Marker Maps Fibromyalgia Pain

A marker that maps painful body areas could validate the widespread nature of fibromyalgia. One promising molecule is TSPO (translocator protein).

TSPO appears on the surface of many immune cells, but only under certain conditions. It acts like a flag, signaling that the cell is actively fighting inflammation. Marco Loggia, Ph.D., from Harvard Medical School, discussed TSPO’s potential role in detecting inflammation and pain.* In particular, he described how researchers are testing it for fibromyalgia and related chronic pains.

Neuroinflammation

To grasp TSPO’s significance, you first need to understand neuroinflammation. This term describes ongoing inflammation in the central nervous system (brain and spinal cord). The key players are glial cells, which are constantly on the lookout for any signs of danger. In healthy individuals, these cells quickly eliminate threats to the nervous system and then revert to their surveillance mode.

“Sometimes these immune responses become problematic,” says Loggia. “Activated glial cells continue unchecked even after the initial threat is resolved. They overstay their welcome and become harmful.” This leads to chronic neuroinflammation, which is linked to diseases like Alzheimer’s, Parkinson’s, and schizophrenia.

TSPO and Brain Imaging

Sampling brain tissue is too invasive. Alternatively, the brain can be imaged using PET (positron emission tomography). PET involves injecting a radioactive tracer that binds to TSPO, producing a signal on the brain scan. In healthy brains, TSPO levels are barely detectable. However, neuroinflammation increases TSPO production, which shows up as hot spots on PET scans.

Loggia studied painful conditions with evidence of neuroinflammation using PET to tag TSPO. Examples included fibromyalgia, low back pain, and migraines. The TSPO hot spots indicate activated glial cells, which may contribute to persistent pain. The location of the TSPO signal is particularly revealing.

Signal Locations

Loggia’s first PET studies using a TSPO tracer were performed on people with chronic back pain. Sometimes, patients showed a strong TSPO signal in the cortex, but not always. Loggia suspected leg pain was the driving force.

“Comparing patients with leg pain versus spinal pain, those with added leg pain showed a greater signal in the cortex,” says Loggia. He also assessed patients for their “fibromyalgia-like” score. The higher the score (more painful body areas), the greater the signal, particularly in the somatosensory region of the cortex.¹

“The somatosensory cortex contains a full representation of the body,” says Loggia. “Different parts of this cortical region process sensory inputs from different body parts.” For low back pain patients, “We saw a TSPO signal elevation in the cortex that matches the regional representation of back and leg pain.”

What about people with migraines? The TSPO signal appears in the cortical area representing the face/head.

Looking at fibromyalgia patients, Loggia says, ”We should see the whole somatosensory cortex light up because patients report widespread pain. And that is what we see.”² Indeed, Loggia’s finding was replicated by an AFSA-funded study.

No Sex Differences

TSPO is a marker on immune cells, and there are often differences in how the immune system works in men and women. However, Loggia did not see any sex differences in his low back pain studies.

Spinal Cord

So far, all studies relate to findings in the brain. Can TSPO pick up pain in the spinal cord? Yes, Loggia showed TSPO can detect areas of inflammation in the spinal cord of back pain patients.³ It also illuminated the surrounding structures, such as the nerve roots and the dorsal root ganglia (or DRGs). The DRGs contain the cell bodies of nerves just before they enter the spinal cord. While the DRGs reside outside the cord, they are enclosed by TSPO-producing glial cells. More importantly, the DRGs are implicated in contributing to fibromyalgia pain.

Peripheral Cells

“Wouldn’t it be wonderful to use the same marker to image inflammation in the brain, spinal cord, and peripheral tissues like joints?” asks Loggia. Since many immune cells produce TSPO, it might work as a marker outside the nervous system too.

Loggia tested TSPO’s ability to detect inflammation caused by knee osteoarthritis. He examined PET scans of people with and without knee pain due to osteoarthritis. Just like the “hot spots” in the brain that reflected inflammatory pain, the TSPO signal was intense for those with osteoarthritis. Loggia could also tell if patients had arthritis in one or both knees.

While knee osteoarthritis is not fibromyalgia, Loggia’s study reveals two important findings:

• The intensity of the TSPO signal is proportional to the level of knee pain.
• The TSPO signal strength correlates with the concentration of several immune substances in the blood.

This suggests that TSPO may detect pain and inflammation in tissues, although more studies are needed.

