It’s clear that glial cells – immune cells found in the brain and the spinal cord – play an important role in producing chronic pain and neuro-inflammation. Glial cell activation in the brain is often measured using the levels of a benzodiazepine receptor, TSPO, which affects immune and neurosteroid functioning in the body and/or brain.
A genetic and brain imaging study suggests many people with fibromyalgia have a propensity for neuroinflamation
In the brain, TSPO regulates the production of neurosteroids which affect GABA. Low GABA levels are associated with chronic pain, mood disorders, and some neurological diseases.
Depending on TSPO’s activities it can either enhance GABA levels and reduce pain, or reduce GABA levels and increase pain. Which way GABA goes is often determined by the amount of serotonin (5-HT) present in the nerve synapses.
Some call serotonin and GABA – the two “feel-good” chemicals in the brain, the ‘great nervous system stabilizers.”
The Study
The translocator protein gene is associated with symptom severity and cerebral pain processing in fibromyalgia Eva Kosek a,b,⇑, Sofia Martinsen a, Björn Gerdle c, Kaisa Mannerkorpi d,e, Monika Löfgren f,Indre Bileviciute-Ljungar f, Peter Fransson a, Martin Schalling g, Martin Ingvar a, Malin Ernberg h, Karin B. Jensen a Brain, Behavior, and Immunity xxx (2016) xxx–xxx
This study examined whether FM patients carry gene variants which make it easier for glial cell activation to occur via the TSPO receptor, or which lower the amount of serotonin present. A positive result would suggest that the brains of people with fibromyalgia are genetically susceptible to producing neuroinflammation and/or reducing GABA levels.
Some studies suggest a strong genetic component exists in FM. Other studies indicate that the nervous system pathways designed to inhibit pain are underperforming in fibromyalgia, while those designed to enhance pain are going full bore.
Somewhat surprisingly no attempts to directly measure the amount of neuroinflammation present in fibromyalgia have been made. One study which found elevated levels of a cytokine (IL-8 – CXCL1) that co-occurs with TSPO in FM patient’s cerebrospinal fluid suggested that glial cell activation may be occurring.
This Swedish study (n=174 FM patients):
- Determined whether FM patients carrying the gene variants which accelerate glial cell activation or diminish serotonin levels experienced more pain
- Used brain imaging to determine if people with these gene variants had increased glial cell activation. They determined this in an indirect way by measuring the activity of a pain-producing pathway that runs from the prefrontal part of the brain to the parietal cortex.
- Assessed pain sensitivity using a pressure test
- Did a subanalysis to determine the effects of anti-depressants on pain
Results
The fibromyalgia patients exhibited a startling propensity to carry the gene variant (TSPO HAB) associated with rapid glial cell activation. Over half of the group (66) carried that gene while another 40% carried a mixed genetic package. Only about 10% of the FM patients carried the low-affinity form of the gene.
Fibromyalgia patients with two gene variants affecting pain pathways were in the most pain
The people carrying the gene variants associated with increased glial cell activation did indeed experience higher levels of pain severity and worse fibromyalgia overall (FIQ -fibromyalgia impact quotient). Neither anxiety or depression was affected by the presence of the variant.
Serotonin gene variants, on the other hand, were not themselves associated with increased pain. People carrying both the glial cell activation and the reduced serotonin genetic variants, however, were in the worst shape of all.
The brain imaging results indicated that the 50% or so of the fibromyalgia patients carrying the high glial cell activating variant demonstrated increased activation of a brain network (frontoparietal) believed to play a significant role in increasing “vigilance” and anticipation. If you have difficulty relaxing, if you feel that your system is always on edge, if you have difficulty concentrating or feel “wired and tired” this activated network could be playing a role in that.
These same patients, interestingly enough, did not exhibit increased pain sensitivity. They were in more pain, but they were not more sensitive to painful stimuli. A pressure pain sensitivity test which involved pressing down on a part of the body until pain registered did not, oddly enough, find increased pain sensitivity in this group.
That suggested that the glial cell activation seen in FM may primarily affect hypervigilance and anticipation (even though it did not affect anxiety). Hypervigilance or increased pain anticipation may, then, play a significant role in the increased pain levels experienced by these patients.
This study suggests that this hypervigilant state may be genetically encoded – ready to pop out when levels of GABA/serotonin are reduced or chronic pain is present. Many studies have shown that hypervigilance and the anticipation of pain can significantly increase one’s pain levels.
Treatment
The authors suggested that treatments targeting glial cell activation could be helpful. Jarred Younger at the Univ. of Alabama at Birmingham is currently testing glial cell inhibitors in both fibromyalgia and gulf war syndrome.
The study results also suggested that FM patients carrying the gene variant that increases the likelihood of glial cell activation might be more likely to benefit from serotonin-enhancing drugs such as SSRIs or SNRIs. A subanalysis found that FM patients with the glial cell enhancing gene variant who were taking antidepressants were in no more pain than the FM patients with the glial cell activity gene variant; i.e. the antidepressants appeared to help reduce pain in this set of patients.
The authors did not mention 5-HTP, a serotonin supplement that a 1990 study found helpful. Dr. Murphree asserts that taking 5-HTP is more effective than trying to squeeze out more serotonin from an already depleted system. He’s found 5-HTP to be particularly helpful with sleep. Another natural health practitioner recommends trying passion flower and St. John’s Wort (but not if you’re currently taking antidepressants) to increase GABA/serotonin levels. Another recommends adding magnesium to the mix.
*Be careful about taking 5-HTP if you’re taking tramadol, dextromethorphan (found in cough syrup) or triptans, as it may increase serotonin too much, resulting in a dangerous condition called serotonin syndrome.
- See Dr. Murphree’s 5-HTP Protocol for Enhancing Sleep in Fibromyalgia
- Using 5-HTP to Increase Serotonin Levels in Fibromyalgia and ME/CFS – From Dr. Murphree
The study suggests that a genetic test could help determine which FM patients would respond to antidepressants. (It should be noted that antidepressants are more than mood enhancers; some “antidepressants” can reduce pain in FM patients who are not depressed.)
Although the authors did not mention them, behavioral approaches designed to reduce hypervigilance and anticipation and induce calm might be helpful as well. Meditation, for instance, has been shown to increase serotonin levels in the brain.
Conclusion
Female fibromyalgia patients carrying a gene variant associated with increased glial cell activation tend to be in more pain and have a lower quality of life than without that gene variant. More studies are needed, but this study suggested that a high proportion (@50%) of FM patients may carry this variant.
Genetic variants common in FM may lead to a hypervigilant state and more pain.
A gene variant which reduces serotonin levels by itself does not appear to increase pain but having both gene variants only adds to the problem.
If you have these variants serotonin-enhancing drugs such as SSRIs or SNRI’s (or supplements such as 5-HTP) or behavioral practices such as meditation might be helpful.
FM patients carrying the glial cell enhancing gene variant were in more pain but did not display increased pain sensitivity during a pressure test. This and the finding that the brain pathways affected by this gene variant are associated with hypervigilance suggest that glial cell activation may put some FM patients into a hypervigilant or “wired and tired” state. Many studies indicate that hypervigilance and the anticipation of pain result in increased pain.
Future drugs that target glial cell activation could be helpful in fibromyalgia.
Thanks, Cort, interesting and complicated. When you start talking hyper vigilance, you start thinking PTSD. A lot of FM folks have physical or emotional trauma in their background and, as a psychologist with FM, I think I can make a good case for FM symptoms as a probabe trauma variant, though I’m not the first to do so. I’m looking into EMDR as possible treatment though I don’t meet PTSD criteria.
Wish I could get some genetic stuff done but not clear where to get this kind of specific stuff.
Hello Steve, I just sent in to be tested to 23 and me. It’s suppose to get the genetic DNA. It most likely will take about a month for me to get any answers. Be prepared to answer many back ground questions about your history of your health. FM is in the questionnaire. Good luck if you try it.
Let us know what you find.
I trying out self-decode to see what they saw about my 23andme results.
Fibromyalgia home remedies are always recommended to treat. Read more http://tiny.cc/y1jpiy
Hi Steve, Just wondered if I correctly interpreted your comment : that you can make a strong case for FM as a (physical) manifestation of physical and/or emotional trauma. As a psychotherapist who specializes in trauma clients, many being abused women, I would say few have FM, many have PTSD. I also have had many clients with FM, due to it being public that I have it, and most don’t have a trauma background. I think it is very important to be extremely careful when implicating a psychological response to trauma as the source for FM. If your supposition is true, we’re back to FM being essentially a form of mental illness, with psychotherapy being the primary treatment: this is a very outdated viewpoint. I think the role of psychotherapy is in helping clients learn to more successfully live with a difficult chronic illness, with the client defining what success is, and to provide non judgmental support. Over the 40 years I’ve worked with incest, rape, domestic violence, war vets, physical abuse, etc., I’ve seen lots of PTSD, but not any statistically elevated amount of FM.
First, Beth, thanks for your EMDR post. Next on my list to contact an expert.
Susan, I also have no history of abuse, neglect, or formal trauma. There is evidence of brain damage with fMRI for those of us with FM as well as those with PTSD. Are they the same areas, I’m not sure. FM is just a constellation of symptoms; you can get there from a car accident or watching a friend die in an IED. A huge of percentage of women I’ve seen at the local public MH Clinic were both traumatized and have FM. Is correlation causation, maybe not for them but I developed FM 30 years ago while my brother was dying of AIDS and also had to help my father, who coincidentally had an MI and bypass, and my sister in law, who became psychotic. We know that stress, of which PTSD is one manifestation, causes physical disorders. I’m not saying that “whiny middle aged women” are causing their FM symptoms, I’m saying there’s a good chance their FM brain damage, inflammation, whatever we call it, was caused by their body’s psychological response to past rape, abuse, etc. reorganizing their nervous system patterns. Certainly not everyone with PTSD gets FM and not everyone with FM has diagnosable PTSD. Conceptually and symptomatically, though, with energized sympathetic systems and diminished parasympathetic ones, they appear related to me and others. Read The Body Bears the Burden and The Body Keeps the Score, both by different top notch non-quack physicians. These disorders change our nervous systems. After having failed every possible pharmacological and non pharmacological FM treatment, I’m going back to dealing with the neuropsychological more directly, first with hypnotherapy for pain, then likely EMDR for…well, trauma- like phenomena that probably caused my pain to become crystallized somehow. I know EMDR therapists are treating FM people both with no trauma history and with past trauma history with some success. While I don’t look forward to revisiting 30 year old traumatic losses, as well as added subsequent ones, there’s nothing left but the OxyContin my PCP wants me to try and that could be the end of the line.
I can say from experience that, empirically, EMDR was quite helpful for me. I, too, had some previous trauma, which is what we focused on at the time… But after reading this article, it’s clear that I am one of those with increased pain, less sensitivity to pressure test (still have tender points, just not allodynia) & general hypervigilence. So I guess my point is, if a patient feels like this & has issues to work on with EMDR, do it! Genetic testing will be icing on the cake, or another level in the future, but why not get some relief today, right? Also, Cort, nice clear write-up. I was validated in several meds & supplements I use. Very useful; thanks!
I tried EMDR for what you speak of above and it didn’t help expensive and nothing. I understand now that the hyper-vigilance is cause by either a physical or emotional trauma concerning toxins.Emotional trauma makes a lot of toxins, when your body can’t detox cause your cup is overflowing, no EMDR therapy can help. According to Dr. Poma at Cellular Health TV.com, if we don’t discover the root or roots we can’t fix ourselves and it all is in the cell. He has so many video/articles that is just so interesting because he talks about mehtylation and the mito and explains what the issues are and that there is a way back. He himself was very ill extremely and it took him a long time to figure the formula to restore cellular health. I am not attached to Dr Pompa or the Revelationhealth.com website. I am merely sharing with you what I have learned and am giving you his name in case you want to check it out. I have been around the block with not being well. So I think I have a feel for at least some of this stuff. You be your own judge. Just listen to his videos and interviews with good doctors. See what you think. Thanks for letting me post here.
Oh sorry I forgot to mention that Dr. Pompa talks about the genes getting turned by different things and that by focusing in on the causes, and other things, our genes can be turned off by what he calls the 5 R’s. You just have to listen to his talks.
Also all this is intertwined with Autoimmune diseases in case you wanted to know. He does have a ton of videos, I mean a ton. You might find some answers. Being Hypometabolic is not new at all. Do You have adrenal issues? Thyroid issues? Think Hypometabolic. Well I don’t mean to sound like I know it all. I don’t. That’s not my intention. Just trying to share with the least amount of typing. Thanks again.
