The Brain in Pain: A Tipping Point?
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 Borsook
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 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.”
From the gut to the brain
Gastroenterologist and neuroscientist Emeran Mayer, University of California, Los Angeles, US, spoke about how visceral pain changes the brain. Visceral pain with no apparent cause is a feature of several common and overlapping syndromes, including irritable bowel syndrome (IBS). The gut is richly innervated and sends a large amount of sensory input to the brain, of which 90 percent is not consciously perceived. One theory is that in IBS, “remapping” of normally subconscious interoceptive inputs in the anterior insula onto circuits involved with salience and arousal generates feelings of pain and discomfort. As time goes by, the expectation of pain and discomfort (e.g., after eating) may further worsen the perception of gut inputs.
As Mayer described it, “In the morning, patients worry about experiencing abdominal pain and discomfort during the day. This prediction will amplify gut signals associated with food intake, resulting in abdominal pain.” He noted that abnormal worrying about symptoms correlates with symptom severity in IBS. Studies suggest that upregulation of sensory processing networks in the brain, with a prominent role of memory, emotions, and cognition, combine to produce a disconnect between stimulus and response in people with chronic visceral pain.
Emeran Mayer
Women are more likely to have IBS than men, and imaging studies show important sex differences in brain structure and function in women versus men with IBS. For example, Mayer and colleagues observed no significant differences in cortical thickness in a large group of 176 healthy controls compared to 90 people with IBS. But when the researchers compared sexes separately, differences emerged both between sexes and between healthy and IBS groups (Jiang et al., 2013). Furthermore, the differences in thickness in the somatosensory cortex and other regions between healthy females and female patients correlated with symptom severity. An important remaining question is whether increased cortical thickness observed in women puts them at risk for chronic pain.
In a series of papers published over the past year, the group has described additional sex-specific structural alterations in patients with chronic visceral pain from IBS compared to healthy controls (Ellingson et al., 2013) and changes in brain networks in women with IBS (Labus et al., 2014).
The group has described sex differences in brain function, too. Intrinsic brain oscillations measured with resting-state functional MRI differed between sexes, consistent with higher levels of emotional arousal in women compared to men. Some of the differences tracked with symptoms (Hong et al., 2013).
Mayer showed new data indicating that functional connectivity of portions of the anterior insula is different between male and female IBS patients. As with earlier studies, they found if they combine sexes, they don’t see significant results, but when they look at males and females separately, the differences emerge. “The key message is it doesn’t make sense not to take sex differences into account, and you need large enough groups to break out males and females for analysis.”
Mayer said that his group is beginning to use differences in brain structure to classify patients. In a large combined data set derived from several studies, diffusion tensor imaging tractography can classify patients with chronic pelvic pain versus healthy controls at 97 percent accuracy, he reported.
A newcomer to the visceral pain field is the microbiome, the collection of microorganisms that populate the intestinal tract. The composition and metabolic activity of the gut microflora is emerging as a critical regulator of human health and disease. The role in visceral pain conditions is an area of active research for Mayer. “We don’t know enough about contribution to chronic pain to discuss this yet,” he said. But his group is collecting gut microbiomes from their patients for analysis, and their very preliminary data are pointing to correlations between gut microbiome metabolites and brain alterations. “It’s very exciting,” Mayer concluded.
In his talk, A. Vania Apkarian, Northwestern University, Chicago, US, suggested a new way to think about chronic pain. Rather than define chronic pain on the basis of its persistence over time (currently, six months is the standard), he suggests a different definition, based on how the pain is processed in the brain.
Previously, Apkarian showed that people with chronic low back pain shift the areas of the brain that are activated by ongoing pain, from mainly sensory areas activated by acute pain, to limbic regions including those involved in emotion and memory (see PRF related news story on Hashmi et al., 2013). For each different chronic pain condition, the details of the reorganization are different, but the general shift from sensory to other regions is the same.
A. Vania Apkarian
Based on this work and the work of others, a picture is emerging in which chronic pain engages the brain’s emotional learning circuitry, in effect reorganizing the way pain signals are processed, and changing the value of pain to the organism. Chronic pain is not acute pain that lasts a long time; it is a different state of the brain and sensory system, Apkarian said.
Apkarian showed new data on the network proprieties of brain activity in people with chronic pain. The brain is organized somewhat like airline traffic in the US, he explained, with local transportation networks converging on hubs that are then linked over longer distances by air routes. If a hub is disrupted, that does a lot of damage to overall communications. Apkarian said he sees hub reorganization in resting-state brain networks in people with osteoarthritis, CRPS, or chronic back pain, and that the degree of reorganization correlates with pain intensity across these three pain conditions. The same networks can be detected on the anatomical level, with correlations in gray matter density. In people with chronic pain, Apkarian sees disruption in normal patterns that are characteristic for the different chronic pain conditions. These changes seem to occur over time: the subjects in this study averaged 12 years of back pain or 1.7 years with CRPS.
These are all cross-sectional studies, and Apkarian updated results on his longitudinal study. Previously, his group reported that the extent of functional connectivity of the prefrontal cortex with the nucleus accumbens as well as white matter properties can predict who will go from acute to chronic pain (see PRF related news story on Mansour et al., 2013; Baliki et al., 2012). He showed new data suggesting that both hippocampus and amygdala morphology in people with acute-onset back pain are also predictive of who will get chronic pain.
Overall, his results support a picture in which chronic pain is the result of an injury or insult acting on a neurological vulnerability, which includes limbic risk factors. The ability to identify people at risk for chronic pain will be very important in the delivery of the right level of care early on to prevent long-term consequences.
For other coverage of the meeting, see Part 1 and Part 2.
Image: © iStockphoto.com/raisbeckfoto
Article Contributors:
