THE GIST
- Main Takeaway – Increased excitability of a part of the brain that regulates movement, pain, and emotions, and may produce fatigue – the motor cortex – links together fibromyalgia, chronic fatigue syndrome (ME/CFS), and long COVID.
- In each disorder, the researchers proposed that the high motor cortex excitability was an attempt to activate the muscles and get the body moving. When we want to do something, the motor cortex and the areas of the brain associated with it plan how to do it and activate our muscles to act.
- It may seem odd that a part of the brain that regulates movement is also so heavily involved in pain as well, but numerous studies have found that it does. The fact that the motor cortex and its network are involved in core aspects of these diseases such as movement, pain, cognition, and fatigue is, of course, rather intriguing!
- Various reasons – most of them concerning an infection and the immune system – have been proposed to cause these motor cortex problems. The authors pointed a finger at the GABA system of the brain to try and explain the dysfunction and to provide treatments.
- If you can handle it, Lyrica can increase GABA levels and can reduce motor cortex activity. Transcranial magnetic stimulation is another option, and what some doctors and researchers may prove to be a game-changer – TMS devices that can be used at home – are becoming available. A recent TMS FM home study that targeted the motor cortex was able to successfully support the motor cortex and reduce pain levels in FM.
- Another possible option is the PEA supplement, which was shown in an Italian study to enhance the GABA system but was unable to move the needle on cognition.
- Perhaps the most important part of the study, though, may have been to demonstrate yet another biological similarity in ME/CFS, FM, and long COVID. That suggests that – as Avindra Nath proposed – understanding and learning how to treat one of these conditions will help us understand and treat all of them. May it be so.
When the brain anticipates something that will provide a “reward”, it activates the motor cortex to get ready for action. The motor cortex then has to plan out what movement to take and direct the muscles to carry out that movement. You’ve got to have a healthy motor cortex to move smoothly and efficiently.
Interestingly, given the recent motor cortex and reward findings in chronic fatigue syndrome (ME/CFS), a fibromyalgia study, “Enhanced motor network engagement during reward gain anticipation in fibromyalgia”, looked at the same part of the brain in fibromyalgia. The study, which assessed motor cortex activity during a “reward-anticipation” task with a functional MRI, found the same thing as the ME/CFS study did – a hyperactive motor network in FM.
The authors suggested that the hyperactivity of the motor cortex was likely compensating for altered “motor processing”. That suggested that the motor cortex was trying hard to either plan for muscle activity or get the muscles going. Enough problems with the motor cortex in fibromyalgia have been found for researchers to propose them to be a biomarker for FM.
If you feel like you’re less coordinated than before you came down with FM, a messed up motor cortex might be the reason why. The increased motor cortex activity may also be implicated in the gait (walking) abnormalities and balance problems, and the reductions in the ability to do fine motor movements like writing and dexterity. Even “gross motor functions” – which appear to refer to the ability to quickly initiate large movements like walking – appear to be impaired in FM. The authors noted that these problems can dramatically impact one’s quality of life.
The Motor Cortex and Pain
It seems odd that a part of the brain dedicated to controlling movement is also deeply involved in producing or inhibiting pain, but maybe it makes sense. The brain sends pain signals out that inhibit movement when we’re injured. Perhaps with the widespread pain found in FM, and often in ME/CFS, the brain has decided to inhibit movement as well. Indeed, problems within the motor cortex, and in the areas associated, have been found in both fibromyalgia and chronic pain studies.
One part of the motor cortex called the the M1 region, is particularly involved in pain perception and processing. Because it’s directly connected to the emotion centers of the brain, it can pack a real punch, and transcranial magnetic stimulation devices that stimulate this part of the motor cortex are being used in pain relief.
The motor cortex, with its ability to influence pain and fatigue sensations, and movement, could conceivably play a key role in diseases like ME/CFS, FM, and, as a recent study indicated, long COVID.
Long COVID Too?
It may come as no surprise – given all the similar findings between long COVID, ME/CFS, and fibromyalgia – that a hyperactive motor cortex has also been found in long COVID.