Yes Dr. Whiting just noted on this thread – https://www.healthrising.org/forums/threads/mella-finds-hypometabolic-state-in-chronic-fatigue-syndrome-plus-rituximab-and-new-drug-for-me-cfs.5004/#post-25386 that he used calorimetry to diagnose hypometabolism – and hypothyroidism.
Thanks for sharing that Lyn 🙂
Let us know if you can do it. I got my gut biome analyzed and it was in a format that just listed the bacteria in a string in a way that I couldn’t figure out.
I am looking forward to genetic testing when the ship comes in and parks under the money tree. I’m looking at 123andme and another site (name escapes my sleepy brain right now) to see if I can get the results I need for more than Fibro. (It has to do with hypothyroidism and Hashimoto’s.) I have Fibro also — for 33 years or more. In addition, I have ME/CFS, RA, Lupus, and so many of the things we get from those, like IBS, fatigue, fetc.
I slowly took myself off of Prozac (40mg) after a successful ride with it since about 1987. I did this as a trial because I got EDS (excessive daytime sleepiness) and couldn’t read one sentence (literally) without falling asleep, couldn’t drive, walk the dog, etc. I had minimum withdrawal from Prozac onIy about three times. Doc put me on Adderall and I had noticed there was a big ZERO feeling of depression and sadness/gloominess for the first time in eons. The miracle drug, it is.
I was also on Gabapentin 2400 mg, originally for restless leg syndrome (Gosh “they” have to change that name!). When I heard that Gaba was being prescribed for Fibro I laughed out loud! But that was then, and I get it now. I think. I still take two 300 mg pills a day for RLS but I’m not sure I need it. I’m just not ready to find out.
My point is that related to the article, I suffered no ill affects from reducing these meds, despite the research shown here. I wonder what my genes will look like!
But I did do something else quite some time after that and changed my diet to gluten-free, dairy-free, soy-free, and a bunch of other stuff. I love eating this way and have added supplements that are really clean.
My inflammation is reduced from the diet for sure. I do not have less pain in my back, but there is a lot of bone loss, disk troubles and spurs (degenerative disk disease) and sciatica, curvature, stenosis.
I truly believe, and have begun some intensive research over the past few months, that our genetic make up, and what we make of that with lifestyles, will prove to determine our health. We are what we ingest and breathe also. To me, the future of medicine is the functional, integrative approach and I hope my grandchildren will grow up knowing what the right things are for caring for themselves and staying healthy and strong!
Thank goodness for Cort and the others like him who make it possible for us to dig deeper, think deeper and work through changes for better health!
I would agree that among the factors that combined to trigger FM in me, were several that could indeed act via a pathway of permanent hypervigilance in the brain. Including chronic stress and physical trauma.
I am not sure, though, how my very focused physical and metabolic approach of the last few years, has wound back my condition. I wouldn’t say that there was any psychological decrease in hypervigilance. The big change I made 20 years ago in my career (quit the unfairly stressed job), would have helped in that direction, but it did not give me the clear improvement that I have had in the last 3 years.
By the way, I am one of the subset of people for whom SSRI’s cause “Akathisia” – this was hell while it lasted, I gave up the SSRI cold turkey when I discovered the connection between what I was going through, and the drug (thanks Google – I was not warned by the prescribing doctor or by the notes that accompanied the drug). Came right within 48 hours, after having got steadily worse as I continued the introductory dose of the drug. This side-effect was much worse than the FM symptoms it was supposed to suppress.
It was so bad that I understand why some people on SSRI’s commit suicide – Akathisia is almost certainly what drove them out of their minds. Most of the medical descriptions understate it as “extreme restlessness”. For me, the “extreme restlessness” was because of a sensation that some horrific “entity”, perhaps like a psychological Black Hole, was swamping me all over from nowhere. The worst urge I had to fight, was the one to throw myself out the window, through the glass, 2 stories up. The idea of being dashed with force against a hard surface such as the ground, presented a kind of prospect of relief. You can take this as a graphic description from a survivor, and pass it on to doctors or whoever might be interested to know.
I contacted an elderly aunt the next day when I realized it was the SSRI doing it (I worried that it was my own depression worsening, for which a higher SSRI dose would have been the next step!), and she said “everyone in our family who has tried SSRI’s has suffered side effects like that, I would have warned you”.
