New Insight into Caffeine’s Effects on Wakefulness, Sleep, and Brain Blood Flow

By Lincoln Tracy | December 11, 2023 | Posted in

Researchers use a microchip/video system to show that chronic caffeine in mice has complex effects throughout the sleep–wake cycle and a paradoxical impact on brain blood flow. The findings have implications for understanding migraine as well as neurodegenerative diseases.

How does caffeine affect the nervous system? Considering that caffeine is everywhere – in what we drink, eat, and supplement our diets with – it may be surprising that the effects of this most popular of psychoactive substances on brain activity and behavior are not fully understood. In light of the role of sleep disruption in migraine as well as evidence that caffeine can trigger or ease the disorder, a better grasp could help people living with headache conditions.

Now, a new study takes an innovative approach to unraveling the effects of caffeine on wakefulness, sleep, and brain blood flow, with implications not only for migraine but for neurodegenerative conditions as well.

Lead authors Kimiya Aframian and Dmitri Yousef Yengej, part of a team of researchers led by senior co-authors Guido Faas and Andrew Charles at the University of California, Los Angeles, US, use a new, minimally invasive microchip/video monitoring system in freely behaving mice to learn more.

The group found that chronic caffeine had complex effects on the timing of awake and sleep states – including effects on REM sleep – and a paradoxical impact on brain blood flow during those states. The direction of changes in blood flow depended upon the phase of the sleepwake cycle in which the animals found themselves.

The investigators’ findings point to possible neuroprotective effects of chronic caffeine and could potentially improve the advice about sleep and caffeine that doctors give their patients with migraine.

Tom de Boer, who studies sleep and circadian rhythms at Leiden University Medical Center, the Netherlands, but who was not involved with the current work, pointed to the study’s investigation of the effects of chronic caffeine as a strength of the research – and an improvement over previous investigations.

“It recently became clear that the effect of chronic caffeine on sleep is different compared to the effect of acute caffeine. It is well known that acute caffeine disturbs sleep and increases waking. But those are results obtained in humans who had to abstain from using caffeine for one or maybe two weeks, and in animals that were naïve to caffeine. However, nobody drinks coffee once every one to two weeks. Most of us use caffeine multiple times per day on a daily basis,” he told Migraine Science Collaborative.

The research appeared in the September 2023 issue of PNAS Nexus, a sibling journal to The Proceedings of the National Academy of Sciences (PNAS).

A technological advance
Previous research has shown that the “awake” feeling caffeine produces comes from its antagonism of adenosine receptors. However, it’s difficult to understand the precise impact of caffeine on the nervous system, considering that its influence varies according to the daynight cycle. Whether caffeine administration is acute or chronic also complicates the picture.

Another challenge is that the methods used to assess caffeine’s effects – such as electroencephalography (EEG), which can measure brain activity during different sleep phases – are invasive in animals. For example, attaching electrodes to rodents for EEG measurements typically requires breaching of the skull.

But the authors recently developed a minimally invasive microchip/video system to overcome such hurdles. The new approach allows for continuous, long-term recording of neurovascular activity, heart rate, and movement in freely behaving mice. Unlike EEG, the researchers can attach the microchip without breaching the skull.

Faas’ background in electrophysiology and biophysics helped push the lab in this more fruitful direction.

“I felt this could be done easily with microchips, and I was able to get a rudimentary setup working pretty quickly,” he recalled. “Then we were lucky to get a postdoc, Dmitri, who is an excellent programmer, and over the last couple of years we’ve built a strong system that can measure not only the optic intrinsic signal [an indirect measurement of neuronal activity based on changes in brain blood flow] but also movement and sleep patterns. It has turned out to be even more powerful than we ever could have realized.”

Caffeine leads to different – but not less – sleep 
The researchers attached the microchip to C57B16 mice before monitoring the animals’ baseline sleep and wake states. Like most other mouse strains, the C57B16 mice typically slept during the light periods and were awake during dark periods – apart from a two- to three-hour “siesta” (including REM sleep) approximately eight hours into the dark period.

The siesta finding piqued Charles’ interest.

“It raises the question of whether the siesta might be genetically programmed in certain individuals,” Charles posited. “We often tell patients not to take naps in response to a migraine attack, even if they have the urge to sleep, because that’s something that can be a trigger for some people. But maybe there are certain patients for whom a nap is their natural sleep pattern and therefore we shouldn’t be telling them not to do it.”

After collecting the baseline data, the researchers added increasing amounts of caffeine to the mice’s drinking water over a four-week period. The amounts equated to five to 20 cups of coffee per day in humans, after accounting for differences in liver size and metabolism.

