Through Brain Imaging Analysis in Rats, Penn Researchers Show Potential to Predict Whether Pain Will be Acute or Persistent

Pain may be a universal experience, but what actually causes that experience within our brains is still poorly understood. Pain often continues long after the relevant receptors in the body have stopped being stimulated and can persist even after those receptors cease to exist, as is the case with “phantom limb” pain.

The exact experience an individual will have after a painful incident comes down to the complex, variable connections formed between several different parts of the brain. The inability to predict how those connections will form and evolve can make pain management a tricky, frustrating endeavor for both healthcare providers and patients.

Now, a team of Penn researchers has shown a way to make such predictions from the pattern of neural connections that begin to take shape soon after the first onset of pain. Though their study was conducted in rats, it suggests that similar brain imaging techniques could be used to guide treatment decisions in humans, such as which individuals are most likely to benefit from different drugs or therapies.

Beth Winkelstein, Megan Sperry, and Eric Granquist
Beth Winkelstein, Megan Sperry, and Eric Granquist

The study, published in the journal Pain, was led by Beth Winkelstein, Eduardo D. Glandt President’s Distinguished Professor in Penn Engineering’s Department of Bioengineering and Deputy Provost of the University of Pennsylvania, along with Megan Sperry, then a graduate student in her lab. Eric Granquist, Director of the Center for Temporomandibular Joint Disease at the Hospital of the University of Pennsylvania in the Department of Oral & Maxillofacial Surgery, and assistant professor of Oral & Maxillofacial Surgery in Penn’s School of Dental Medicine, also contributed to the research.

“Our findings provide the first evidence that brain networks differ between acute and persistent pain states, even before those different groups of rats actually show different pain symptoms,” says Winkelstein.

The researchers induced either acute or persistent temporomandibular joint (TMJ) pain in different groups of rats. They then performed PET scans on the rats at the start of the experiment, as well as seven and fourteen days afterwards. At seven days, rats in both acute and persistent groups were still showing symptoms of pain, while at fourteen days, only the persistent group was.

By finding correlations in activity between different brain regions in these scans, the researchers were able to draw networks of the connections between those regions and assess how their structure changed over time. While the behavioral symptoms of pain in the two groups would make them hard to distinguish at first, differences in their brain networks showed which would go on to experience persistent pain.

“At day seven, peripheral sensitivity, measured by an increased reflex response to stimulation of the TMJ, is detected in both groups,” says Sperry. “However, at day seven, increased clustering, node strength, network segregation, and activation of prefrontal limbic pathways are observed only in the group that experience persistent pain. At day fourteen, increased clustering and node strength are more pronounced in the persistent group, especially within the limbic system.”

The researchers also pretreated a subset of rats in the persistent pain group with an anti-inflammatory drug used in humans, including TMJ patients, to prevent joint damage and pain. They found that rats in this group did not undergo the same network adaptations and activation of pain-associated neural circuitry that their untreated counterparts did.

“These findings suggest that brain networks could be used to guide therapeutic development and predict which patients could benefit from therapy,” says Sperry. “Network data from PET imaging, MRI, and electroencephalography could be particularly useful as selection tools for enriched clinical trials or for screening prior to invasive procedures.”

The study comes at a time when research on TMJ and other temporomandibular disorders are of increasing priority. Citing the Penn team’s earlier work, The National Academies of Science, Medicine and Engineering issued a report earlier this year that emphasized how such disorders remain poorly understood and undertreated.

“And although this study focused on the development of TMJ pain,” says Winkelstein, “it is expected that this experimental approach could be extended to other pain disorders and diseases of the central nervous system to investigate critical shifts in disease states that promote chronic symptoms.”

This research was supported by the Catherine D. Sharpe Foundation, Oral and Maxillofacial Surgery Foundation, and Oral and Maxillofacial Surgery Schoenleber Research Fund.

Sperry is now a postdoctoral fellow at the Wyss Institute and Tufts University.