A small Italian study that went to town trying to figure out the cause of fatigue in long COVID ended up landing on the motor cortex network. The authors proposed that “pathological changes in the motor system”, and disrupted feedback to the primary somatosensory cortex (which feeds information to the motor cortex), and/or changes in patients’ motivation were to blame. (Don’t worry too much about the motivation part – it was hardly mentioned in the paper.)
In the same way that exercise stressors dig more deeply into what’s going on in ME/CFS, the authors found that during a “fatiguing task”, corticomotor neurons were unable to inhibit activity in the motor cortex – leaving it overcharged. Plus, the amped motor cortex was unable to quickly shut itself off after the cognitive exercise. Similar findings of a system that is unable to turn itself off after exercise have been found in ME/CFS.
The authors described the motor cortex excitability found in long COVID in a strikingly similar way as others have described it in ME/CFS and FM: as a compensatory attempt of the motor cortex network to counteract “a reduced peripheral capacity to generate force”; i.e. the motor cortex has revved up its engines in an attempt to get the muscles to move.
In a recent Unraveled Patreon podcast Dr. Ruhoy brought up the idea that the increased motor cortex excitability could be producing contracted muscles and impair the ability to sleep well.
Once again we see problems with “inhibition”; i.e. the inhibitory systems in the body failing to rein in active processes. The balance or homeostasis is gone leaving overly active systems to chew up resources, produce pain, etc. The motor neurons are unable to slow down the motor cortex; the parasympathetic nervous system is unable to tame the sympathetic nervous system, and in fibromyalgia (and how knows, perhaps ME/CFS as well), the inhibitory pain network is unable to keep the pain-enhancing network in check.
How an infection might produce fatigue, cognition, and mood issues in long COVID by impairing GABA production in the brain. (From the Italian study)
The study also found – as a prior Japanese study did – that “cognitive control”, or the ability to maintain focus, diminishes over time in long-COVID patients during cognitive tasks. The Japanese study found that in people with ME/CFS, the parasympathetic nervous system failed to shut down the sympathetic nervous system after a cognitive test was completed. They proposed they’d found a way to assess post-exertional mental fatigue. It’s not a difficult test – it lasts sixteen minutes and involves EEG and heart rate variability measures – and has never been validated. It’s amazing how many clues to ME/CFS and long COVID exist in the ME/CFS literature.
The authors of the long COVID proposed, as others have, that problems with the GABA system and, to a lesser extent, cholinergic activity were involved in producing the fatigue and cognitive problems in long COVID – and proposed that similar studies be done in other post-viral conditions.
Why this is occurring and what to do about it is, of course, the gold question and we don’t know. Various authors suggested it could be due to a neuroimmune response, inflammatory response, issues with the ACE-2 receptor (found on GABAergic neurons), and/or small fiber neuropathy. Note how many of these circle back to the immune system. The important thing, right now, is that the same areas of the brain are showing up repeatedly in ME/CFS, FM, and long COVID – and that’s a good sign for all these diseases.
While, in the end, it may take an immune intervention to get at the cause of these disorders, some ways to enhance GABA activity in the brain and calm the motor cortex down exist.
Treatment
Transcranial magnetic stimulation may be help to help some people. Home-based options are becoming available.
A recent overview found that when FM drugs work, they impact these areas. Drugs such as Lyrica that enhance “intracortical inhibition”, increase GABA levels, and can reduce motor cortex activity, can “moderately” reduce pain, improve mood, and reduce pain catastrophizing.
Transcranial magnetic stimulation is another option, and what some doctors and researchers think may prove to be a game-changer – TMS devices that can be used at home – are becoming available. A recent TMS FM home study demonstrated the role that motor cortex excitability, in particular, may be having on pain.
The 102-person, randomized, placebo-controlled study included 20 sessions of tDCS (2 mA for 20 minutes each day) trained on the prefrontal cortex or the motor cortex. It found that training the TMS on the prefrontal cortex improved pain scores over placebo by about 40%. The effect doubled, though, relative to placebo, when the TMS was trained on the motor cortex. Plus, the participants in the motor cortex arm also showed an increased threshold for pain as well as an activation of their pain inhibition circuit.
