Several commonalities exist between chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM). Both appear to feature low heart variability, small fiber neuropathy (SFN), neuroinflammation, some similar brain imaging results, evidence of impaired energy production, possible mitochondrial involvement, possibly narrowed blood vessels, plus a whole boatload of similar symptoms.
Brain derived neurotrophic factor has a a bright side and a dark side
Recently, a new and intriguing intersection opened up. Several studies over time have found increased levels of brain-derived neurotrophic factor (BDNF) in fibromyalgia and now one found it in ME/CFS as well.
BDNF has been a pretty hot research topic in FM since 2007 when increased serum elevations were first found in FM patients. Since then, no less than 20 studies have featured it – making it one of the most studied factors in FM.
Increased BDNF levels have found in the blood and the cerebral spinal fluid of FM patients, and two studies have identified a small genetic change called a polymorphism in the BDNF gene in FM.
BDNF is a fascinating substance. A neurotrophic (nerve growth factor), BDNF helps the nerves grow and is vitally important for neuroplasticity and learning. Mice genetically engineered to grow without BDNF often die, and exhibit problems with coordination, balance, hearing, taste, and breathing.
BDNF levels rise with exercise, and exercise has been widely promoted to increase BDNF levels, improve cognition and memory, and improve brain health. Increased BDNF levels are believed to be one of the reasons people tend to feel sharper after exercise. BDNF’s possible enhancement of the feel-good chemical GABA could help account for the “runner’s high” some of us used to experience. It turns out that a byproduct of exercise called lactate also promotes BDNF expression in the brain.
So far, so good. Given the high lactate levels that have been found in both ME/CFS and fibromyalgia, and the high BDNF levels in FM, one might think people with these diseases would be candidates for MENSA with their superb memories and enhanced cognitive capabilities.
That obviously hasn’t happened. It turns out that BDNF has a dark side as well. Injury or trauma causes BDNF to activate pain pathways and trigger sensations of pain. That’s adaptive in the short term – the pain causes us to attend to injury – but long-term elevations could result in chronic pain.
BDNF may enhance central sensitization by triggering the expression of glutamate – an excitatory neurotransmitter. The chief producers of neuroinflammation – the microglia – are a primary source of BDNF in the brain. Delivering BDNF to the dorsal ganglia – that relay sensory signals to the central nervous system – has been shown to produce allodynia in rodents.
BDNF has also been implicated in “long-term potentiation” which results in chronic nerve hyperexcitability. Some believe that BDNF’s effect on neuroplasticity and memory could cause the brain to lock onto pain signals and retain pain memories.
Still, BDNF’s role in FM is unclear. Like other factors, BDNF can have anti-pain and pro-pain effects. High BDNF levels could either reflect an attempt to reduce pain or be a cause of pain.
The Gist
- Brain derived neurotrophic factor (BDNF) promotes nerve growth in the brain and across the body.
- BDNF does a lot of good. It promotes learning, memory retention and brain health. Increased BDNF levels during exercise may contribute to a”runners high”.
- BDNF has a dark side, though. It triggers the expression of glutamate – an excitatory neurotransmitter associated with inflammation in the brain. The microglia – the chief initiators of neuroinflammation – are major sources of BDN. BDNF has been implicated in the turn from acute into chronic pain and may even help to more deeply embed memories of pain.
- BDNF levels have been found increased in the blood and spinal fluid of FM patients where it’s been the object of much study. In ME/CFS the results have been mixed with one study finding low levels, another normal levels and this recent study high levels.
- The study also found, for the first time, an epigenetic modification which could help explain the increased levels found
- If exercise increases BDNF expression which then tweaks the pain producing pathways in the brain (central sensitization) and increases microglial cell activation (and neuroinflammation) a direct link between exercise and post-exertional malaise may have been found.
- Next, ME Research UK is funding a BDNF study which includes exercise and digs deeper into the possible epigenetic issues with BDNF as well as assessing another exercise induced factor.
- BDNF is just one factor, though, in the pain production process and other factors are surely involved. Still seeing BDNF reach stratospheric levels during exercise in ME/CFS would be something to behold.
- Treatment options appear to be limited on the drug side but two studies, including one by Ashok Gupta, suggest that mind/body techniques may be able to lower BDNF levels.
Chronic Fatigue Syndrome (ME/CFS)
BDNF’s long history in FM and its possible connection with chronic pain and neuroinflammation and exercise makes it a pretty intriguing target for ME/CFS, and two small studies were done about five years ago. One, to its surprise, found dramatically decreased BDNF levels, and the other found normal BDNF levels.
The Belgian Nijs group, which had done a major overview of BDNF and FM in 2015, found something different. The study “DNA Methylation and Brain-Derived Neurotrophic Factor Expression Account for Symptoms and Widespread Hyperalgesia in Patients With Chronic Fatigue Syndrome and Comorbid Fibromyalgia“, was released just a couple of weeks ago.