Treatment Response

If TSPO can pick up pain and inflammation, it might be useful for measuring physiological responses to treatment. Often, therapies for fibromyalgia don’t pan out because short-term improvements are fueled by hopeful thinking. A tool that objectively tracks improvements in pain after treatment is needed.

For example, in knee osteoarthritis, total knee replacement removes the source of inflammation, yet 30 percent of patients continue to experience pain. Loggia found that TSPO signals in the brain before the knee replacement helped predict response to the surgery.

The pre-surgery signal was more intense for patients who still had knee pain one year later. “This suggests that the TSPO signal we are measuring is not an epiphenomenon,” says Loggia. “It appears to have something to do with the establishment or maintenance of persistent pain.”

High-intensity signals in the sensory cortex reflect the “fibromyalgia-like” nature of the pain. These TSPO signals also depict the degree of neuroinflammation in the brain. As new treatments are developed for fibromyalgia, researchers might first put them to the “TSPO test” or something similar.

Beyond TSPO

Loggia highlights using TSPO as a marker for chronic pain and neuroinflammation. However, detecting TSPO using PET requires injecting a radioactive tracer, which is not ideal. Fortunately, new tools are being developed.

“Many groups around the world are looking at the concentration of brain metabolites believed to be linked to glial cell activity,” says Loggia. In fact, several research teams are focused on fibromyalgia. The next step will be to compare these metabolites with TSPO findings in the same patient. If a substantial overlap exists, these metabolites may be a suitable alternative. But for now, Loggia concludes, “The use of TSPO to image peripheral and central nervous system inflammation (and pain) is opening new doors.”

1. Alshelh Z, Loggia ML, et al. Brain 145(3):1098-1110, 2022. Free Article
2. Albrecht DS, Loggia ML, et al. Brain Behav Immun 75:72-83, 2019. Free Article
3. Albrecht DS, Loggia ML, et al. Pain 159(5)968-977, 2018. Free Article

* Neuroinflammation: Does it have a role in human chronic pain? by Marco Loggia, Ph.D., presented at the International Association for the Study of Pain (IASP) World Congress, August 5, 2024.

Targeting the Gut in Fibro

Your gut bacteria or microbiota form a living community that communicates with your brain. In fact, your microbiota exert significant control over your overall health. Five years ago, Amir Minerbi, M.D., Ph.D., of Israel published a groundbreaking study showing microbiota abnormalities in fibromyalgia.¹ Today, the microbiota is the focus of a novel method to treat fibromyalgia.

If studying your gut microbes seems off topic for fibromyalgia, see our article on Gut Influences. Ordinarily, the microbiota and central nervous system have a “healthy” relationship. But in people with fibromyalgia, the bugs living in the gut are different from healthy, pain-free people. New research by Minerbi’s team reveals that the altered microbiota are linked to fibromyalgia symptoms.²

Transferring Fibro to Mice

Transplanting the microbiota from fibromyalgia patients into the digestive tract of mice causes the animals to become pain sensitive. The process is called fecal microbiota transplantation (FMT).  The changes in pain sensitivity during the first two weeks are linked to alterations in the mouse’s microbiota. Not only does the microbiota of the mice mimic that of the fibromyalgia patients, but the mice also develop fatigue. FMT from healthy people has no impact on symptoms or the mouse’s microbiota.

Pain Precedes Depression

All too often, fibromyalgia is wrongly dismissed as depression or anxiety. The medical community calls these “affective traits.” Understandably, affective traits negatively impact a person’s health and contribute to reduce pain thresholds. However, it is frustrating for patients to be told that their fibromyalgia is caused by their state of mind.

To set the record straight, Minerbi selected fibromyalgia patients who did not have symptoms of depression or anxiety. “It was important to show that pain hypersensitivity is not mediated by affective traits,” says Minerbi. “The fact that pain is detectable in the mice days following FMT but depressive signs arise months later is a hint that pain precedes depression.”

“The notion of ‘it’s all in your head’ or ‘fibromyalgia is a psychosomatic condition’ should be eliminated from the medical discussion,” says Minerbi. “Patients, families and clinicians need to know this.”

Altered Metabolism

Gut microbes can influence the production of pain-enhancing amino acids like glutamate and alter fat metabolism. The microbiota can also increase the production of bile acids that cause pain, rather than relieve it. These unwanted effects are well-documented in people with fibromyalgia.  And it turns out, the mice receiving FMT develop the same metabolic abnormalities as the patients.

