Chronic Pain Detected in the Brain for the First Time

— Real-world signals were seen mostly in the orbitofrontal cortex

An x-ray image of a patient with electrodes connected to both sides of their brain.
Frontal x-ray image showing brain recording electrodes connected to a brain stimulating and recording implant on both sides. Credit: Prasad Shirvalkar

Chronic pain was detected in the human brain for the first time, researchers reported.

Data were collected over months from four participants with refractory neuropathic pain who had intracranial electrodes implanted, according to Prasad Shirvalkar, MD, PhD, of the University of California San Francisco, and co-authors. Over 3 to 6 months, participants reported their pain levels several times a day at home while the electrodes recorded their brain activity.

The recordings showed that chronic pain states were mostly associated with activity changes in the orbitofrontal cortex, Shirvalkar and colleagues wrote in Nature Neuroscience. This differed from transient or acute pain, which was associated with anterior cingulate cortex signals in two participants.

Functional MRIs have shown that the anterior cingulate cortex and orbitofrontal cortex regions are activated during acute pain experiments, Shirvalkar noted.

"We were interested to see whether these regions also played a role in how the brain processes chronic pain," he said in a press briefing. "We were most interested in questions like how pain changes over time, and what brain signals might correspond to or predict high levels of chronic pain."

Pain is one of the most fundamental experiences an organism can have, Shirvalkar observed. "Despite this, there is still so much we don't understand about how pain works," he pointed out. "By developing better tools to study and potentially affect pain responses in the brain, we hope to provide options to people living with chronic pain conditions."

Chronic pain has no objective biomarkers to help guide diagnosis and treatment, Shirvalkar added.

In the U.S., the prevalence of chronic pain is about 21%, affecting an estimated 51.6 million adults. New cases of chronic pain occur more frequently than new cases of diabetes, depression, or hypertension.

This study, which was supported by the NIH's BRAIN and HEAL initiatives, may be a first step toward developing novel methods for tracking and treating chronic pain, noted Walter Koroshetz, MD, director of the National Institute of Neurological Disorders and Stroke. "We are hopeful that building from these preliminary findings could lead to effective, non-addictive pain treatments," Koroshetz said.

Shirvalkar and colleagues surgically implanted electrodes that targeted the anterior cingulate cortex and orbitofrontal cortex of four participants. Three participants had post-stroke pain and one had phantom limb pain.

Participants were asked to evaluate the pain they were experiencing -- strength, type of pain, and how the pain made them feel -- several times a day. They then clicked a remote-control device to create a 30-second brain recording of that moment.

Using machine learning methods, the researchers successfully predicted the pain severity scores of each individual from their orbitofrontal cortex activity with high sensitivity. Each person showed unique brain activity.

"Each patient's biomarker was actually like a unique fingerprint," Shirvalkar said. "I think that tells us something very important."

In a separate analysis, Shirvalkar and colleagues examined how the anterior cingulate cortex and orbitofrontal cortex responded to acute thermal pain. In two participants, activity in the anterior cingulate cortex predicted acute pain responses.

The findings suggest that signals in the orbitofrontal cortex can track current chronic pain severity for neuropathic pain syndromes such as central post-stroke pain or phantom limb pain, the researchers said. The data also suggest that the brain may process chronic and acute pain differently in chronic pain patients.

"Global cerebral pain networks in all participants likely underwent rewiring over many years living with chronic pain," Shirvalkar and co-authors wrote. "Still, ongoing 'background' chronic pain may have influenced acute pain perception even in the unaffected body side," they noted.

Future work involving more participants may help determine whether different pain conditions share the orbitofrontal cortex activity found in these participants or how signatures may vary among persons with different pain conditions, the researchers added. Whether similar signals could be recorded non-invasively with electroencephalography (EEG) is not known.

  • Judy George covers neurology and neuroscience news for MedPage Today, writing about brain aging, Alzheimer’s, dementia, MS, rare diseases, epilepsy, autism, headache, stroke, Parkinson’s, ALS, concussion, CTE, sleep, pain, and more. Follow


This study was funded by grants from the NIH BRAIN Initiative, the NIH HEAL Initiative, and the Defense Advanced Research Projects Agency (DARPA).

Medtronic provided research devices for use in this study and technical support through a research agreement with the University of California San Francisco, but no financial support. Authors declared no other competing interests.

Primary Source

Nature Neuroscience

Source Reference: Shirvalkar P, et al "First-in-human prediction of chronic pain state using intracranial neural biomarkers" Nat Neurosci 2023; DOI: 10.1038/s41593-023-01338-z.