In “Key Milestones Contributing to the Understanding of the Mechanisms Underlying Fibromyalgia“, two Australian researchers give a fascinating overview of what they consider to be the breakthrough findings in FM.

There’s a lot going on in FM patients’ brains. But could the brain account for all the problems in FM? (Image by Oberholster Venita from Pixabay)

Tellingly, they quickly highlight neuroinflammation. In one of the first sections, “Neuroinflammation as a Peripheral Pain Mechanism”, they assert that neuroinflammation “likely contributes to many of fibromyalgia’s clinical features” … and may even produce the small nerve fiber neuropathy and found in the skin and corneas of many FM patients.

Not only that, but they lump FM’s allies (irritable bladder syndrome, migraine, restless legs syndrome (RLS), multiple chemical sensitivity (MCS)) in the same basket. (Why they didn’t include chronic fatigue syndrome (ME/CFS), I don’t know, but it would surely fit for them.)

The Nervous Nerves in Fibromyalgia

The good news is that if neuroinflammation is the cause of the multiple problems in FM, then at least we’ve defined a central cause. It’s an interesting one because back in the 1990’s, when central sensitization was first uncovered in FM, it was believed caused by the hyped-up activity of pain nerves – specifically the A-delta nociceptors connect to the dorsal horn of the spinal cord – and leading to the brain.

After repeated stimulation some pain producing nerves in FM get “wound up” = ready to send out pain signals at the slightest stimuli. (Image by PublicDomainPictures from Pixabay)

The dorsal horn of the spinal cord is going to be mentioned several times. It carries sensory signals from the peripheral nervous system to the central nervous system,

Next, researchers showed that in a process called “windup”, that if they repeatedly stimulated C-nociceptive (pain transmitting) nerves, those nerves would stay activated far longer in FM patients than in healthy controls. In healthy controls, the pain nerves quickly calmed down, but those nerves in FM got “wound up”.

Plus, they were able to show the nerves in FM patients were primed to act more quickly – they seemed to spontaneously erupt into action more. Those twitchy nerves affected the muscles as well. It takes less stimulation to produce a pain-evoked muscle response in FM than in healthy controls.

FM researchers next added yet another nerve to the FM hit list. Peripheral A-beta nerve fibers function as relays to the dorsal horn of the spinal cord from deeply embedded mechanoreceptors that respond to pressure. Some believe a sensitized pathway from the mechanoreceptors to the dorsal horn is producing the pain FM patients feel while bending, moving, etc. – anything that puts pressure on those mechanoreceptors.

The mechanoreceptor issue may have special relevance for the upper body, neck and head pain often seen in FM as the mechanoreceptors are particularly deeply embedded in and around the spinal column. That’s interesting given that recent study suggested that a type of connective tissue massage on the neck significantly reduced pain, muscle fatigue, and feelings of tension and anxiety.

Note that no mention has been made of the brain yet. Despite all the nerve issues found, the authors don’t believe they can explain the constant pain FM patients are in. The brain, they assert, must be involved. So how could the brain affect the activity of pain nerves in the body?

The Brain

Neurotransmitters

There’s a lot going on in the brains of FM patients. Take the two neurotransmitters primarily involved in the pain response – substance P and glutamate. Both these neurotransmitters turn on the N-methyl-D-aspartate (NMDA) receptors that increase the pain response – and both are increased in FM.

Substance P can do everything from sensitive nerves outside the spinal cord to enhancing the activity of pain processing regions in FM: it’s elevated in FM.

Substance P is a neuropeptide that is released from sensory nerves which can travel the length of the spinal cord. It by itself is able to sensitize the nerves in the dorsal horn of the spinal cord mentioned earlier. It’s also abundant in the emotional and pain centers of the brain. People with FM have been shown to have up to three times the normal levels of substance P in their brains.

Glutamate is the main excitatory neurotransmitter in the brain, but high glutamate levels can burn out nerves and activate the microglia. Studies suggest the neurons in FM patients’ brains are just itching to produce glutamate.

While not all the findings below have been validated, it’s possible that many other neurotransmitters may be altered in FM (calcitonin gene-related peptide, brain-derived neurotrophic factors, corticotrophin-releasing hormone, hemokinen-1, neurokinin A, neurokinin B, adrenomedullin, vasoactive intestinal peptide, neuropeptide Y, and gastrin-releasing peptide.)

Reduced Pain Inhibition 

But how are these problems affecting the pain signals coming up from the body? There are pain producing pathways that ascend to the brain and there are pain inhibiting pathways that descend from the brain to the spinal cord. One might think the ascending pain pathways are the problem, but no – it’s the poor performance of the descending inhibitor pain pathways that many FM researchers believe is really ramping up the pain in FM.

The recognition that inhibitory pain pathways descending from the brain play a major role in how much pain we experience sparked a revolution in our understanding of pain. Prior to that understanding, it was believed that pain signals were simply sent straight to the brain and that was it.

Now we know that how much pain we feel is, to a good extent, controlled by the brain. During times of danger, for instance, the brain may temporarily completely inhibit pain signals from the body. In the case of fibromyalgia, the opposite appears to be happening – the brain’s weak inhibitory pain pathways are believed to be allowing too many pain signals through.

Open checkpoints or gates may be allowing pain signals from the body to blast the brain.

It’s important to note that pain and sensory signals to the brain are always modulated. The brain can’t function if it’s exposed to every bit of sensory input the body is experiencing. It weeds out innocuous signals so that the more important signals can get through.

Ascending pain signals are believed to go through a series of checkpoints, or gates, which determine if they should continue on their journey. If those gates are stuck open – causing a cascade of signals to hit the brain – they could very well produce something like FM.

Problems with descending inhibitory pain pathways in FM and other chronic pain states are demonstrated by an interesting test. The arm is laid in cold water (causing pain) and then the pain sensitivity of another area of the body is tested.

Through a phenomenon called “controlled pain modulation”, causing pain in one area of the body causes other areas of our body to become less sensitive to pain. Animal studies show that the controlled pain modulation process is initiated in the brain and is believed to cause an increase in the activity of descending pain inhibitory pathways. Studies indicate that the activity of the pain processing regions of the brains of healthy controls actually declines when they undergo this test. This process is not working well in FM, though, and in some cases is not present at all.

There is a catch, though, to this descending pain inhibition hypothesis. It’s possible that the descending inhibitory pain pathways are working just as hard as they can in FM, but their inhibitory signals are simply being overwhelmed by a barrage of pain signals emanating from the damaged nerves in the body.

Plus, not all FM patients display problems with descending pain inhibition – for a substantial number of patients, their problems lie elsewhere. In fact, some researchers believe the cold pressor or thumbnail pain test could help doctors better treat their FM patients. One study, for instance, suggested that diabetes patients with descending pain inhibition problems do better with duloxetine that those who do not have this problem.

Autonomic Nervous System

The authors mostly ignore the autonomic nervous system, but studies have shown that reduced pain inhibition pathways are associated with low heart rate variability (HRV) in chronic pain. Low HRV refers to an inability of the parasympathetic nervous system (rest and digest) to control the sympathetic nervous system (fight or flight); in other words, another modulating process has gone awry in FM.

But what is the connection between the autonomic nervous system (ANS) and pain modulation? The ANS is one of the two main stress response systems in the body and pain has been shown to increase sympathetic nervous system activity. It’s possible that the reduced pain inhibition processes are also failing to activate that other notable modulator and calmer – the rest and digest, or parasympathetic nervous system, in the body – leaving one not only in pain, but edgy and having trouble sleeping as well.

That suggests that FM doctors should also consider assessing autonomic nervous system functioning. Mestinon (pyridostigmine bromide), an ANS regulator, has been helpful for some people with ME/CFS, who tend to have similar problems. The Open Medicine Foundation is funding the first ever Mestinon study in ME/CFS.

Brain Scans

Some think problems with the insula could produce many of the symptoms in FM.

Brain scans find yet more evidence of brain problems. SPECT scans have found altered blood flows in numerous parts of the brain (prefrontal cortex, thalamus, insula, somatosensory cortex, amygdala, caudate nucleus, inferior pontine tegmentum, parietal cortex, and the gyrus rectus).

Functional MRI (fMRI) studies indicate that the pain processing areas of the brain are more quickly activated than usual to painful stimuli. Even in its resting state, the fibromyalgia patient’s brain shows greater connectivity to the pain processing regions of the brain (insula and others) than usual.

At the end of the brain section, the authors return to neuroinflammation – perhaps the central process responsible for the symptoms found in FM. The evidence for neuroinflammation in FM is climbing. High levels of the pro-inflammatory cytokine IL-8 in the spinal fluid, evidence of brain glial cell activation, and high levels of metabolites associated with inflammation suggest that neuroinflammation may be widespread.

Conclusion

This brief nervous system primer on FM shows how much has gone awry.  It’s no wonder that FM has been called the “quintessential pain syndrome”.

From a bevy of hyperactive nerves in the periphery, to the possible loss of gating mechanisms, to high levels of pain enhancing neurotransmitters, to problems with the pain inhibiting pathways, to increased activation of the brain’s pain producing organs, to evidence of neuroinflammation, it seems that virtually every aspect of pain production process in the brain and nervous system is out of kilter in some way.

The fact that the brain can reach down into the spinal cord (and into the peripheral nerves?) and turn off pain signals is remarkable indeed. The brain’s amazing reach can be demonstrated by the role the insula – a small organ located in the middle of the brain – may be playing in FM. A recent review suggests that besides pain, problems in the insula could be contributing to the “heart rate and blood pressure, bladder and bowel symptoms, and anxiety and sleep disturbances” found in FM.

The central role the brain may play in FM suggests that rewiring the brain using drugs, neuroplastic approaches, magnetic stimulation, or other techniques could produce dividends. It also helps to explain why some drugs work when they do. Lyrica has been shown to reduce glutamate levels in the insula. Duloxetine may work better in FM patients who have controlled pain modulation (CPM) issues. The fact that many patients don’t benefit from these drugs is not surprising. More and more evidence suggests that FM is a quite heterogeneous condition.

While the authors believe the brain is producing all the symptoms in FM, a minority view believes it’s possible that the opposite is happening: that hyperactive nerves in the periphery  flooding the spinal cord with pain signals and overriding the brain’s natural pain inhibitory signals.

Some anecdotal reports suggest that things like vagus nerve stimulation (of a balky parasympathetic nervous system) can be quite helpful in the right patient. With that in mind, we should keep a close eye on the NIH’s SPARC Initiative, which  is dedicated to find ways to tweak the peripheral nerves, including the vagus nerve, for better health. Even if peripheral nerve problems turn out not to be the biggest drivers of pain in FM and similar diseases, they are clearly contributing to the problem.

Could the upper body pain in FM be caused by twitchy nerves communicating signals from the deeply buried mechanoreceptors? (Was the success of the (small) FM connective tissue neck massage study do to its ability to take pressure off the deeply embedded mechanoreceptors and their nerve pathways?)

The recognition that neuroinflammation, on the other hand, may be driving the pain in FM opens up an intriguing new target that could reap dividends given the intense interest given neuroinflammation in much better funded diseases. Many treatments are currently being assessed.

Whatever is happening, the many documented problems in the brain and nervous system in FM make it incredible that any doctor could believe this disease is not very, very real. They also may hint at why FM is so difficult to treat – the entire pain producing process has been affected.

One last note: given that a significant subset of FM patients do report an infectious trigger it’ll be very interesting to see how many cases of FM show up in the long haulers. Hopefully long hauler studies will help what’s happened in both ME/CFS and FM.