The mice didn’t just have increased glutamate in their blood, the concentration of this pain transmitter was also elevated in the central nervous system. This goes to show that transferring microbiota into the gut significantly impacts brain function.

Immune Changes

Your intestines are lined with immune cells. In addition, lymph and a variety of immune cells surround your digestive tract. If the microbiota in the gut is altered in an unhealthy way, the immune system might become actively defensive. This angle was explored by Minerbi’s colleague, Arkady Khoutorsky, DVM, Ph.D.*

Looking at the numbers of immune cells in the blood of mice, Khoutorsky found the memory B cells were nearly depleted. Memory B cells help your immune system remember prior exposures of potentially threatening agents. If the agent enters your body again, your memory B cells pump out antibodies to neutralize the threat. Khoutorsky did another test that showed increased activation of the immune system. 

People with fibromyalgia have activated immune cells in their brain called microglia. Minerbi found these same cells to be on guard in the brains of mice exposed to fibromyalgia FMT. To measure the microglia’s role, he blocked their activation with a medication prior to the FMT. The ability of fibromyalgia microbiota to produce pain sensitivity was greatly reduced. “These results indicate that the development of pain after fibromyalgia FMT is partially mediated by the microglia.”

The Neurons

Most fibromyalgia patients will say their skin burns, their muscles ache, and their brain function is dulled (e.g., fibrofog). It’s hard to believe that the far-reaching effects of fibromyalgia are solely due to malfunctions in the brain and spinal cord. Conversely, if the muscles were the source of disease, how would one explain the common symptoms of fibrofog and sleep disorder?

Prior studies show the dorsal root ganglia (DRG) are the target of a misbehaving immune system in fibromyalgia. “The DRG is an attractive target” says Minerbi. “But in our study, there are changes in all levels of the pain-signaling pathways. The peripheral small nerve fibers, the DRG, the spinal cord, and the cortical structures in the brain are all involved.” At least, this is what Minerbi found in the mice when he looked at the effects of FMT from fibromyalgia patients. So, the neurons at all levels of the nervous system may be contributing to your symptoms. 

FMT in Fibro Patients

A small trial of FMT from healthy subjects to fibromyalgia patients led to a 30 percent reduction in pain. But just doing the FMT alone did not work. Patients had to be given antibiotics before the ten-week trial (five transfers every two weeks).

“The microbiota in the gut is a stable environment,” says Minerbi, “and it’s resilient to transient perturbations. The amount of bacteria we give in FMT is many orders of magnitude smaller than that of the established microbiota in the gut.” So, antibiotics are given to clear out the existing bacteria and allow the transplanted bacteria to take hold.

Based on the success of this small trial, a large placebo-controlled study is underway. Minerbi’s team will be looking at which bacteria improve the most, in addition to alterations in the metabolic and immune system variables.

“We hope this will help explain why certain fibromyalgia patients respond better than others,” says Minerbi. “We also want to identify the biological mechanisms responsible for symptom improvements.”

Designer Treatments

Even if FMT turns you off, it provides much-needed answers from a research perspective. Perhaps the greatest downside of FMT is that it cannot be commercialized. Minerbi points out that some companies already have FDA-approval for microbiota-based therapeutics. Basically, these companies aim to develop specially formulated probiotics to treat illnesses like fibromyalgia.                               

“We aim to identify the bacterial species that are critical for effective fibromyalgia treatment out of the hundreds that are given during FMT,” says Minerbi. “Then these species can be developed into future therapy for the disease. Since fibromyalgia is a diverse condition, there may need to be more than one formulation.” Indeed, tailored treatment based on one’s microbiota composition may be required.

In the Meantime …

If you are tempted to purchase a variety of probiotics to see if they will tame your fibromyalgia, press the pause button. Hundreds of bacterial species live in the gut but only a few are contributing to your fibromyalgia symptoms. On the other hand, Minerbi says that the probiotics on the market do not contain any species suspected to be involved in the disease. You are also up against the fact that your existing microbiota community is resilient to change.

It’s frustrating to know that a disruption of your microbiota is likely linked to your symptoms, but you can’t just correct it with probiotics. Until designer probiotics become available, Minerbi recommends a low-sugar and gluten-free diet, exercise regularly, and get plenty of sleep. These measures are known to help maintain a healthy community of gut bacteria.