These are some of the results I got from my 23andMe test. wonder have any others got similar results. and any comments to make.
NAME CONFIDENCE STATUS
Alpha-1 Antitrypsin Deficiency
Established Research: Multiple studies with 750+ participants, or scientific consensus
Variant Present; Possibly Higher Risk “Has one M and one Z version of the SERPINA1 gene. People with this combination may be at increased risk for liver disease, and may experience decreased lung function if they smoke.”
Alzheimer’s Disease (APOE Variants)
Established Research: Multiple studies with 750+ participants, or scientific consensus
ε4 Variant Present; Higher Risk
Early-Onset Primary Dystonia (DYT1-TOR1A-Related)
Established Research: Multiple studies with 750+ participants, or scientific consensus
Variant Absent; Typical Risk
Factor XI Deficiency
Established Research: Multiple studies with 750+ participants, or scientific consensus
Variant Absent; Typical Risk
Familial Hypercholesterolemia Type B (APOB-Related)
Established Research: Multiple studies with 750+ participants, or scientific consensus
Variant Absent; Typical Risk
Familial Transthyretin (TTR) Amyloidosis
Established Research: Multiple studies with 750+ participants, or scientific consensus
Variant Absent; Typical Risk
Hereditary Breast and Ovarian Cancer Syndrome (BRCA1- and BRCA2-Related, Selected Mutations)
Established Research: Multiple studies with 750+ participants, or scientific consensus
Variant Absent; Typical Risk
Hereditary Hemochromatosis (HFE-Related)
Established Research: Multiple studies with 750+ participants, or scientific consensus
Variant Present; Typical Risk
Hypertrophic Cardiomyopathy (MYBPC3 25-base-pair Deletion)
Established Research: Multiple studies with 750+ participants, or scientific consensus
Variant Absent; Typical Risk
Inherited Thrombophilia (Factor V Leiden- and Prothrombin-Related)
Established Research: Multiple studies with 750+ participants, or scientific consensus
Variant Absent; Typical Risk
Parkinson’s Disease (LRRK2- and GBA-Related)
Established Research: Multiple studies with 750+ participants, or scientific consensus
Variant Absent; Typical Risk
The genotyping services of 23andMe are performed in LabCorp’s CLIA-certified laboratory. The tests have not been cleared or approved by the FDA but have been analytically validated according to CLIA standards. The information on this page is intended for research and educational purposes only, and is not for diagnostic use.
AATD is caused by variation in a gene called SERPINA1 that encodes the alpha-1 antitrypsin (AAT) protein. This protein normally protects lung tissue from damage. The variants that cause AATD trap the abnormal AAT protein in the liver and reduce levels of this protein in the bloodstream and lungs. AATD can lead to emphysema (a type of chronic obstructive pulmonary disease) and liver disease.
The three versions of the SERPINA1 gene covered by this report are called PI*M (the normal version), PI*S, and PI*Z. A person inherits a copy of the gene from each parent, yielding six possible combinations: MM, MS, MZ, SS, SZ, and ZZ.
PI*Z is the most severe variant and the ZZ genotype accounts for 95% of cases of AATD. People with the SZ genotype are at an increased risk for COPD, particularly if they smoke. The MZ genotype causes only a mild reduction in AAT protein levels, but may lead to decreased lung function in smokers.
