Signature on fMRI May Offer Objective Pain Biomarker

Megan Brooks

April 11, 2013

Researchers say they've identified a distinct neurologic pattern on functional MRI (fMRI) that is specific to heat-induced pain and sensitive to the analgesic effects of opioids.

The "nociceptive pain signature" could have a wide range of uses, if confirmed and extended in future studies, Tor D. Wager, PhD, from the Department of Psychology and Neuroscience, University of Colorado, Boulder, who was involved in the research, told Medscape Medical News.

"It could be used to confirm pain in those who cannot report accurately (eg, the very old, very young, cognitively impaired) or whose reports are not completely trusted by medical or legal decision-makers," he explained. "It could be used alongside other measures, such as pain reports, facial expressions, and behaviors, in 'multi-axial' pain assessment strategies based on multiple measures."

However, he adds, "It cannot and should not be used as a 'pain lie detector' because some individuals may have real pain that is not captured by the pattern we identified here."

The research is published in the April 11 issue of the New England Journal of Medicine.

"Great Practical Importance"

The coauthors of an editorial say the fMRI-based pain signature may be of "great practical importance" given the lack of objective measures of physical pain.

Dr. Tor D. Wager

"Imagine how all fields of medicine would be altered if pain could be objectified by a measure that did not require direct patient reporting," write Assia Jaillard, MD, PhD, MRI Unit, Centre Hospitalier Universitaire (CHU) de Grenoble in France, and Allan H. Ropper, MD, Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts.

Dr. Wager and colleagues conducted a series of studies involving 114 healthy men and women. Using fMRI and machine-learning methods, they identified a pattern of fMRI activity across brain regions associated with heat-induced pain. The pain signature is widely distributed across multiple regions and includes the thalamus, the posterior and anterior insulae, the secondary somatosensory cortex, the anterior cingulate cortex, the periaqueductal gray matter, and other regions, the researchers say.

In 1 study, the neurologic signature showed sensitivity and specificity of 94% or more (95% confidence interval [CI], 89% - 98%) in discriminating painful heat from nonpainful warmth, pain anticipation, and pain recall.

In a separate study in a different sample of participants, the pain signature discriminated between painful heat and nonpainful warmth with 93% sensitivity and specificity (95% CI, 84% - 100%).

In a third study, the neurologic signature discriminated between physical and social pain, which activates many of the same brain regions as physical pain, with sensitivity of 85% (95% CI, 76% - 94%) and specificity of 73% (95% CI, 61% - 84%).

Dr. Jaillard and Dr. Ropper say the social pain assessment findings are provocative. But they caution that, for this assessment, participants recalled a recent romantic breakup while viewing a picture of their ex-partner, which is an "uncertain stimulus with respect to neural processes that are engaged."

In their final study, Dr. Wager's team tested the responsiveness of the pain signature to the opioid analgesic remifentanil. They found that activity in the strength of the signature was "substantially" reduced when remifentanil was administered.

Toward a Better Understanding of Pain

In this 'neurologic pain signature,' activity in yellow predicts higher pain, blue lower pain. Courtesy Dr. Tor Wager, University of Colorado

Beyond its use as an assessment tool, the neurologic pain signature could help to identify separate contributions of multiple brain systems to pain, Dr. Wager told Medscape Medical News.

"It is likely that pain is not one 'thing' and that a mix of different experiences and judgments contribute to a person's assessment and reporting of pain. By identifying neural patterns that track certain types of pain in specific circumstances, we can better understand the different contributions made by each system to different types of pain, in different circumstances. This could allow us to identify different neurophysiological 'ingredients' of pain that respond to different treatments," he explained.

The pain signature could also help in evaluating existing treatments at the brain level and better understanding which pain-related processes are influenced by different treatments in different patient groups, Dr. Wager said. "Many treatments can relieve pain, from opiates to acupuncture to meditation, but it is not yet clear how all these treatments work in the brain or whether they work in the same way, or whether they have the same long-term implications for the health of the brain and the person," he explained.

Despite the promise of this research, the results require "cautious evaluation for several reasons," Dr. Jaillard and Dr. Ropper write in their editorial. They note that the researchers studied only cutaneous pain and not pain in the context of disease, so the findings may not apply to clinical circumstances, something the authors also make clear in their article.

The findings also don't shed light on the issue of chronic pain, "one of the most vexing problems in general medicine," Dr. Jaillard and Dr. Ropper note. They also write that the "spatial resolution used in the study was limited, reflecting the low sensitivity of the 1.5-T fMRI system that was used for most of the testing, and this may have led to the misidentification of small deep-brain structures that contributed to the neurologic signature response for pain."

They say further studies in diverse clinical circumstances with the use of more-sensitive MRI acquisition techniques are needed to validate any pain biomarker.

Dr. Wager and colleagues agree that more study is needed. "We are currently testing the generalization of the neurologic pain signature to other types of pain (cold, electrical, ischemic, mechanical, inflammatory, etc.)," Dr. Wager told Medscape Medical News. "We are also beginning to test it in patient groups, to develop the signature as a method for detecting hypersensitivity and allodynia, conditions of enhanced pain in response to normally innocuous or mildly painful stimuli."

Dr. Wager said his team is also using the neurologic pain signature to assess several kinds of psychological interventions, including cognitive regulation of pain, acceptance and mindfulness, expectation, distraction, and other interventions. "Ultimately, we would like to develop an understanding of how psychological and pharmacological interventions affect the way the brain constructs pain, and how 'deeply' these interventions influence how the brain processes pain-inducing signals from the body."

The study was supported by grants from the National Institute on Drug Abuse, the National Institute of Mental Health, and the National Science Foundation. Disclosures for authors and editorialists are available at

N Engl J Med. 2013;368:1388-1397, 1447-1449. Abstract Editorial


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