Research takes time, and this is frustrating to hear. But keep in mind that seven years ago the microbiota was not known to be involved in fibromyalgia. “The results are promising, so there is hope on the horizon,” says Minerbi.

*  Minerbi’s team of collaborators include Yoram Shir, M.D., Arkady Khoutorsky, DVM, Ph.D., and Emmanuel Gonzales, Ph.D., of McGill University in Canada and Nicholas Bremerton, Ph.D., of University College in Dublin.

1. Minerbi A, et al. PAIN 160:2589-2602, 2019. Free Abstract
2. Cai W, Shir Y, Minerbi A, Khoutorsky A, et al. BioRxiv Oct 28, 2023. Free Report

The Ups & Downs of Exercise

Exercise floods the body with feel-good endorphins, clears the mind, and ramps up the cardiovascular system. It’s invigorating, unless you have fibromyalgia. The processes controlling cardiovascular workouts do not work correctly, causing exercise difficulties in fibromyalgia patients.

Dane Cook, Ph.D., of the University of Wisconsin, says, “People with fibromyalgia show an abnormal response to gentle exercise.” ¹ According to a report by Bruno Gualano, M.D., of Brazil, fibromyalgia patients do not accelerate their heart rates adequately during increased activity.² And a study by Jose Parraca, Ph.D., of Portugal, shows that the oxygen supply to the muscles is impaired (even at rest) in people with fibromyalgia.³

The above studies highlight a variety of reasons why you encounter difficulties with overexertion. Yet, understanding what you are up against will help you tailor activities to accommodate your dysfunctional response to exercise.

System Controllers

Control of heart rate is based on input from two different nerve branches: your sympathetic (fight or flight) and your parasympathetic (rest and digest). Together, they make up your autonomic nervous system—it’s the network of nerves that communicate between your spinal cord and your peripheral tissues (e.g., your muscles and organs).

To ensure your organs respond appropriately to any challenge, your nervous system must be responsive and flexible. The control dials for either branch must be capable of going from zero to zoom in a split second. Let’s face it, your environment and activity levels are constantly changing, so a flexible autonomic system is essential.

The diagram shows how the two opposing on/off inputs from your sympathetic and parasympathetic nerves control your heart rate. Think of it like two kids on a seesaw that works best if balanced (i.e., both children weigh the same). Yet the timing from one lift off to the next varies, just like your heartbeat, because the system has built-in flexibility.

If you dash out of a burning house, your adrenaline-controlled sympathetic branch should kick in to get your body moving and your heart pumping. If you are digesting your dinner or trying to fall asleep at night, the calming actions of your parasympathetic branch should take over.

Low Heart Rate

People with fibromyalgia have too much sympathetic nervous system activity, even when relaxing.⁴ Mild challenges to the body, such as standing up or being exposed to cold, may also lead to unwanted symptoms. When switching from reclining to standing, your heart should pump more blood to the brain to prevent lightheadedness. Exposure to cold requires increased circulation of warm blood to your extremities to prevent Raynaud’s-like symptoms (painful spasms in the hands and feet).

Reduced heart rate in response to exercise is a risk factor for cardiovascular disease. This prompted Gualano to look at the differences in cardiac functions between fibromyalgia patients and healthy controls during exercise. Not only did he measure the heart rate at peak exercise capacity, but he also looked at how fast the heart slowed down after ceasing activity. Ideally, the heart rate should increase rapidly to adjust to the body’s physiologic demands, but once resting, its rate should drop quickly.

“Fifty-seven percent of the fibromyalgia patients exhibited slow heart rate response to exercise, but none of the healthy controls,” says Gualano. “The reduction in heart rate was also slower in the fibromyalgia group during the two minutes post-exercise.”

Why was the heart rate so low in people with fibromyalgia? Gualano says, “The autonomic nervous system is not as flexible as it should be.” Exercise ought to prompt the sympathetic system to get the heart pumping while forcing the calming parasympathetic branch to withdraw control. The reverse should occur during rest, yet an imbalance called dysautonomia exists.

The cause of dysautonomia remains unclear. Gualano emphasizes the sympathetic system is super-charged at rest and unresponsive when challenged. A hyperactive sympathetic system leads to a chronic pounding on the receptors in the heart that help regulate how fast it beats. After a while, these receptors become indifferent to the sympathetic system’s demands, which makes the heart less responsive to activity challenges.

