Patients and doctors alike know that sleep and pain present something of a vicious cycle: pain makes sleeping difficult, and losing sleep makes pain worse. But the brain mechanisms behind this phenomenon have remained unknown.
Now, a new study using functional magnetic resonance imaging (fMRI), a type of brain scan, shows that a night without sleep lowers the pain threshold of healthy human subjects by ramping up brain activity in the primary somatosensory cortex, a region key to detecting pain. At the same time, the researchers saw decreased activity in brain areas that help temper pain.
The work from Matthew Walker at the University of California, Berkeley, and colleagues also included an online study showing that nightly fluctuations in sleep quality had an impact on day-to-day pain. That finding suggests that even small improvements in sleep could ease pain.
Patrick Finan, who studies the relationship between sleep and pain at Johns Hopkins University in Baltimore but was not involved in the work, called it “the first sleep deprivation study to look at pain sensitivity through the lens of neuroimaging.”
“The study took a fairly straightforward approach to asking the question, ‘What are the effects of one night of total sleep deprivation on pain sensitivity?’ ” Finan said. The finding of heightened pain sensitivity is in line with results from other studies, “but the real novelty is that they found the neural correlates of that increased sensitivity,” meaning the specific brain areas responsible for the effects.
The work was published March 20, 2019 in the Journal of Neuroscience.
Sleep deprivation in the lab = lower pain thresholds
For the study, 25 healthy subjects aged 18 to 30 spent one restful night in the sleep lab and one night where they were not allowed to sleep at all. Lead author and graduate student Adam Krause first tested baseline pain thresholds—the point at which people first report pain—using a heat stimulus to the leg.
After a sleepless night, the threshold at which subjects registered the stimulus as “unpleasant” fell by over a degree Celsius, on average. This meant that they had become more sensitive to pain.
“Pain threshold is rather subtle—it’s not always appreciated. It’s not just sensitivity to heat; it also represents an unconscious decision to say, ‘ok this heat is no longer safe and benign, it’s threatening,’ ” Krause said.
Subjects rated an unambiguously painful heat stimulus as similarly painful in rested and sleep-deprived states. This indicated that the pain threshold, but not overall pain sensitivity, had shifted.
Why might people become more sensitive to potentially harmful stimuli when sleep deprived?
“It’s a very challenging state; it’s not a natural one,” Krause said. Because we are more vulnerable, “it makes sense there would be short-term changes in our response to threats.”
Brain activity goes both up and down
To take a look at changes in the brain that may have accompanied the increased pain sensitivity, Krause then collected fMRI data from the subjects during a painful heat stimulus.
When choosing which brain regions to focus on, the researchers teamed up with Tor Wager, a brain imager at the University of Colorado, Boulder. Wager previously identified a “pain signature,” or pattern, of fMRI brain activity seen in response to physical pain in healthy subjects (see Pain Research Forum related news).
When the researchers looked at pain signature regions activated by a painful probe to the left leg, they found increased activity in the right somatosensory cortex during sleep deprivation, as they expected, compared to the rested condition. But pain-related activity declined after a night without sleep in the thalamus, the insula, and the nucleus accumbens (NAc). These are all brain areas that have been linked to pain processing in some way.
“We naïvely expected to simply see hyperactivity in all pain areas. But surprisingly, we saw both increases and decreases in the brain in response to pain,” Krause said.
But the finding of decreased activity made more sense, he said, “when we dug into what those regions do for pain in the normal, rested state.” The insula is involved in mapping the body’s internal state. Meanwhile, the NAc signals saliency (the degree to which something painful stands out from other stimuli) and value (the importance placed on a stimulus). Both the insula and NAc have been implicated in descending modulation of pain, which refers to how the brain can tamp down pain.
Sleep loss, Krause said, seems to “disrupt the brain’s natural ability to regulate pain and provide relief.”
Importantly, the extent of the changes in brain activity predicted the change in subjects’ pain threshold.
Finan and colleagues also published a paper last month using neuroimaging to probe the relationship between sleep and pain. Though that study had different aims and methods, Finan also saw a decrease in NAc activity during pain caused by sleep loss.
In Krause’s study, people also completed questionnaires about their mood. There were small but not significant changes in positive and negative mood and anxiety following sleep loss compared with rest. But these changes did not correlate with changes in the pain threshold. This showed that mood was not the primary driver of those changes.
Every night matters
For the laboratory experiments, participants received what Krause called “a hefty dose of sleep deprivation” for a completely sleepless night. “We understand that’s not typical of how people lose sleep. Usually, we wake up too early, or we wake throughout the night with fragmented sleep.” But the researchers wanted to see the strongest effect possible in the experimental setting.
That begs the question of whether smaller fluctuations people experience in sleep from night to night could really make a difference in the pain experience.
Krause and the team addressed the issue in a two-day online study of 236 people with an average age of 36, some of who had chronic pain. Surprisingly, how much total sleep people got seemed not to have an impact on pain reports. But when sleep efficiency—the percentage of time spent in bed actually asleep—or subjective report of sleep quality went down, reports of pain went up the following day.
Researchers have debated for years whether sleep loss causes pain or the other way around, largely concluding that the influence goes in both directions. Although the authors could not clearly pin down a causal relationship between sleep and pain, their analysis suggested that sleep loss preceded increases in pain. That meshes with Finan’s 2013 review of a decade of research on that topic.
“We found in the review that sleep loss or disturbance seems to more powerfully influence pain than the reverse direction.”
Wager wrote in an email that the study provides further evidence for the importance of behavior in affecting human health.
“Sleep is an important part of biobehavioral health — a set of practices that can improve our wellbeing, whatever our starting point. Much of medicine does not focus systematically on sleep or other behavioral aspects of heath, so in many cases, we will have to take an active role in understanding and improving our health. Sleep is a critical part of that, and there are things we can do to improve it.”
This story first appeared on the Pain Research Forum and has been adapted for RELIEF.
Stephani Sutherland, PhD, is a neuroscientist and freelance journalist in Southern California. Follow her on Twitter @SutherlandPhD
Image credit: Yulia Ryabokon/123RF Stock Photo.