The total amount of time the animals spent in awake and sleep states did not change with chronic caffeine. It did, however, reduce the time spent awake during the rest phase (defined as the time when the animals are mostly asleep), essentially “consolidating” sleep during that phase. It also shifted the rest and active (mostly awake) phases by up to two hours relative to the light/dark cycle – meaning the rest phase started later relative to the light period and extended longer into the dark period, with equivalent changes observed for the active phase relative to the dark period.

Similarly, chronic caffeine did not alter the total amount of REM sleep the mice had over a 24-hour period. But it shortened, and in some cases completely abolished, the REM sleep in the siesta period, and it delayed the start of REM sleep during the normal sleep periods.

“The implications of the findings for humans are that they challenge the perception that caffeine’s interference with sleep is due to a reduced quality of sleep. Since most people don’t have the luxury of sleeping in during the morning, they will perceive that they haven’t slept as well even if the quality of the sleep is actually the same or better,” Charles said.

A paradoxical and potentially protective process
Chronic caffeine also affected cerebral blood volume (CBV; an indirect measure of neural activity) – increasing average CBV during the latter part of the rest phase despite consolidation of sleep and decreasing CBV in the latter part of the active phase. One would typically expect to see decreased CBV during sleep and increased CBV during the active phase.

Charles feels the paradoxical finding may be relevant for the migraine patients he sees in the clinic.

“My approach is to say, okay, you can have caffeine, but have it before noon and keep the amounts consistent from day to day so the patients aren’t going through periods of sustained withdrawal, even if they are going through periods of relative withdrawal at night, where the increases in brain blood flow might be a good thing,” Charles said.

The “good thing” Charles was referring to is the potential neuroprotective effect of caffeine through its impact on CBV.

“That is intriguing because it raises the possibility of being relevant to both migraine and neurodegenerative disease, where it’s thought that increases in blood brain flow during sleep could help flush out brain waste.”

Of note, previous work had shown that caffeine reduces the risk of neurodegenerative disease, especially Parkinson’s disease.

The researchers are not sure what is driving the paradoxical effect of caffeine on CBV but suspect it may be due to the unique effects of adenosine on neural and vascular activity.

de Boer appreciated the consistency of the findings relative to his own work, acknowledging that some people still struggle with the counterintuitive associations between caffeine use and sleep.

“The study confirms our findings with chronic caffeine in our mouse study en passant, which took some convincing to get published and where I still get into discussions about because it is counterintuitive to what we think, or thought, we understood about caffeine use and sleep,” he explained.

A base to build upon
de Boer sees several possible avenues for future research.

“If you want to know whether caffeine changes the chances of having migraine, the application of chronic caffeine can be tested on a migraine mouse model and you can see whether the number of attacks or the threshold to induce an attack changes. Another great step would be to look at brain clearance in mice on chronic caffeine to see whether the suggested next step in the mechanism [enhanced waste clearance] really takes place,” he said.

Faas and Charles are pleased with what they have learned using their non-invasive microchip approach but have already identified other potential applications.

“We’ve shown we can look at the effects of different variables, including drug treatments, over extended time periods in a very practical way. We can use this as a drug characterization and discovery approach to look at drugs that affect migraine and sleep, and we can further investigate how migraine models affect sleep,” Charles said.

The team is also working on refining the microchip, such as by allowing for the continuous measurement of intracranial pressure, and is developing other experimental approaches that could utilize the technology to measure physiological responses to other kinds of stimuli.

“We’re developing a technique where we can deliver a heat stimulus without picking the mouse up, which allows us to measure sensory sensitivity. This is important because mice are prey animals, and prey animals don’t like to be handled; it’s extremely stressful for them. Even if you train animals for being handled, the experimenter always exerts an effect by holding or interacting with the mouse,” Faas said.

Lincoln Tracy, PhD, is a researcher and freelance writer based in Melbourne, Australia. Follow him on Twitter @lincolntracy.

Image credit: 123RF Stock Photo.

References

Effects of chronic caffeine on patterns of brain blood flow and behavior throughout the sleep–wake cycle in freely behaving mice.
Aframian et al.
PNAS Nexus. 2023 Sep 19;2(9):pgad303.

Continuous long-term recording and triggering of brain neurovascular activity and behavior in freely moving rodents.
Yengej et al.
J Physiol. 2021 Oct;599(20):4545-59.

Effects of chronic caffeine consumption on sleep and the sleep electroencephalogram in mice.
Panagiotou et al.
J Psychopharmacol. 2019 Jan;33(1):122-31.

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Dr. Lincoln Tracy is a researcher and freelance writer from Melbourne, Australia. As a researcher, he uses data from an international clinical quality registry to explore burn injuries in Australia and New Zealand. As a freelance writer, he turns basic, translational, and clinical research into high-quality news, features, interviews, meeting reports, and podcasts. As a person, he is one half of one of two sets of twins in his family. Follow him on Twitter @lincolntracy.

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