PET/MR Imaging Shows First Evidence of Neuroinflammation in Chronic Pain Patients’ Brains

For the first time, researchers have used neuroimaging strategies to find evidence of neuroinflammation in major regions of the brains of patients with chronic pain.

By showing that levels of an inflammation-linked protein are raised in regions known to be involved in the transmission of pain, the study, published online January 12, 2015, in the journal Brain, offers new opportunities to explore potential new treatment approaches and identifies a potential new way around one of the most challenging limitations in the study and treatment of chronic pain: the lack of an objective way to gauge the presence or intensity of pain.

“Finding increased levels of the translocator protein in regions like the thalamus—the brain’s sensory gateway for pain and other stimuli—is important, since we know this protein to be highly expressed in microglia and astrocytes, the immune cells of the central nervous system, when they are activated in response to some pathologic event,” said Dr. Marco Loggia, assistant professor of radiology at Harvard Medical School (Boston, MA, USA) and Massachusetts General Hospital (MGH; Boston, MA, USA) , and lead author of the report.

“Demonstrating glial activation in chronic pain suggests that these cells may be a therapeutic target, and the consistency with which we found glial activation in chronic pain patients suggests that our results may be an important step towards developing biomarkers for pain conditions,” Dr. Loggia said.

Whereas many studies have distinctly linked glial activation with persistent pain in animal models, none has earlier validated glial activation in the brain of humans with chronic pain. The current study initially enrolled 19 patients with chronic lower back pain and 25 healthy control participants. In a subset of 10 patients and nine pain-free controls who were carefully selected from the initial larger group based on age, sex, and genetic characteristics, brain imaging studies were conducted with one of the Martinos Center for Biomedical Imaging’s integrated positron emission tomography/magnetic resonance imaging (PET/MR) scanners using a new radiopharmaceutical that binds to the translocator protein.

Dr. Loggia and colleagues discovered that translocator protein levels in the thalamus and other brain regions were substantially higher in patients than in control subjects. The PET signal increases were so remarkably consistent across participants, Dr. Loggia noted, that it was possible to identify who were the patients and who were the controls just by looking at the individual images before the detailed statistical analysis of the data.

Among patient participants who had been asked to report their current levels of pain during the imaging session, those with the highest levels of the translocator protein had reported lower levels of pain. “While upregulation of the translocator protein is a marker of glial activation, which is an inflammatory state, animal studies have suggested that the protein actually limits the magnitude of glial response after its initiation and promotes the return to a pain-free, pre-injury status,” Loggia explained. “This means that what we are imaging may be the process of glial cells trying to ‘calm down’ after being activated by the pain.”

Those participants with less pain-related upregulation of the translocator protein may have a more exaggerated neuroinflammatory response that ultimately leads to more inflammation and pain, according to Dr. Loggia. Even though larger studies would be needed to additionaly support this analysis, this evidence suggests that pharmaceutical agents called translocator protein agonists, which intensify the action of the translocator protein, may benefit pain patients by helping to limit glial activation.

Loggia noted that the ability to image glial activation could identify patients for whom the drugs targeting the process would be most appropriate. Future studies should investigate whether the same glial activation patterns are seen in patients with other forms of chronic pain or whether particular “glial signatures” may differentiate specific syndromes or pathologic processes.

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