Pain Is Not All the Same

Brain imaging studies like functional magnetic resonance imagery (FMRI) have provided tantalizing insights into the operation of the human brain. In this blog I’m going to review and highlight research and novel approaches by one of the leading researchers in the rapidly evolving area of chronic pain and the brain, Dr. A. Vania Apkarian, and his colleagues at Northwestern University, Chicago, Illinois.

Apkarian suggests that trying to study chronic pain using acute stimuli is like trying to pound a circular peg into a square hole … It doesn’t work

In the last 20 years an immense number of reductionist research papers exploring rodent models of chronic pain have been published but few new pharmaceuticals have been developed. Dr. Apkarian argues that some of the failings of pain research in the last 20 years have come from experimental designs focused on nociception and acute pain instead of the chronicity of chronic pain. He asserts that the pain processes in acute and chronic pain are very different.

The participants in most animal and human studies are subjected to a painful (acute) short term physical stimulant and their brain response is measured.  Dr. Apkarian, though, questions if rodent models of acute pain can tell us about long-lived chronic pain in humans. He also notes that in these studies pain is rarely triggered where chronic pain is typically felt in humans, such as the tender points or allodynia locations in fibromyalgia patients.

Many pain researchers, then, are applying an acute pain stimulus to a site that is not correlated with chronic pain in humans. What are these results telling us? Not much about chronic pain, says Dr. Apkarian.

Perhaps the most successful concept animal models have taught us about pain is the idea of Central Sensitization.  Central sensitization occurs when pain sensation is amplified (hypersensitivity) and when normally non-painful sensations such as touch, sound, light, and even smell are  translated into pain sensations. The central sensitization concept, which involves pain amplification at the brain level, expanded the focus of chronic pain research from peripheral pain processing to the spinal cord circuitry and into the brain.

Our understanding of the critical elements that induce and maintain central sensitization, however, is still very limited. We don’t know why the sensitization starts or how it turns into chronic pain.  Those questions are the focus of Dr. Apkarian’s research.

A Unique Approach to a Chronic Pain Therapy

Research indicates that different brain regions are involved in producing chronic pain and acute pain.  Acute painful stimuli in healthy people generally activate the somatosensory, insular, and cingulate cortical regions, while painful stimuli in people with chronic pain activate prefrontal cortex and limbic regions. This brain region difference implies that the processes for acute pain and chronic pain are different.

Research indicates that the brain activity patterns of each chronic pain condition (fibromyalgia, chronic low back pain, Chronic Regional Pain Syndrome (CRPS), etc.) appear to be unique to that condition. Chronic low back pain (CBP) patients show different brain wave patterns from Chronic Regional Pain Syndrome (CRPS) patients which, in turn, are different from the brain wave patterns in fibromyalgia patients. More importantly, he says, the implication that distinct chronic pain conditions have unique brain signatures opens the possibility of developing novel, specific therapies for each pain condition.

Instead of the somatosensory and other cortices that handle sensory signals, Apkarian’s studies suggest the prefrontal cortex and limbic system (pictured here) are involved in chronic pain.

Rather than the reductionist approach identifying the nerve fiber types, ion channels, etc. involved in pain the Apkarian lab took a top down approach by looking at the process of chronic pain from the brain’s perspective. Instead of building surrogate animal models of chronic pain in humans, the Apkarian lab is applying brain imaging information gathered in humans to rodent models of chronic pain, with the objective of developing new drug therapies.

Brain imaging of spontaneous pain (spontaneous pain is the ever present and ever fluctuating pain that all chronic pain patients experience) in humans showed the medial prefrontal cortex (PFC) and amygdala were deeply involved. The Apkarian lab interpreted this as implying that lateral atrophy of the PFC may underlie the enhanced activity in medial PFC.

In addition, rodent studies suggest NMDA transmission in the cingulate cortex may play a critical role in neuropathic pain. The Apkarian lab put these two facts together and wondered if D-cycloserine (DCS), an antibiotic, might be a potential drug for neuropathic chronic pain patients.

D-cycloserine is not your normal antibiotic. Not only is it able to cross the blood-brain barrier and penetrate into the central nervous system, it also enhances the activity of the N-methyl-D-aspartic acid (NMDA) glutamatergic receptors in the nucleus of the amygdala. Administered systemically or centrally, DCS has been shown to enhance cognitive processes, improve attention and memory, and facilitate fear extinction.

To me, enhancing the activity of NMDA seems counterintuitive.  I’d learned that NMDA was one of the bad boys you tried to quiet in pain, but here the Apkarian lab was trying to enhance its activity!

Human trials using an antibiotic that penetrates the brain which will hopefully will extinguish pain memories is under way.

The Apkarian lab theorized that DCS-induced reinforcement of NMDA-receptor mediated transmission in the prefrontal cortex enabled the prefrontal cortex to disengage spontaneous pain from its previously learned associations which it then placed into memory (similar to fear extinction).

They hypothesized that DCS should enhance the extinction of pain-related memories and thus exhibit anti-nociceptive properties for neuropathic pain.  (If your pain is associated with, say, walking, then walking will bring up pain memories and you will feel pain.)

So they tested the effects of DCS on chronic neuropathic pain behavior in lab rats. [1]The main finding was that repeated treatment with DCS reduced two signs of neuropathic pain in rats:  tactile sensitivity and protective paw posturing.

This anti-pain effect was dose-dependent, and the effect increased in efficacy for up to three weeks. Upon cessation of treatment, DCS effects on pain behavior persisted for a duration proportional to the length of treatment.

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A human clinical trial of DCS and chronic  back pain by Northwestern University in association with the Apkarian lab is slated to be completed this spring, 2014. Dr. Apkarian states that this is the first clinical drug therapy study directly derived from human brain imaging results.