It produced two novel findings. Serum BDNF were significantly increased in ME/CFS, plus an epigenetic change was found which could explain why BDNF levels were increased.
Epigenetics refers to modifications of our gene expression which occur in response to things like infections, dietary changes, and stress. These things turn on and off our genes. They present the potential of a gene expression shift, which could explain how a simple infection could turn into a chronic illness. A BDNF epigenetic modification is particularly intriguing as an infection has been shown to trigger an epigenetic modification of BDNF before.
While this is only one study, the high BDNF levels found make sense given what’s been found in FM. If they hold up, they’ll further tie the two diseases together.
Given that both diseases feature difficulties with exercise and increased lactate levels, one wonders if exercise could be triggering the microglia to produce BDNF (and other pro-inflammatory substances), producing neuroinflammation, central sensitization and PEM (post-exertional malaise).
We’re naturally very focused on energy production, but it was years ago that Ben Natelson, as I remember, suggested that exercise could also be causing PEM by tweaking the nerves in these diseases. The burning muscles and pain that I associate with overexertion certainly feels like the nerves are not happy.
The memory connection is intriguing as well. BDNF supports memory formation in the hippocampus. Could it also be deeply encoding pain memories and sensations in FM and ME/CFS – making it more difficult to escape them?
The Nijs group was careful to point out that chronic pain is a complex condition which is not likely to be produced by a single factor. BDNF may be an intermediate factor in the neuroinflammation that could be at the heart of these diseases, but the possible connection between exercise, lactate, BDNF, neuroinflammation, central sensitization, PEM and ME/CFS/FM is nothing if not intriguing.
ME Research UK quickly followed up on the Nijs group’s promising finding by funding a study that adds an exercise test (:)), and that more deeply examines the potential epigenetic contribution, and looks at enzymes called HDACs which could be producing exercise-induced symptoms. If the study shows that exercise vaults the already high BDNF levels in ME/CFS into the stratosphere, we may really be onto something.
Treatment
If high BDNF levels are an issue, what can be done about them? Exercise is usually prescribed for its analgesic or pain-reducing effects, but it has the opposite effect in ME/CFS and has to be done carefully in FM.
The exercise test in ME Research UK’s next ME/CFS BDNF study could tell us much…
The Nijs paper mentioned a few drugs that are quite exploratory in nature at this point. Infliximab infusions may be able to reduce BDNF levels in the blood. Phencyclidine, a noncompetitive NMDA receptor antagonist, appears to decrease BDNF expression at the gene level.
While meditation/mindfulness practices have been used to boost BDNF levels in healthy controls, two studies suggest they may be able to calm them down in FM. A 2019 randomized controlled trial found that a mindfulness-based practice called attachment-based compassion therapy (ABCT) was more effective than relaxation therapy in reducing BDNF and pro-inflammatory factors.
Just this year, Ashok Gupta’s mindfulness plus amygdala and insula retraining program was also more effective than relaxation therapy at reducing BDNF levels in FM, and in improving functioning, and in reducing anxiety and depression as well. A blog exploring that study is coming up.
The BIG (Little) Drive Roars On!
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That’s very interesting, thank you. Sometimes, for me the couple of days after a walk that is at my limits, and doing push ups I wake up with a very heavy feeling in my limbs and I need to back off for a few days. Is this probably the feeling of lactate in the limbs or something like small fibre affects? thanks
It may be. That heaviness is very characteristic. I experience it a lot.
Oh, my gosh! This article tonight explains many attributes about my ME/CFS in a way that makes perfect sense. I was sure that our pain was related to our intelligence, and I also knew that spending time studying was one way to calm down the incessant pain and electrified brain before going to sleep at night. (or at least TRYING to go to sleep.) Thank you so much. You are responsible for so many breakthroughs on this chronic and acute misery. I’m humbled and grateful!!!
Curious,
how is neuroinflammation classified?
how is FM classified?
Questions are as a result of the following statement:
“Objective: There is a growing interest in evaluating the effectiveness of compassion interventions for treating psychological disorders.“
listed at start of pubmed article:
“Efficacy of “Attachment-Based Compassion Therapy” in the Treatment of Fibromyalgia: A Randomized Controlled Trial
Jesús Montero-Marín et al. Front Psychiatry. 2018.”
link:
https://pubmed.ncbi.nlm.nih.gov/29387020/
This connection is interesting to me since I’ve read some FM research that indicated high ACE scores (for early childhood trauma) was frequently found in FM patients. Perhaps this increases BDNF? I was a phone counselor for the Fibromyalgia Assoc. of Greater Washington and I also noticed that early trauma experiences predated the development of FB in my case and others I spoke to over the phone. As for exercise, I gradually worked my way up minute-by-minute to 30-45 min, a day of recumbent aerobic activity. I don’t have CFS. But, if I had just jumped on my machine and tried to do ten minutes on the first day, it would have taken me 2 weeks to recover.
