Every year, millions of people suffer from acute back pain. For some people, the pain persists for weeks (subacute pain) and then resolves, while others go on to develop long-term, debilitating chronic pain. Who will make that transition and how it happens remain mysterious. Now, using brain imaging, A. Vania Apkarian and his colleagues at Northwestern University, Chicago, US, have identified structural differences in the brain’s white matter—the bundles of axons that carry communications between neurons throughout the brain—in people whose pain persisted compared to those who recovered. If replicated in larger studies, the structural discrepancy may provide a biomarker of vulnerability to chronic pain. The group presented their findings in October at the 2012 annual meeting of the Society for Neuroscience in New Orleans, US.
Previous studies from the group found changes in grey matter volume and differences in functional connectivity in the brains of people who recovered from low back pain compared to those who made the transition to chronic pain (Baliki et al., 2012). That work also showed that early differences in functional connectivity, or the tendency for certain brain areas to activate together, could forecast which people would go on to develop persistent pain. Now, says Apkarian, they have determined that “the structure of your brain and, in particular, the hard-wired communication pathways, predict whether you’ll develop chronic pain.”
All together, the work from Apkarian’s group is reshaping the way researchers think about the transition from acute to chronic pain. This new work helps to fill out the time-line of events. People with this structural vulnerability, say the researchers, seem to develop a heightened emotional-learning response after injury, which in turn reorganizes cortical grey matter and functional connectivity into a chronic pain state.
The new study used diffusion tensor imaging (DTI), which measures the movement of water molecules in white matter bundles to determine “essentially the integrity properties of the white matter,” Apkarian said. Ali Mansour, who presented a poster describing the work, explained the technique. A free molecule of water is equally likely to move in any direction. But in a defined structure, such as a white-matter bundle, water is much more likely to move in one of two directions, along the axon tract. More restricted water movement, indicated by a higher fractional anisotropy (FA) value, signals a more tightly organized tract; a lower value indicates less structured connections. The investigators imaged the brains of 46 patients with subacute low back pain repeatedly over one year and found that, compared to people whose pain resolved, the people with persistent pain presented with lower FA values in specific brain areas: parts of the superior and inferior longitudinal fasciculus and regions of the anterior and posterior cingulate cortices.
Apkarian and colleagues designed their study to test the idea that the differences in brain structure might serve as a biomarker for the risk of chronic pain. To that end, the researchers split the group of subjects arbitrarily in two. In the first “discovery” group, they found less-organized white matter in half the participants’ brains. After a year, all 12 of those with lower FA had persisting pain, whereas the other 12 had recovered. In the second “validation” group, they tried to predict pain outcomes based on the FA values in the identified brain areas. From the earliest scan, structural measures predicted whether people would mend or transition to chronic pain with about 80 percent accuracy.
A particular strength of the work was the careful longitudinal assessment of patients with new low back pain, according to clinical neurologist Markus Ploner of the Technische Univeristät, München, Germany, who was not involved with the study. After screening hundreds of subjects from clinics across the Chicago area to find those with pain lasting between six and 14 weeks who had been pain free for the previous year, the researchers followed the patients for a year to determine who got better and who developed chronic pain. "The definition of two neat groups does not necessarily match clinical reality, but helps [us] to understand the crucial transition process from acute to chronic pain," said Ploner.
The structural quality held steady in each group over the course of the year, suggesting that white-matter features predisposed people to chronic pain rather than undergoing remodeling after injury. This is perhaps not surprising, given the more static nature of axon bundles compared to grey matter, where synaptic plasticity occurs. In support of the idea that the white matter structure was a stable individual trait, a separate group of patients with long-lasting, chronic back pain displayed FA values that were indistinguishable from those with persistent pain at one year.
In healthy control subjects, FA values ran the gamut from those seen in the people who recovered to those who developed persistent or chronic pain; the average was somewhere in between. The researchers interpret that as a range of structural integrity across the entire population. “White brain matter—the axonal properties—is stable and predictive,” said Apkarian. “In a sense, it renders a portion of the population vulnerable to injury.” How might this vulnerability arise? “We’re assuming it has some genetic component, and we’re in the process of testing that,” he said.
The experience of back pain can be quite heterogeneous across the population, and so can its many sources. But how the pain developed in the first place was not considered in the study, suggesting that the biomarker indicates vulnerability regardless of how the pain arose. “The brain structural properties robustly predict who will make the transition. What happened to start doesn’t matter,” said Apkarian.
While the imaging techniques are not exactly new, Ploner says, Apkarian “has helped introduce them to pain research … and made major contributions to the field of chronic pain and brain plasticity” in so doing. Ploner described Apkarian as “the pioneer in this field,” but added, “replication is urgently needed.” That’s not likely to happen soon; Apkarian estimates the cost of these experiments, which were possible only with the support of the National Institute of Neurological Disorders and Stroke (NINDS), at over $2.5 million.
Stephani Sutherland, PhD, is a freelance neuroscience writer based in Southern California.
Image: Van Wedeen, Martinos Center and Dept. of Radiology, Massachusetts General Hospital and Harvard University Medical School.