Pain is an unpleasant but necessary sensation. The few people born without the ability to feel it must approach day-to-day tasks with extra caution. Without the ability to sense the effects of a broken bone or burned skin, it’s difficult to avoid harm. On the other hand, too much pain can be debilitating. Individuals with chronic pain often experience a host of additional negative effects on mental and physical health. Despite recent advances in uncovering the underlying mechanisms of pain perception in the brain, scientists are still debating the questions of where and how pain is processed.

Over the years neuroscientists have identified the “pain matrix,” a set of brain areas including the anterior cingulate cortex, thalamus and insula that consistently respond to painful stimuli. Some researchers have since applied this concept to conclude that that rejection hurts because social pain and physical pain share similar mechanisms in the brain. Others have suggested that brain imaging could be an objective measure of pain for diagnosis and drug development, and even as evidence in court.

In recent years, however, a number of studies have cast doubt on the idea that these brain areas are specifically coding for pain. In the most recent study, published this week in JAMA Neurology, neuroscientists at the University of Reading and University College London scanned the brains of two individuals born without the ability to feel pain and four healthy volunteers while they received painful “pinprick” stimuli. The scientists found similar patterns of activity in the brain areas widely associated with pain in both groups, providing evidence that the pain matrix may be responding to other senses.

“If this was the only evidence that we had so far, I would be a bit more cautious in the interpretation,” says André Mouraux, a neuroscientist at Université Catholique de Louvain in Belgium who was not involved in the study. However, this is not the first piece of evidence that these areas are not specific to pain. For example, in 2011 Mouraux and his colleagues discovered similar activations in the brains of healthy individuals to both painful and non-painful stimuli. “Altogether, the story becomes convincing,” Mouraux says. Because the pain-related regions are involved in so many other cognitive processes, most researchers are adopting the view that the pain matrix is more generally responsible for processing attention-grabbing stimuli.

According to the study’s authors, the idea of a pain matrix is still pervasive and drives many incorrect scientific conclusions. “It is very tempting to put someone in the scanner, give a stimulus causing pain and record a brain response that—often, but not always—correlates with the intensity of the pain perceived, and conclude that the response reflects pain,” says Giandomenico Iannetti, a neuroscientist at University College London.

Finding Pain in the Brain

Pain’s locus in the brain is hotly contested subject. Recently, a number of high-profile papers reporting brain areas specific to pain have come under fire. For example, in March 2015 a group at Oxford University published a study in Nature Neuroscience claiming that the dorsal posterior insula was the “ouch center” of the brain. The study received widespread criticism from the pain research community, including an article by several influential scientists rebutting the claims. Researchers have since found that this area is actually responsive to both painful and non-painful stimuli.

Then in December a group of neuroscientists at the University of California published a paper in PNAS claiming that another area, the dorsal anterior cingulate cortex, was selective for pain. This too led to a critical reaction paper, this time in the same journal that published the original study.

The biggest issue with these studies—and many neuroimaging studies—are the limitations of reverse inference, where researchers use types of brain activity, sometimes referred to as “blobs” for the shapes they form on fMRI scans, to deduce that a specific cognitive event like processing pain is occurring. While this is technically not impossible to do, especially with new techniques that apply machine learning, “blobology” is a very tricky business.

Take the dorsal anterior cingulate cortex, for example. Neuroscientists have associated it with a variety of functions in addition to pain, including attention, working memory and conflict monitoring, meaning that when this region lights up in a scanner, any number of these processes could be occurring.

Some researchers are not too impressed with the recent JAMA Neurology results, either. According to Tor Wager, a neuroscientist at the University of Colorado, “They’re not isolating the pain-related activity in controls and so they don't have a basis for quantifying the difference.” What they should have done, he says, is measure the change in brain activity as the painful stimulus increased in the group that could feel pain, then compare this to the change in activity in the pain-free individuals while they received the same stimulus.

Wager believes that while areas in the pain matrix may not be specific to pain, certain patterns of activity in this network are. His group found evidence of this in a 2013 study in which they reported distinct patterns of activity for physical and social pain within similar brain regions. “I believe, until proven otherwise, that the pain network is largely encapsulated within the pain matrix,” Wager says. “But it doesn't mean that measuring the blobs is sufficient.”

Beyond the Blobs

Although the search for pain markers in the brain may sound like battle of wits between academics, there are high stakes to this endeavor. The costs of chronic pain—in terms of medical expenses and lost productivity as well as suffering and opioid addiction—are tremendous. To measure pain, clinicians currently rely largely on patients to report how they feel. These ratings are highly subjective, which can be an issue for drug development—for example, when researchers try to rule out placebo effects. Having a neuroimaging technique that could reliably detect pain signals could be a hugely beneficial tool for diagnosis and drug development.

There are limitations to keep in mind, however. “The most dangerous utility is [using neuroimaging] to rule out that somebody is in pain,” says Tim Salomons, a neuroscientist at the University of Reading and head author of the current study. Rather than identifying whether someone is experiencing pain, neuroimaging will more likely be helpful in providing information about how much pain a person is feeling or how effective a drug is in mitigating pain. “People are suffering and we actually could do something about that—but we [first] have to understand the science better,” Wager says.