Hi Cort,
Ongoing interesting findings indeed. I have seen references to BDNF in my integration of research on trauma and its effects on risk for chronic illness. Effects are not psychological, but epigenetic as you say (and also influence physiology, nervous system regulation etc).
I have seen just a little bit on it, but it suggests that BDNF may be involved very early in life right after birth and have something to do with fear / and fear condition, with effects on the amygdala and elsewhere.
I don’t fully understand what all this means (does anyone, really?!), however I find it another intriguing aspect. Like Maureen, I find a relationship of (in my case very subtle trauma) and attachment trauma with my own ME/CFS… I also see ME/CFS as a body caught in states of physiological freeze/hibernation, as found by Naviaux at UC San Diego. Working on healing these has been a big part of my own healing journey.
Here are quotes from one article:
BDNF, is critically involved in neuronal synaptogenesis, demonstrating drastic increases during the early postnatal period (Karpova, 2014). Furthermore, dynamic changes in DNAm at BDNF was previously linked to fear conditioning (Lubin, Roth, & Sweatt, 2008)
….
The strength of the association between antenatal maternal anxiety and DNAm patterns relevant to amygdalar and hippocampal volumes was found to depend on this BDNF variant (Chen et al., 2015).
DNA methylation (DNAm)
As always Cort really interesting. I am here crying all day long grieving and grieving my days of being a gym rat and hiking for hours and walking everywhere. WOW. Who would have thought perhaps it contributed to the bed bound disability I’m suffering now! Too much of a good thing they say, right ? As you stated Veronique , I too suffer from trauma . CPTSD and it’s getting harder to distinguish for me the separation from my physical pain and my emotional pain as the years go on.
I haven’t been able to read much lately so I have a lot of catching up to do here with your always insightful articles Cort !
Thanks for all you do to bring to the forefront so much research and knowledge to share with the puzzling problems with chronic illness.
Without trying to go too techincal, it seems that increased BDNF might try to repair and restore memory AND skills in ME patients’ brains.
Why? Because we might have increased destruction of the connections between the neurons that make and store both our memories and skills. Those connections are made by very thin (far thinner then the diameter of a neuron or brain cell) and very long wires, far longer then the diameter of a neuron.
See https://en.wikipedia.org/wiki/Neuron for the techy stuff.
“The axon is a finer, cable-like projection that can extend tens, hundreds, or even tens of thousands of times the diameter of the soma in length. The axon primarily carries nerve signals away from the soma, and carries some types of information back to it. Many neurons have only one axon, but this axon may—and usually will—undergo extensive branching, enabling communication with many target cells”
Such wire that is compared to the brain cells themselves extremely thin and extremely long, would be far more exposed too and far more vulnerable to any form of inflamation or imune havoc in the brain then the main “bulky” part of the brain neurons themselves.
So, if even the main part of the brain neurons would suffer from our chronic increased “low grade” brain inflamation, then chances are good that those very long and thin wires suffer a lot more.
In layman terms: when the individual brain cell would look like a beet (the vegetable), the the connections between brain cells would more look like the thinest of “hair roots” that you can see if you pull the beet gently out of the soil. Those are so delicate that someone who buys their vegetables at the grocery might never have seen such “hair roots” on beets in their life. They just break off before they reach the store.
So it sort of makes sense that those connections are the first to suffer from whatever goes wrong in our inflamed brains long before the bigger cell cores get affected doesn’t it?
When having had a few very bad crashes I lost plenty of skills, like my ability to speak was very bad, my skill to walk around a corner or getting up from a chair was completely gone. I had to relearn opening a door and passing through it without slaming into it. I bumped many times on the door because I stepped forward before taking the door handle, turning it, puling or pushing the door open and then walk through the opening. It may seem very stupid to try and walk through a door before opening it, but I did many times. With such weakened muscles it never hit hard as I did everything wrong in slow motion.
So, several deep crashes wiped plenty of my skills in a way impossibly to differentiate from how Issie discribes how she experienced TIA’s or transient Ischemic Atacks. I had to relearn those skills but all on a “figure it out yourself” way as “ofcoarse” there was no need to give me real rehabilitation theraphy as I “only had CFS (if that even existed)” :-(.
Those crashes wiped skills fairly randomly and some memories are gone forever too.
I can imagine that, when those skills and memories are day by day “under (more mild compared to these extreme crashes) fire” in ME patients that the brain has to repeat and restore those connections time and again in order to not lose too much of them. That would include repeating the most recent memories (that are often weaker then the very old ones) too and those involve being in pain…
One such chemical that can create havoc on those connections is… acetaldehyde. There is scientific research documenting that. Too much acetaldehyde just can break them beyond repair.
