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The Brain in Pain: A Tipping Point?

At the 2014 Keystone Symposium on the Brain, a talk by CLBB Faculty David Borsook, MD, PhD, member of the CLBB Pain Working Group addressed the neurobiology of chronic pain. View the original posting and more coverage of the event at Pain Research Forum

Meeting co-organizer David Borsook, Boston Children’s Hospital and Harvard Medical School, Boston, US, led off a session on the question of what happens to the brain in chronic pain.

The brain is a state, and that state changes with pain, Borsook said. “Like epoxy—it is gooey when you first mix it, but then it solidifies. Likewise, pain transforms the brain, and we need to understand this transition better—from the premix to the solid state.”

Borsook said he sees three kinds of patients: those who get better as a natural course of the disease, those who improve nicely on a specific treatment, and a third group that does not respond to standard treatments, or even very aggressive therapy. “That suggests something about the brain has changed in these resilient-to-treatment patients,” he said. The challenge with chronic pain, as with any disease, is to identify those at risk of progressing to that resistant stage and to treat the problem early on.

What is the role of peripheral versus central processes in this progression of pain? “It is becoming trendy to consider how these systems may interact in a way to produce syndromes that are neither peripheral nor central,” Borsook said. But, he said, “Whatever the disease, whether it affects the peripheral nervous system or the central nervous system, pain occurs in the brain, and there is adaptation, or maladaptation, over time, to create chronic pain, or not. Pain by its very nature is a brain process!”

David Borsoo

Borsook reviewed several new circuits in the brain that are known to be changed in pain, involving the cingulate, the habenula, the insular cortex, and the basal ganglia. Each has proven involvement in chronic pain, and each is a target for new therapies, including, potentially, deep brain stimulation. That therapy involves implanting electrodes in the brain and is approved to treat Parkinson’s disease and depression. Deep brain stimulation is the subject of a new $30 million DARPA-funded initiative at Massachusetts General Hospital, with additional funding going to the University of California, San Francisco, US, to map brain circuits involved in neurological disease, including chronic pain, and develop implantable devices to modulate them.

As part of their pain research program at the Center for Pain in the Brain, Borsook and colleagues work with children with complex regional pain syndrome (CRPS), a condition that is difficult to treat in adults, but where younger people often show a good response to existing therapies. Borsook and coworkers have shown that CRPS is associated with functional changes in the brains of children, some of which reverse with successful treatment, but some of which do not (Linnman et al., 2013). Borsook’s colleagues at Boston Children’s Hospital have been very successful treating children with CRPS with a program of aggressive cognitive behavioral therapy and have shown that this treatment modulates activity in circuits involving the amygdala (Simons et al., 2014). More recently, they identified resting-state connectivity changes with the habenula in children with CRPS (Erpelding et al., 2014; Becerra et al., 2014 [in press]) and are now looking at whether treatment can normalize those changes.

This all argues for early identification of circuits at risk and aggressive therapy. “We need to catch patients in the early stages, either by predicting the process or by understanding their responses to treatments,” Borsook said. “The idea is that patients in pain are on a slide, and the further down they get, the harder it is to get back.” The tipping point comes, Borsook said, when circuits move from redeemable dysfunction to being irreversibly broken.

That includes response to drugs such as opioids. “We all think we are doing a good thing by giving this drug and that drug,” he said, but more and more examples show that drugs can sometimes trigger plastic changes that may make the situation worse: methadone addicts are more sensitive to pain, for instance, and opioid use can chronify migraine.

Borsook invoked the concept of allostatic load to explain the nature of the complexity and comorbidity of chronic pain, where a failure to adapt to repeated stress leads to maladaptation. He called chronic pain “a downhill march into allostatic disarray.” Moreover, it is “a disorganized downhill march: I’m in pain, I’m depressed, I’m addicted,” Borsook said. “For me, chronic pain patients are like cancer patients, but without a death sentence. So they are looking for anything and everything to get pain free or improve their pain status.”

Read more coverage from the 2014 Keystone Symposium on the Brain at Pain Research Forum.