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Brain Networks Predict Transition to Chronic Pain, New Study Suggests

Valeo, Tom

doi: 10.1097/01.NT.0000437151.32588.d3
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In a new study, DTI scans showed decreases in fractional anisotropy — a measure of the diffusion of water molecules in the brain — in multiple white matter bundles in people who developed chronic pain, including connections between the medial prefrontal cortex and the nucleus accumbens. This finding suggests either a deterioration of myelin, which is common with age and various dysfunctions, or, perhaps, inborn differences in connectivity.

The connectivity of the brain's white matter appears to play a crucial role in determining which people with lower back pain will go on to develop chronic pain, and which people will get better, according to a study published in the October issue of the journal Pain.

The results suggest that early and aggressive treatment may help prevent the acute pain from making changes to the brain that produce chronic, and perhaps permanent, pain, according to senior author Apkar Vania Apkarian, PhD.

“In our paper last year in Nature Neuroscience, we suggested that early treatment is in fact protective,” said Dr. Apkarian, professor in physiology, anesthesiology and physical medicine and rehabilitation at Northwestern University's Feinberg School of Medicine. “That seems to benefit patients. Even anti-inflammatories seem to give some protection, and giving them early seems more efficacious.”

The research reported in Pain is part of an ongoing study by Dr. Apkarian's lab of longitudinal changes in brain structure and function in pain patients. Their previous research has detected changes in gray matter in pain patients, and personality changes, but both appear to be caused by the pain.

In the current study, Dr. Apkarian and his colleagues have detected what appear to be inherent characteristics of the brain that predispose some people to developing chronic pain.

The researchers performed functional MRI and diffusion tensor imaging (DTI) on 46 people who had experienced subacute back pain for at least four but not more than 16 weeks. They followed the group for a year, administering periodic questionnaires about their pain. About half recovered during the year, while the other half had pain throughout.

The DTI scans showed decreases in fractional anisotropy — a measure of the diffusion of water molecules in the brain — in multiple white matter bundles in people who developed chronic pain, including connections between the medial prefrontal cortex and the nucleus accumbens. This finding suggests either a deterioration of myelin, which is common with age and various dysfunctions, or, perhaps, inborn differences in connectivity.

“The anatomical wiring of the brain across the population varies, and there is a subset of subjects vulnerable to chronic pain based on the axonal connectivity of their whole cortex,” said Dr. Apkarian. “Whether that's due to a gene, or to developmental changes, or just a part of the spectrum of variation of connectivity, we just don't know.”

The involvement of the medial prefrontal cortex, which plays such a large role in self-awareness and the regulation of emotion, could result in a form of emotional learning, according to Dr. Apkarian. “The brain is interpreting the back pain as an emotional learning signal that in turn reorganizes the cortex in a way that produces a persistent chronic pain state,” he said. “This is an idea we are testing in both humans and non-human animals.”

This finding provides what amounts to a biomarker for predicting who will develop chronic pain. “To me, the most important part of this study is the fact that, for the first time, we have detected a solid signal that identifies people vulnerable to becoming chronic pain patients,” said Dr. Apkarian. “The surprise to the community is that this signal has been found in brain connectivity. For 50 years, people have been looking for signals in the spinal cord, in the ligaments, in the skin, in the bone, in the nerve, and not much has come out of that. The signal we have detected in the brain seems very robust, validated, and reproducible, and provides a very high power of prediction — somewhere between 80 and 100 percent correct, which is massive. We wanted to publish in Pain so the pain community cannot ignore this. We need to start a new discussion of what is chronic pain.”

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While the data are “clear,” their interpretation “remains opaque,” according to George Bartzokis, MD, professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at the University of California, Los Angeles, who has done extensive research on the development, maintenance, and degeneration of myelin.

“You can say yes, there are some changes (in connectivity), but lots of things could be causing it,” said Dr. Bartzokis. “For example, when you're in pain, your cortisol levels usually go up, and when cortisol goes up, that can impact myelination. Cortisol and stress make the body say, let's not build anything or repair anything. Therefore, remyelination and repair stop.”

Misha-Miroslav Bačkonja, MD, medical director of neuroscience at CRI Lifetree in Salt Lake City, and adjunct professor of neurology at the University of Wisconsin, Madison, considers the research “elegant” and a logical extension of the work Dr. Apkarian has done for a decade, but he would like to know more about the clinical background that led to the findings.

“They have demonstrated clearly that the patients with subacute pain who recovered already were different at the subacute phase of low back pain,” he said. “The DTI signature they found is very different for patients who develop chronic pain. On the other hand, these results don't tell us why these patients are more likely to develop chronic pain — whether the finding is the cause or the result of processes that ultimately lead to chronic pain.”

Still, merely identifying the existence of a predisposition to chronic pain may help to improve diagnosis and ultimately treatment, Dr. Bačkonja added.

“Although the pain might start with a slipped disk or some other injury or insult, when the pain becomes chronic you see changes throughout the pain-related nervous system,” he said. “I'm puzzled by some of my colleagues in pain medicine who can't accept that chronic pain is a chronic disease, like diabetes. Now we have clear evidence that the entire system is affected.”



Dr. Apkarian's research, funded by the National Institutes of Health, the National Institute on Drug Abuse, and the National Institute of Neurological Disorders and Stroke (NINDS), provides an important first step toward ameliorating chronic pain, Linda L. Porter, PhD, a NINDS health science policy advisor for pain, told Neurology Today.

“I think it's a really important paper that builds on work reported a year or so ago where Dr. Apkarian and his team detected a decline in cortical gray matter among pain patients,” Dr. Porter said. “Both papers use imaging technology to predict which people who suffer acute back pain will go on to have chronic pain, and which will recover.”

The findings of Dr. Apkarian and his colleagues may provide the long-sought biomarker that identifies those most susceptible to developing chronic pain, she added.

“We know that after surgery for breast cancer or knee replacement, a certain number of people will go on to have intense neuropathic pain for months, years, or longer, and we don't know why,” Dr. Porter said. “It sometimes doesn't appear to involve nerve damage. If we could apply this technology with other pain conditions, we might learn how to help them avoid chronic pain.”

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Patients who developed chronic pain displayed lower fractional anisotropy (FA) in three clusters:

  • The temporal part of left superior longitudinal fasciculus (p-corrected = .027).
  • A cluster encompassing left retro-lenticular part of the internal capsule (p-corrected = .025) and the external capsule (p-corrected = .031).
  • The left anterior limb of the internal capsule (p-corrected = 0.032) and part of the corpus callosum including the anterior corona radiata (p-corrected = 0.022).

The researchers then pooled all voxels from the three clusters to calculate FA in all patients, corrected for the potentially confounding influence of age, and extracted a mean FA measure.

When subjected to receiver operating characteristic (ROC) curves, which identify true positives from total actual positives, Group FA at baseline accurately predicted which patients would develop chronic pain.

Tom Valeo

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•. Mansour AR, Baliki MN, Huang L, et al.Brain white matter structural properties predict transition to chronic pain. Pain 2013;154(10):2160–2168.
    •. Baliki MN, Petre B, Torbey S, et al.Corticostriatal functional connectivity predicts transition to chronic back pain. Nature Neurosci 2012;15(8):1117–1119.
      •. Neurology Today archive on chronic pain:
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