One way to create too much acetaldehyde is having plenty of oxidative stress in the cell cores. Many things can cause that, including chronic hypoxia. See the similarities with “real” TIA? Too much oxidative stress after a too strong bout of hypoxia…
Chronic alcohol abuse is known to be detrimental to memory. See also for example https://orbi.uliege.be/handle/2268/29818 with title “Acute and chronic effects of acetaldehyde on learning and memory in mice” saying:
” In the second part of the studies, we show that 10 daily acetaldehyde injections to mice led to a severe and persistent anterograde amnesia in both the pavlovian and the operant learning tasks”
That’s 10 days only…
So, I wouldn’t get to enthusiast about trying to lower BDNF levels a lot just yet. That is, if you value your skills and memory on the longer run.
I have to agree with Dejurgen.
Having had what appeared to be two TIA and my losing some abilities with each of them, that didn’t come back, my brain is very, VERY valuable to me. (Dejuergen and I have had very similar experience with this and long lasting consequences due to them. Don’t let people tell you TIAs don’t affect you……they do.)
My brain function may in fact be one of the most important things to me. Having watched my mom have dementia. MY dad because of brain cancer, get it. (And my doing their end of life parent care.) And now doing parent care for a father in law with it. And helping with my mother in law who also had it.
BDNF is what those with brain function issues (like having bad genetics for the APOE4 gene, Alzheimer’s), try to increase. (Thankfully I didn’t get that one.) There are supplements that help increase it. And also Intermittent fasting can also increase it.
I don’t want less of it, I want more! I’ve seen what it is like when it is apparently too low in dementia. Very horrible illness. There is very little ability or quality of life for those.
Evidence is mixed and certainly not simple. It is questionable whether chronically raised levels of BDNF do occur in FM or ME.
It may be that neural hyperexcitability raises BDNF which may be a transient effect only.
See:
“No evidence for altered plasma NGF and BDNF levels in fibromyalgia patients”
David Baumeister, Wolfgang Eich, Silvia Saft, Olga Geisel, Rainer Hellweg, Anja Finn, Camilla I. Svensson & Jonas Tesarz
Scientific reports 9: 13667 (2019)
Yes there is that study but it’s the standout so far, I believe. The other studies done have found differently.
I am just gob-smacked by this unexpected to me linking of early childhood trauma and prolonged fear with ME/CFS. The subject is too full of PTSD for me to mention any of it, but the concept really fits my life experiences. Please describe for us what “compassion intervention” is. I can imagine that’s what friends are for, but I would appreciate knowing what is specifically projected to help us. It took writing a whole book of over a thousand pages to help me recover from so many traumas and then sickness that never, ever goes away.
When I was 6 years old, I suffered a concussion after being hit on the head by a racing bycicle down a slope. As a child and teenager I remembered being labeled “slow”, “lazy”and “distracted”, although I did well in school. I felt chronically tired, thoug. As an adult, after a few months in a very demanding job, I gradually developed CFS and FM, which keeps me almost home bound. Anybody would comment on my history, please?
We’ll get into this more but Mary Ackersely and others in dysautonomia and mold/environmental illness field are very cognizant of the effects that concussion can have. I will have something on this coming up.
NEUROINFLAMMATION explains why my head feels as though it is about to EXPLODE after strenuous exercise or even a little gardening on a warm day.
I have had bad Migraines since I was ten years old, and SEVERE FM for Thirty Five years. I also have ‘Pain Memory’, Brain Stem Sleep Apnea, IBS, and Ankylosing Spondylitis. Fibromyalgia is a crippling disease that totally ruins your life.
I have read that FM can be caused by malformations of the Cervical Spine. This seems logical to me! — Could reduced drainage of “Cerebrospinal Fluid” from the Brain be the cause of Neuroinflammation?
The ONLY relief that I have had since being diagnosed with FM (15 years ago) is with Bowen Therapy PLUS Ionic Foot Detox. I have had both of these (separately) previously with limited success (I have tried many different ‘cures’ over the years – without success) – but you need to do a foot detox straight after having Bowen Therapy to get rid of the Toxins that have built up in the system. Acupuncture could also work with Detox, but the only thing that always works for me is Bowen. This indicates that the Lymph System (amongst other things!) is also involved in my FM.
FM probably has lots of different causes – in different people, but Bowen Therapy plus ‘Ionic Foot De-Toxing’ could be of benefit to some FM sufferers. We just have to keep plodding along – and see WHAT ‘Therapy’ works for us!
I would like to see some studies done with Bowen Therapy plus Ionic Foot Detoxing – as I am sure that some FM sufferers could benefit.
Fibromyalgia is like a nightmare. It’s not easy for people who are diagnosed with it to live peacefully, as we can see right away from some comments above. I hope that healthcare experts will soon find an effective remedy for this disorder.