A NEW THEORY OF CHRONIC PAIN

In 2012 Dr. Apakarian proposed a new theory of chronic pain that incorporates the emotional suffering and behavioral/cognitive modifications caused by the reorganization of the circuits in the brain. He emphasized that sensory processing issues – long thought to play a key role in chronic pain – probably do not.

… chronic pain can no longer be viewed as a pure perceptual state, that is, persistence of pain.

… Overall, the brain activity patterns and the changes in morphology and connectivity show a general picture that more closely resembles the addicted brain and provides no evidence for increased sensory processing of pain.

Reorganization and representation primarily involve limbic and prefrontal brain circuitry and minimally impinge on sensory properties of pain. We presume and hypothesize that these changes are a reflection of both the suffering and coping strategies that impinge on learning and memory and on hedonics of everyday experience.

Emotional and Motivational Circuitry Targeted

Apkarian asserts the state of the brain’s emotional and motivational circuitry is more important in causing chronic pain than the brain’s sensory circuits. The anxiety, depression, and dramatically reduced quality of life found in people with chronic pain reflects the intense emotional component present. (Apkarian’s most recent study, however, did not find that anxiety or depression were associated with altered connections in the brains of people with chronic pain.)

Apkarian’s work suggests that in chronic pain the emotional circuits of the brain start processing pain signals.

The fact that drugs (aspirin and opiates) that are highly effective in treating acute pain often have little effect in chronic pain suggests the two conditions are quite different. This suggests to  Apkarian that therapies targeting emotional suffering (the cortical limbic circuitry) may be more effective.

Therefore, we theorize that identifying and manipulating processes underlying the emotional suffering (cortical-limbic circuitry) should be more successful in treating chronic pain than the standard approaches … that have concentrated on the source of nociceptive signals in the skin and spinal cord.

Dr. Apkarian has some brain imaging research results to back up his proposed theory. Some of his lab’s other recent results were highlighted in recent blogs by Cort Johnson:

• Bad Wiring: Were You Set Up For A Life of Chronic Pain? A Source of Chronic Pain
• Shape Shifting Pain: When the Brain Becomes Emotional

The Apkarian Lab was the first to examine brain activity in a common pain condition as it transforms over time. They scanned the brains of 46 people who had low back pain for about three months before coming to the hospital but who had not had any pain for at least a year before. The researchers scanned the subjects’ brains and evaluated their pain with doctor’s examinations and questionnaires four times over a period of one year. About half of the subjects recovered at some time during the year, while the other half had pain throughout which the researchers categorized as “persistent” (think “chronic”).

The brains of the people who later developed chronic pain appeared to be primed to do so.

Previously, the Apkarian laboratory showed that the volume of grey matter in the brains of the same subjects who had persistent pain decreased over the same year. Grey matter describes the area of the brain where the central bodies and branched antennae, or dendrites, of nerve cells reside. In this study, at the beginning of the experiment the researchers measured the structure of brain white matter, which connects brain cells in different parts of the brain. They found a consistent difference in white matter between the subjects who recovered and the subjects who experienced “persistent” pain. 

The researchers also found that the white matter of subjects who had “persistent” pain were similar to people with long term chronic pain. In contrast, the white matter of the subjects with acute pain who recovered looked similar to that of healthy control subjects. Next the researchers asked whether the white matter differences they saw during the initial brain scans predicted who would develop chronic back pain. They found differences in brain white matter found at the beginning of the pain process predicted at least 80 percent of the outcomes!

They also looked at the brain activity signatures of some of these patients. The acute back pain patients who had high functional connectivity between the medial prefrontal cortex and nucleus accumbens (areas more related to emotions) at the outset of the study were more likely to experience persisting pain.

“Brain signatures of pain became more emotional in nature, although the description by the patients of their pain remained constant. … The idea that certain perceptions, like pain, are only encoded by certain brain regions has left its mark on psychology and neuroscience. This is the first unequivocal evidence that that cannot be tenable. ” 

It’s important to note that the studies were done on patients with chronic low back pain. The Apkarian lab results, among others, have made it apparent that the brain signatures for different chronic pain states are different, so it’s not clear that these findings apply to other chronic pain states such as fibromyalgia, complex regional pain syndrome (CRPS), the various forms of chronic neuropathic pain, etc., as Apkarian theorizes.  One area that has not been explored is how chronic pain brain signatures change over time.  Time and more research will hopefully tell the story.

Conclusions

The Dr. Apkarian’s lab reverse translational approach to chronic pain has resulted in clinical trials of an antibiotic for chronic neuropathic pain. Their research suggests people with “chronic” back pain had unique white matter brain signatures prior to the development of their chronic pain, and upon developing the chronic back pain have very different brain activity signatures from patients who have acute low back pain.

The brain signatures of the people who develop chronic back pain show increased activity in the areas of the brain that are connected to emotions. This increased activity may be due to atrophy in the prefrontal cortex, the part of the brain that controls executive functioning.

Apkarian targets an entirely different part of the brain than other pain researchers

Brain imaging studies have shown no evidence of increased nociceptive representation in the brain but rather point to enhanced activity in the emotional cortical-limbic circuitry. This has led Dr. Apkarian to theorize that identifying and manipulating the processes underlying emotional suffering may be much more successful than the current methodologies which have been largely unsuccessful.

On a personal note, I spent the two days before this final edit of this piece, crashed and mostly in bed, humbled by the severity of the pain I was experiencing.  So I want to emphasize that these researchers are not saying that your chronic pain is “all in your head” or “chronic pain patients are faking it”, but that some chronic pain conditions apparently result in a very complex dance between emotions and chemistry being performed and, like many of you reading this, I am simply exploring the moves to this dance in a quest to quiet the pain.

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