A Step Toward An Objective Brain Biomarker of Chronic Pain: ToP(S) That!

A new study puts forth a brain activity biomarker that predicts experimental pain, and back pain in patients. Image credit: Weerayut Kongsombut/123RF Stock Photo.

Published June 16, 2021

Editor’s note: This story first appeared on the IASP Pain Research Forum and has been edited for RELIEF.

Discovering a pain biomarker – an objective, measurable indicator of pain – is what many consider the Holy Grail of pain research. Right now, doctors rely on patients to self-report their pain or to rate it on a pain scale. What patients say about their pain is extremely valuable and always to be taken seriously, but a more objective indicator would help improve the assessment and treatment of pain.

In recent years, patterns of brain activity seen under painful conditions (known as pain signatures) have received a great deal of attention from pain researchers as possible pain biomarkers. Now, a new contender for a biomarker based on brain imaging has emerged.

A recent study led by Choong-Wan Woo (Sungkyunkwan University, Suwon, South Korea) and Tor Wager (Dartmouth College, Hanover, US) reports a pattern of brain activity, in healthy study volunteers, that reliably predicted sustained experimental pain. This pattern also successfully predicted pain in patients with low back pain. The brain activity pattern was dubbed the Tonic Pain Signature (ToPS).

“This paper is significant in that it provides a novel brain signature for the sustained pain experience, and by doing so brings us incrementally closer to a brain signature of chronic pain, which is inherently elusive,” said Katherine Martucci, a pain neuroimaging researcher at Duke University, Durham, US, who was not part of the study.

The study was published in Nature Medicine on January 4th, 2021.

The Tonic Pain Signature (ToPS) in healthy study volunteers
A key feature of the pain that patients experience (known as clinical pain) is its sustained nature. But this has been difficult to objectively assess since it is affected by many different factors such as mood, emotion, and attention.

To overcome this challenge, Woo, Wager, first author Jae-Joong Lee (also at Sungkyunkwan University) and colleagues decided to first focus on sustained (also known as tonic) experimental pain. They reasoned that this would more closely approximate chronic pain in people than other lab studies that looked only at acute (short-lasting) experimental pain.

So the group began by trying to identify a brain signature for acute heat pain. Nineteen healthy participants received hot sauce containing capsaicin (the component of chili peppers that makes them “hot”) on the tongue to cause tonic heat pain.

The study subjects then underwent functional magnetic resonance imaging (fMRI), a type of brain imaging, for five minutes. The authors then looked at the patterns of brain activity, in response to the hot sauce, in different brain regions, and correlated that activity with the pain that the subjects experienced.

Based on the data from that experiment, the researchers were able to identify a pattern of brain activity, which they called ToPS, that was able to predict sustained heat pain in several different groups of study volunteers – that is, ToPS could successfully predict changes in pain ratings made by the study volunteers over the course of receiving the hot sauce.

“It’s important to understand that our ToPS model is based on experimentally induced sustained pain because this is different from acute pain, and more similar to clinically important chronic pain diseases,” said Lee.

Any good brain biomarker of pain must be able to differentiate when someone is in pain versus when they are experiencing something else that is aversive but not painful – think of eating something bitter or smelling something bad.

So the authors set up an experiment where healthy volunteers received the hot sauce on the tongue while others received quinine, which has a bitter taste. ToPS successfully discriminated whether the person had received capsaicin or quinine, with 76% accuracy. This was important as it showed that ToPS was specific to pain.

What about pain that patients actually experience?
The next question was whether ToPS could predict clinical pain in patients. Here, the authors tested ToPS using fMRI datasets from 70 patients with subacute back pain (pain lasting longer than acute back pain but not yet considered to be chronic) and 25 patients with chronic back pain. ToPS reliably predicted individual differences in pain severity in these two patient groups,

The authors then tested ToPS on two more chronic back pain datasets from Japan (24 patients, 39 healthy controls) and the United Kingdom (17 patients and 17 controls). They found that ToPS discriminated patients with chronic back pain from healthy controls with 71-73% accuracy.

Together, the findings showed that ToPS performed well in patients with pain, just as it did in the healthy volunteers from the laboratory studies.

Sustained pain activates diverse brain networks.
The researchers next asked what specific brain activity patterns underlie ToPS. In the hot sauce experiments, the team found that higher pain correlated with increasing functional connectivity among four different brain networks. (Functional connectivity refers to neurophysiological activity in brain regions that is correlated with activity in other brain regions).

The networks the researchers identified are involved in integrating many different types of sensory input and in attentional processes.

Results also showed lower pain with increasing connectivity among brain areas important in processing the context in which pain occurs and in endogenous pain modulation – the brain’s own natural ability to tamp down pain.

The group next looked in more detail at specific regions of the brain commonly examined in brain imaging studies in the pain field. They saw that connectivity between a brain region called the dorsolateral prefrontal cortex (dlPFC) and other regions well known to play a role in pain predicted higher sustained pain. Meanwhile, connectivity between the dlPFC and the brainstem predicted lower pain.

“This new signature aligns with other individual neuroimaging findings that have shown us brain regions and connections relevant for chronic pain. It’s both reassuring and exciting that their advanced and intricate brain signature of tonic pain is still complementary to what we’ve learned about the brain related to chronic pain,” Martucci said.

Finally, the authors found that patterns of brain activity during tonic and clinical pain were similar, whereas different patterns emerged in experimental phasic pain. In the current study, the latter refers to pain in response to a short-lasting painful heat stimulus in healthy subjects. This shows that sustained pain is not the same thing as phasic pain.

“It is an easy assumption to make that painful stimuli that last a few seconds and those that last a few minutes are similar, with many of the same [brain] pathways involved,” senior author Tor Wager said. “We found that this is not the case – they are represented differently.”

Ultimately, the findings “offer us a glimpse of a future with neuroimaging-based characterization of clinical pain and sets us one more step of the way towards that future,” Martucci said. “We need these types of models to be continually presented and refined in order to advance brain signatures of pain.”

Fred Schwaller, PhD, is a freelance science writer based in Germany.