Looking into the brain when in pain

ACC and OFC

Location of the anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC), which is particularly active in chronic pain. © Prasad Shirvalkar

Millions of people around the world suffer from chronic pain, but until now there have been few ways to measure this pain objectively. Now, for the first time, it has been possible to identify brain activity that is characteristic of chronic pain in four patients with implanted electrodes. With the help of a computer-aided evaluation of the recorded brain waves, the researchers were able to predict the individual pain intensity and also determine that the signature of chronic pain differs from that of acute pain perception. These findings open up new opportunities to be able to measure pain objectively in the future.

Pain is an important warning signal from our body. But there is pain that remains. Chronic pain often persists long after the original cause has healed or been eliminated. This is due to the so-called pain memory. This occurs when the initially strong and persistent bombardment of pain signals leads to changes in gene activity, cell metabolism, signal transmission and the activity of nerve cells in the spinal cord and brain. As a result of these changes, the pain can take on a life of its own: hypersensitivity develops, through which even harmless stimuli trigger pain. "Pain is one of the most fundamental experiences an organism can have," says lead author Prasad Shirvalkar of the University of California, San Francisco. "Nevertheless, there is still a lot that we don't understand about pain and its mechanisms."

Where does chronic pain show up in the brain?

A problem for pain research and pain therapy has been that there is no objective measurement method for chronic pain. Physicians are dependent on the questioning and self-assessment of the patients. It is also only rudimentarily known where chronic pain manifests itself in the brain and whether this differs from brain activity in acute pain. Studies suggest that areas in the prefrontal cortex behind the forehead are particularly involved in the perception of pain. A chance to find out more presented itself to Shirvalkar and his team in the form of four patients with severe, persistent chronic pain. One suffered from phantom limb pain after an amputation, while the other three patients suffered from chronic pain after a stroke.

In the study, the researchers implanted electrodes under the skulls of the four pain patients in such a way that they specifically recorded activity in two areas of the prefrontal cortex, the anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC). “Functional magnetic resonance imaging (fNRT) measurements show that both areas light up when there is acute pain,” says Shirvalkar. "We wanted to find out whether these regions also play a role in the processing of chronic pain. We were particularly interested in whether there are brain signals that are related to the intensity of the pain.” For a period of three to six months, the four test subjects indicated how intense their chronic pain was several times a day using a standardized pain scale. At the same time, the electrodes recorded their brain activity. In this way, the team collected data for three to six months and then evaluated it using an adaptive algorithm.

Orbitofrontal Cortex as a key region

The evaluations showed that there is indeed a specific, recognizable pattern of brain activity in chronic pain. According to this, the orbitofrontal cortex is particularly active when a person suffers from chronic pain. The more intense the pain, the higher the activity measured in the OFC. "The chronic pain condition could be significantly decoded in all patients on the basis of the mutual orbitofrontal cortex," report Shirvalkar and his colleagues. To a lesser extent, the anterior cingulate cortex (ACC) was also activated. Both measurements together enabled the team to read the pain of their subjects with sometimes more than 80 percent sensitivity and specificity from their brain activity. "These results are a proof of concept that signals from key neuronal regions can be used to determine clinically relevant pain conditions in humans," the researchers state.

In a supplementary experiment, they also exposed their test subjects to acute pain stimuli in order to uncover possible differences in the neuronal processing of chronic and acute pain. It was shown that the anterior cingulate cortex becomes active in acute pain perception and only to a lesser extent the orbitofrontal cortex. "This observation is consistent with previous imaging studies in which experimental pain stimuli also activated the ACC as a key node," the scientists write. In her opinion, these results not only provide more insight into where chronic pain is processed in the brain, they could also make it possible to measure pain objectively in the future. However, it must first be investigated whether these specific activity patterns can also be measured in patients with other types of chronic pain. If this is the case, the new findings could also open up new starting points for pain therapy. "By developing better tools to study and potentially influence pain responses in the brain, we hope to find ways to improve the lives of people with chronic pain," says Shirvalkar.

Source: Prasad Shirvalkar (University of California, San Francisco) et al., Nature Neuroscience, doi: 10.1038/s41593-023-01338-z

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