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Probing the Intersection of Sleep and Pain with Brain Imaging

Sleep loss leads to increases in activity in the somatosensory cortex and decreases in the insula, thalamus, and nucleus accumbens

by Stephani Sutherland


25 March 2019


PRF News

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Sleep loss leads to increases in activity in the somatosensory cortex and decreases in the insula, thalamus, and nucleus accumbens

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.

 

A new functional magnetic resonance imaging (fMRI) study now shows that a night without sleep lowered 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 the nucleus accumbens, thalamus, and insula, brain areas that help temper pain.

 

The work from Matthew Walker, University of California, Berkeley, US, 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 mitigate pain.

 

Patrick Finan, who studies the relationship between sleep and pain at Johns Hopkins University, Baltimore, US, but was not involved in the new 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 sensitivity is consistent with results from other studies, “but the real novelty is that they found the neural correlates of that increased sensitivity.”

 

The work was published January 28, 2019, in the Journal of Neuroscience.

 

Sleep deprivation in the lab means 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 using a thermal stimulus to the leg. After a sleepless night, the threshold at which subjects registered the stimulus as unpleasant fell by more than a degree Celsius, on average.

 

“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, ‘Okay, 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, indicating that pain threshold but not overall sensitivity had shifted.

 

Why might humans 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 that 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 decreased pain threshold, 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, US. Wager previously identified a “neurologic signature of pain,” that is, a pattern of fMRI brain activity seen in response to physical pain in healthy subjects (Wager et al., 2013PRF 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 had expected, relative to the rested condition. But pain-related activity declined after a night without sleep in the thalamus, the insula, and the nucleus accumbens (NAc).

 

“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, while the NAc signals saliency and value. Both have been implicated in descending modulation of 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 pain threshold in the sleep-deprived study participants.

 

“They saw increases in activity in somatosensory cortex at the same time as decreases in the thalamus, insula, and nucleus accumbens,” Finan said. “That absolutely fits with an interesting narrative” that pain hypersensitivity results from an imbalance in sensory-discriminatory and evaluative processes. “It also fits with the idea that sleep deprivation-induced pain sensitivity is not a simple construct in that it is not represented in a single brain region or pattern, but is more complex. These findings reveal some of that complexity.”

 

The nucleus accumbens takes the spotlight

“One of the surprises for me,” Wager wrote in an email to PRF, “was that sleep affects signals in the nucleus accumbens, which is also a mediator of effects of self-regulation of pain. This suggests effects on the evaluative aspects of pain, which is important for the behavioral and functional impact of pain.”

 

Finan and colleagues also published a paper last month using neuroimaging to probe the relationship between sleep and pain (Seminowicz et al., 2019). Though that study had different aims and methods, Finan also saw a decrease in NAc activity during sleep loss-induced pain. “We saw that under normal rested conditions, nucleus accumbens activation increased at the start of a painful stimulus, consistent with aversive signal detection. That signal was attenuated following one night of experimental sleep disruption, a paradigm involving multiple forced nocturnal awakenings,” he said.

 

“We were really interested in the role of the nucleus accumbens at the cross-section of pain, sleep and reward,” said Finan. “We set out to study that by manipulating all three elements, and then we looked at how the NAc responds in various conditions.” Why all the interest in the NAc? “One reason was that preliminary data showed that sleep loss augments pain sensitivity, but it also blunts positive affective experience. In addition, some earlier work showed that sleep loss attenuated the ability of positive affect to inhibit pain. Those behavioral findings might be related to NAc function.” (See PRF related news.)

 

In the study from Krause et al., subjects also completed questionnaires to assess their mood following each night. 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 pain threshold, suggesting that mood was not the primary driver of those changes.

 

Every night matters

For the laboratory experiments, subjects 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 they 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—a question previously investigated using daily diaries (e.g., see Tang et al., 2012 Lewandowski et al., 2017). The researchers addressed the issue in a two-day online study of 236 subjects with an average age of 36, some of whom 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 (Finan et al., 2013). “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 significance of behavioral determinants of health. “Sleep is an important part of biobehavioral health—a set of practices that can improve our well-being, whatever our starting point. Much of medicine does not focus systematically on sleep or other behavioral aspects of health, 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.”

 

The issue is complex, though, Finan said. “Looking at the literature as a whole, the notion that sleep loss is hyperalgesic is probably more simplistic than the data bear. The study by Krause et al. shows some evidence that would broadly support that idea, but their methods allow for a more nuanced understanding of the relationship between sleep and pain.”

 

Stephani Sutherland, PhD, is a neuroscientist and freelance journalist in Southern California. Follow her on Twitter @SutherlandPhD.

 

Image credit: Yulia Ryabokon/123RF Stock Photo.

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