The study showed the more the hippocampus — the brain’s memory center — talked to the cortex — involved in long term memory storage — the more likely the person is to develop chronic pain. In addition, the higher a person’s anxiety immediately after the car accident, the more precisely scientists could predict the chronic pain people reported one year after the accident.

This is the first study to show that only a few days after a given injury, the brain can adapt in a way that imparts a risk for the development of chronic pain.

The study will be published October 24 in Nature Mental Health.

The communication between the hippocampus and the cortex is thought to be indexing the formation of new memories related to the subjects’ accident and pain, said first author Paulo Branco, assistant professor of anesthesiology and pain medicine at Northwestern University Feinberg School of Medicine. “The hippocampus is responsible for consolidating new memories into long-lasting ones,” he said.

While the investigators don’t know why this heightened connectivity is a risk factor for chronic pain, they hypothesize that the brain of these individuals has encoded a strong memory associating a head and neck movement with pain.

“This creates expectations and associations,” Branco said. “If the memory has high emotional significance, then it makes these patients associate this movement with pain. When the brain receives these signals, it pays more attention to them based on the painful memories that were formed by the accident.”

“While we commonly think of pain as relating only to an injury, it is the brain that actually makes up the pain experience,” he said. “The brain makes the decision about whether a movement should be painful or not, and we think this may rely on previous experiences stored in memory.”

Knowing timing of chronic pain shifts focus to prevention

“Now that we know there is this critical time period when this happens, we can focus our treatment efforts at this early stage to prevent chronic pain rather than try to cure it, which is much more difficult,” said corresponding author Apkar V. Apkarian, director of the Center for Translational Pain Research and a professor of neuroscience at Northwestern University Feinberg School of Medicine.

“Since anxiety plays an important role for the brain changes, targeting the anxiety immediately after the injury may be able to halt these changes, possibly through anti-anxiety drugs or other medications,” Apkarian said. “Future novel treatments targeting hippocampal activity and connectivity through pharmacology or through neuromodulation techniques also are possible.”

The Apkarian lab has shown in previously published research that, beyond injury parameters, the brain plays a critical role in the development and maintenance of chronic pain. But until now the mechanisms of that remained poorly understood. How and why does the brain predispose patients to develop chronic pain? And is there a critical period during which brain changes occur that place patients at risk for chronic pain? The new study answers those questions.

Chronic pain exacts a significant burden on society, severely impacting the physical and emotional well-being of millions of patients worldwide. In the U.S., about 3.3 million adults currently suffer from chronic pain after whiplash injury, and many more from other chronic pain conditions. Current treatments for chronic pain remain minimal and unacceptable, the investigators said, and as a result a large proportion of patients use opioids, contributing to the ongoing national opioid epidemic.

How the study worked

This large-scale longitudinal study was conducted through a collaboration between the Technion-Israel Institute of Technology, Northwestern University, and McGill University. Investigators collected the largest longitudinal brain imaging dataset to date with more than 200 whiplash patients recruited, 177 of whom completed magnetic resonance imaging testing. The goal of the study was to identify early predictors of the transition from acute to chronic pain. This patient population provided a unique opportunity to study early brain changes after injury, as the onset of pain can be traced back to the time of the accident. The data was collected from March 2016 until December 2021.

Patients underwent functional magnetic resonance imaging within three days of injury, allowing investigators to examine brain activity in regions implicated in learning and memory at this critical timepoint. These patients were then followed over the next 12 months to assess pain levels and track which individuals developed chronic pain and which ones recovered. Participants also performed a large array of psychological and psychophysical tests, which investigators used to complement brain imaging findings.

What’s next in this research?

In the short term, the investigators plan to further study the underlying mechanisms behind the hippocampal response to injury, by assessing which additional physiological (cortisol, inflammation) and psychological (trauma and stress-related disorders, fear of movement) factors may further drive these brain mechanisms. They also aim to test whether these findings are generalizable across other chronic pain conditions. In the long term, the goal is to target these maladaptive responses early after injury to test their causal role in the development of chronic pain. This could involve the use of pharmacological treatments, cognitive-behavioral therapy, or transcranial magnetic stimulation.

This research was supported by the Department of Defense award W81XWH-15-1-0603, the National Institute on Drug Abuse grant P50DA044121, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01AR074274, of the National Institutes of Health.