Fibro is to Blame

Could Gualano’s finding be due to a lack of exercise or a reduced fitness level? Or could symptom severity play a role? The answer is no, based on two reports from another Brazilian team.

The first study compared fibromyalgia patients to healthy controls who were matched for their level of physical fitness.⁵ Despite the same fitness levels, the fibromyalgia group had a reduced heart rate response to an exercise challenge. The speed at which their heart rate returned to resting levels was also slower. In addition, measures of autonomic nervous system function revealed an imbalance between the sympathetic and parasympathetic branches.

The above findings run counter to what is known about exercise and fitness levels, at least in healthy people. When a healthy person becomes sedentary, their sympathetic and parasympathetic systems become unbalanced, but they can correct this with exercise. So, the same research team sought to answer another question: could the dysautonomia in fibromyalgia be related to symptom severity?

Dividing fibromyalgia patients into two groups based on symptoms, moderate and severe, they compared fitness measures and autonomic functions to a healthy group.⁶ Although the level of physical fitness was worse for the severe fibromyalgia group (compared to the moderate), their autonomic nervous system function was equally impaired. 

What does this mean for you? Lack of exercise or symptom severity do not appear to contribute to your level of dysautonomia. In fact, the sympathetic dominance with reduced parasympathetic activity is likely adding to your fibromyalgia symptoms, rather than being the result of inactivity.

Altered Response

If exercise does not increase heart rate appropriately, what about the rest of your cardiovascular system? Cook’s team looked at how this system worked in fibromyalgia patients (compared to controls) while performing mild exercise. He found the heart pumps harder during exercise in fibromyalgia patients, and the rest of the cardiovascular system doesn’t keep up.

“These results indicate that exercise for fibromyalgia patients is more difficult than for healthy individuals on many levels … but it doesn’t mean that increasing physical activity won’t help some of these abnormalities.”

Muscles Lack Oxygen

To increase delivery of oxygen and nutrients to your muscles, your sympathetic constricts blood vessels to speed up the flow. However, your parasympathetic is responsible for relaxing or expanding the arteries so that a larger quantity of blood can be delivered.

Given the studies showing an overpowering sympathetic system with inadequate parasympathetic activity, are your muscles getting the oxygen they need? No.

Parraca’s team in Portugal assessed the amount of oxygen delivered before, during and after exercising the thigh muscle in fibromyalgia patients and healthy subjects. The healthy group showed an increase in oxygen consumption during the exercise, while there was virtually no change in the fibromyalgia group. Even at rest, the oxygen supply was significantly less in the patients.

Another finding by Parraca’s team shows that people with fibromyalgia experience a 50 percent drop in saliva secretion during exercise.⁷ Why is this important? Saliva flow is controlled by your parasympathetic system, and its dramatic decline is a sign of dysautonomia. It also explains why you may develop dry mouth when you exercise or overexert yourself.

Staying Active

Intense exercise will set you back, so the best you can do is move regularly at your preferred pace. If you maintain your own natural speed (which is much slower than healthy people), energy consumption is optimized. Moving too fast or vigorously may force your muscles to operate without enough oxygen and lead to more symptoms.

Another study shows that a self-paced program (on land or in the water) leads to slow improvements in speed over two to three months.⁸ Benefits in physical function take time and cannot be rushed. And if you can keep it up, you may also notice improved coordination and cognition.

One more point: make use of warm water. Heat invokes the parasympathetic system to relax your blood vessels to help your muscles receive more oxygen and nutrients. In addition, you have heat sensors in your tissues that work to help relieve pain. If you are struggling with an exercise program, warm water therapy may be the solution for you. If this is not feasible, the next best thing is taking a hot shower or bath just before working out.

1. Cook DB, at al. Med Sci Sports Exerc 44(6):1186-93, 2012.
2. Da Cunha Ribeiro RP, Gualano G, et al. Arthritis Res Ther 13:R190, 2011.
3. Villafaina S, Parraca JA, at al. Biomedicines11:132, 2023.
4. Lerma C, at al. Arthritis Ther Res 13:R185, 2011.
5. Schamne JC, et al. J Clin Rheumatol 27(Suppl 2):S278-S283, 2021
6. Sochodolak RC, at al. J Exerc Rehabil 18(2):133-40, 2022.
7. Costa AR, Parraca JA, at al. Diagnostics 12:2220, 2022.
8. Tiinus PM, at al. J Sports Sci Med 1(4):122-27, 2002.