NAME CONFIDENCE STATUS
Proton Pump Inhibitor (PPI) Metabolism (CYP2C19-related)
Established Research: Multiple studies with 750+ participants, or scientific consensus
Rapid
Hepatitis C Treatment Response
Established Research: Multiple studies with 750+ participants, or scientific consensus
Reduced
Pseudocholinesterase Deficiency
Established Research: Multiple studies with 750+ participants, or scientific consensus
Increased
Abacavir Hypersensitivity
Established Research: Multiple studies with 750+ participants, or scientific consensus
Typical
Acetaldehyde Toxicity
Established Research: Multiple studies with 750+ participants, or scientific consensus
Typical
Clopidogrel (Plavix®) Efficacy (CYP2C19-related)
Established Research: Multiple studies with 750+ participants, or scientific consensus
Typical
Fluorouracil Toxicity
Established Research: Multiple studies with 750+ participants, or scientific consensus
Typical
Phenytoin Sensitivity (Epilepsy Drug)
Established Research: Multiple studies with 750+ participants, or scientific consensus
Typical
Simvastatin-Induced Myopathy
Established Research: Multiple studies with 750+ participants, or scientific consensus
Typical Risk
Sulfonylurea Metabolism
Established Research: Multiple studies with 750+ participants, or scientific consensus
Typical
Thiopurine Methyltransferase Activity
Established Research: Multiple studies with 750+ participants, or scientific consensus
Likely Typical (Normal Activity)
Warfarin (Coumadin®) Sensitivity
Established Research: Multiple studies with 750+ participants, or scientific consensus
Typical
The genotyping services of 23andMe are performed in LabCorp’s CLIA-certified laboratory. The tests have not been cleared or approved by the FDA but have been analytically validated according to CLIA standards. The information on this page is intended for research and educational purposes only, and is not for diagnostic use.
The PI*S variant causes only a slight reduction of AAT in the bloodstream. Most studies indicate that there is no increased risk for disease in MS individuals. SS individuals are rare and have not been studied extensively, but it is thought there are few effects in these people.
Both the PI*Z and PI*S variants are found mainly in people with European ancestry. The Z variant is most common in northwestern Europe, especially Scandinavia. The S variant is more common in southern Europe. Both of these variants are very rare in Asian and African populations.
In addition to the PI*M, PI*S, and PI*Z versions of the SERPINA1 gene, there are more than 20 known rare variants that can lead to AATD. There are also several known variants of the gene with no clinical effects. 23andMe reports data for the PI*M, PI*S, and PI*Z versions only. If you are concerned about AATD, consult a health professional.
Citations
Just to add that the NIH released a few studies in January 2015 that show that cinnamon can greatly reduce the activity of inflammatory glial cells in the brain which the authors feel could be the cause of symptoms of MS and Dementia aswell as other auto-immune diseases.It is postulated just a teaspoon in a drink or equivalent in capsules could do the drink(cinnamon can irritate the liver in some people though!).
Thanks, Cort, once again for bringing an important study to us. I also did 23andMe, but I don’t have a clue as to how to find the genes they’re talking about in this study.
I used Genetic Genie to interpret methylation mutations (of which I have several and believe I’m benefitting from using the Myhill protocol to correct that.) Beyond that, I’m lost.
Now it makes sense why some companies are not doing the medical side of DNA.
I’ve now sent mine to 23andMe.
Cort
How does one pick a site to have them interpreted? There don’t seem to be any regulations regarding any of this collection and reading of DNA-medical. How does one know how accurate they are with interpretation?
It is my understanding that low dose naltrexone inhibits glial cell activity. My current psychiatrist agreed to prescribe this medication typically used by opioid and alcohol abuse patients. I was desperate for relief from chronic and terrible pain. I take 25 mg of naltrexone every other day, and it has helped diminish my fibromyalgia pain significantly. It also improves my overall ability to interact with other people. I also take generic flexeril which affects serotonin mildly and eases muscle pain related to fibromyalgia. And, finally, I take neurontin, which works on gaba receptors and reduces nerve pain. I still have arthritic pain, and it is not clear what will reduce this pain. I have briefly tried celebrex, and it did appear to lower arthritis pain, but I had to stop celebrex temporarily due to another medical problem. None of these drugs work for everyone. Natrexone may work on a subset of the population with certain genetic characteristics. Naltrexone is not approved by the FDA for use in treating fibromyalgia, and it may never be approved as it is a very inexpensive drug and will not yield huge profits for drug manufacturers; thus, I am using it off label. As for antidepressants, they can have a major effect on mood and on the endocrine system for some people. Philip Hayward’s description of the possible and horrendous side effects of antidepressants should be required reading for any patient taking SSRI drugs. I have years and years of experience in use of SSRIs, and I can attest that these drugs made me very depressed. My doctors responded by increasing the dosage until a psychiatrist finally realized what was happening and told me that I should not take these drugs! I recognize that antidepressants are being used for fibromyalgia patients that are seeking for relief from pain, but I can attest that patients on antidepressants are poorly monitored by their physicians for side effects. The difference between antidepressants and flexeril which also affects serotonin is that antidepressants are far more powerful than the muscle relaxant.