy type 1 exhibit patterns of slow brain pulsations that resemble those seen in healthy sleep. The findings, published in PNAS, suggest that orexin—a neuropeptide involved in maintaining wakefulness—may play a key role in the brain’s fluid-clearing system, known as the glymphatic system. This study offers insights into how altered brain activity in narcolepsy may influence the transport of waste out of the brain, a process believed to be important for protecting against neurodegeneration.
Narcolepsy type 1, also known as NT1, is a rare neurological disorder characterized by the loss of orexin-producing neurons in the hypothalamus. People with this condition often experience sudden sleep episodes, cataplexy, and fragmented nighttime sleep. While the disorder is typically understood in terms of disrupted arousal and sleep-wake regulation, recent work has begun to explore its broader effects on brain physiology.
One area of interest is the glymphatic system, a clearance pathway that removes metabolic waste from the brain. This system is more active during non-rapid eye movement (NREM) sleep, when the brain enters a state of slow, rhythmic pulsation. These pulsations are thought to drive the flow of cerebrospinal fluid (CSF) through brain tissue, aiding in the removal of waste products such as amyloid beta.
Because orexin influences both arousal and noradrenaline release—two systems that affect these pulsations—the researchers wanted to understand whether people with narcolepsy type 1 exhibit brain pulsation patterns similar to those seen in sleep. They proposed that orexin deficiency might reshape the forces driving glymphatic flow, and that these changes could be measured using advanced brain imaging.
“NT1 is a rare and life-long disease and thus new research shedding insights into the pathology is valuable to these patients,” said study author Matti Järvelä of the University of Oulu. “Our lab is interested in brain pulsations that drive intracranial fluid flow and thus facilitate brain clearance. As NREM sleep, a state where orexinergic activation is low, has been shown to increase efflux of fluid and waste from the brain, NT1 presents a natural human model to study how the lack of orexins/hypocretins may affect the drivers of this efflux.”
The researchers used a fast functional MRI technique called magnetic resonance encephalography (MREG) to measure brain pulsations in three groups: 21 individuals with narcolepsy type 1, 79 healthy people who were awake during scanning, and 13 healthy individuals who were scanned while in NREM sleep. All participants were scanned at the same hospital under standardized conditions, with additional measurements of EEG, heart rate, breathing, and blood pressure.
The research team focused on three types of physiological brain pulsations that are believed to drive CSF flow: slow vasomotor waves (linked to blood vessel tone), pulsations tied to the heartbeat, and pulsations associated with respiration. They examined the strength and complexity of these pulsations using several signal analysis methods, including spectral power, coefficient of variation, and spectral entropy.
To validate that MREG could detect these types of fluid-related brain activity, the team also built a phantom model by pumping water through a pineapple using a peristaltic pump. This allowed them to test how water flow affected the MRI signal, simulating CSF and blood flow in the brain.
The researchers found that people with narcolepsy type 1 exhibited elevated vasomotor brain pulsations—similar to those observed during sleep—even while awake. These pulsations were stronger than those seen in healthy individuals who were awake but comparable to those in the sleeping group. This suggests that the absence of orexin leads to a brain state that resembles sleep in some physiological respects, at least in terms of how blood vessels oscillate.
“My initial thought was that the strength of especially vasomotor pulsations would be somewhere in between the states of healthy wakefulness and sleep,” Järvelä told PsyPost. “It was very interesting to find that this does not seem to be the case and that the lack of orexins may have such a powerful effect on brain pulsations.”
At the same time, the narcolepsy group showed lower cardiac-related pulsations than both the healthy awake and sleeping groups. These heartbeat-driven brain pulsations are thought to be especially important for pushing cerebrospinal fluid into the brain’s tissue. The drop in cardiac pulsations among people with narcolepsy could point to a weakened ability to initiate the clearance of metabolic waste, which typically depends on such rhythmic arterial pressure.
The respiratory-related pulsations were strongest in the sleeping group and weaker in both the narcolepsy and awake groups. This indicates that breathing-induced brain fluid movement is most active during sleep and is not markedly different between narcolepsy and normal wakefulness.
A measure called spectral entropy, which reflects the complexity of brain signals, was also lower in the narcolepsy group than in healthy individuals. Low entropy indicates that the brain signal is more regular and predictable, as is typical during sleep. In fact, the narcolepsy group had even lower entropy in some regions than the healthy sleep group, suggesting an unusual concentration of slow oscillatory activity.
When the researchers analyzed a particular area in the occipital lobe, they found that arterial brain pulsations in this region could reliably distinguish between the three groups. This area partly overlaps with the default mode network, which plays a role in internally directed thought and has been implicated in brain clearance. The distinction was especially strong between the narcolepsy and sleep groups, as well as between the narcolepsy and awake groups.
The phantom model further supported these findings. The experiment showed that increased water flow produced stronger signal oscillations in the MRI data, confirming that the observed brain signals likely reflect real physiological changes in fluid dynamics.
“While NT1 is a chronic disease, there may be a silver lining to it in the form of increased slow cerebral vasomotion that drives brain clearance,” Järvelä explained. “The power of this vasomotion does not, at least statistically, differ from that seen in NREM sleep where the brain clearance is most active.”
“The results also underline the importance of sleep to facilitate brain homeostasis and long term health, and suggest that there may be a way to enhance vasomotor pulsations with a pharmacological intervention – albeit this has not been studied at the current time. Well-functioning brain clearance is of importance, as dysfunctional waste clearance from the brain may underlie prevalent neurological diseases e.g. Alzheimer’s disease.”
As with all research, the study has limitations that should be taken into account. First, while the data suggest altered brain pulsations in narcolepsy type 1, the exact mechanisms remain uncertain. Orexin deficiency likely affects multiple neurotransmitter systems, especially noradrenaline, but the relative contribution of each is unclear. Additionally, although the participants with narcolepsy were instructed to stay awake during scanning, the researchers could not confirm this with simultaneous EEG for all participants, raising the possibility that some may have briefly dozed off.
“It is not yet clear what downstream effect or indeed effects of orexin depletion is the main character behind our pulsation findings, but the earlier literature points to decreased cortical excitation and inconsistent noradrenergic tone from locus coeruleus,” Järvelä noted. “Also, the results quantify the forces driving brain clearance, but as we are studying macroscopic phenomena, we do not directly observe the microscopic motion of brain metabolite waste products in NT1. As always, more research is warranted.”
Future research may explore whether pharmacological manipulation of the orexin system affects these pulsations. If orexin antagonists used as sleep aids induce brain pulsation patterns similar to narcolepsy, this might offer clues about how to regulate brain clearance.
“It would indeed be interesting to see whether orexin antagonists would have the same effect on brain pulsations as NT1 and if agonists would have the reverse effect,” Järvelä said. “Apart from using orexin antagonists as sleep medication, there may be potential to use them to boost brain clearance.”
The study, “Orexin effect on physiological pulsations of the human brain,” was authored by Matti Järvelä, Janne Kananen, Heta Helakari, Vesa Korhonen, Niko Huotari, Tommi Väyrynen, Katariina Hautamäki, Lauri Raitamaa, Johanna Tuunanen, Mika Kallio, Johanna Piispala, Hanna Ansakorpi, and Vesa Kiviniemi.