A Solve M.E.-funded rTMS ME/CFS study focused on both the prefrontal cortex and the motor cortex reportedly began in 2021.
Meanwhile, an Italian randomized, placebo-controlled study, “Co-ultra micronized palmitoylethanolamide/luteolin normalizes GABAB-ergic activity and cortical plasticity in long COVID-19 syndrome”, suggested that PEA might be able to help as well.
It gave PEA-LUT 700 mg + 70 mg (Glialia product in Italy) or placebo twice a day to 34 long-COVID patients for eight weeks, and used transcranial magnetic stimulation before and after the study to assess GABA activity in the brain. (PEA – which is part of the family of endocannabinoids – affects GABA activity via the endocannabinoid system in the brain.) The study, which did not assess pain levels, found that PEA-LUT did improve motor cortex physiology but unfortunately did not significantly improve cognition using the tests done. Its ability to affect this part of the brain, though, suggested that PEA might be helpful for some – and it’s been used in ME/CFS/FM and long COVID.
Conclusion
A “bad” motor in the brain appears to play a role in ME/CFS, FM and long COVID.
While motor cortex excitability has been found in the past in ME/CFS – and has been proposed to play a role in the fatigue present – it’s never aroused that much interest. That may be changing. Nath’s recent finding, an abundance of findings in fibromyalgia and chronic pain, and now its emergence in long COVID suggest that this intriguing part of the brain that can affect fatigue, movement, and pain should be getting a closer look.
The striking similarities in these diseases continue to pile up. From the autonomic nervous system to the blood vessel, metabolic, cardiovascular, gut, and brain findings, these diseases look more alike than ever. There’s a tie that binds all these findings together. No one knows what that is at this point, but it suggests – as Avindra Nath has proposed – that finding out how to understand and treat one should help us understand and treat all of them. May it be so.
Short comment for now: given that there’s an autonomic component & that the pathology is mostly unconscious, Occam’s razor would say to look at the brainstem circuits that drive cortical structures (including motor cortex).
But there’s a cohort that would like to keep the focus downstream on cortex to keep showing pretty fuzzy brain pictures (and feeding ‘all in the head’ narratives) rather than drilling into specific autonomic circuits like today’s neuroscience routinely can.
Please consider not falling for the schtick!
I absolutely agree with you.
I was wondering about that. If the motor cortex is hyperactivated trying to get the muscles activated – if that’s what’s actually happening – then is the main problem downstream (brainstem or wherever?).
Speaking as someone who doesn’t know anything really about how all this works I also wonder if some parts of the motor network could be impaired and the motor cortex is trying to compensate for that.
Thanks for the really great summary! Nice to see more overlap among the research. Does anyone have any advice or know how you can get an at-home TMS device for FM in the USA?
Just wondering if anyone here has tried any of these therapies? The TMS treatment in Australia needs to be done in clinic with oversight by psychiatrists etc at a fairly prohibitive cost – but I’ve seen great reviews from genpop using a $300 DCS device (like Neuromist or TheBrainDriver) which sound appealing to try. Tempted to get one but maybe a complete waste of time – or maybe only worthwhile with someone giving informed guidance on the exact placement of electrodes…?
Thanks for digging up the commonality on this one Cort.
My questions are:
– As far as I can tell, the NIH study wasn’t big, but it was expensive. That is, the grip testing component that lead to the motor cortex hypothesis was n = 8. Were the other studies (fibromyalgia, long-Covid) significantly larger?
– The article above refers to the motor cortex as more of a symptom than a root of the aetiology in these other studies. This seems to be in contrast to the NIH study that appeared to portray the motor cortex as the core driver of the aetiology post infection?
– Building on a previous rant (sorry Cort), how does the observed behaviour of the motor cortex differ from that of healthy controls when they are pushed either chronically or acutely beyond their limit? Like day 3 of an ultra endurance event. In other words is the motor cortex result truly novel, or just novel relative to the assumed circumstance? My thinking here is essentially, if it ain’t broke, don’t fix it.
Iono, I have wondered the same thing. Why have I not seen a multi-day endurance test. 48 hours after a high energy event I am just dead. Surely, a test at that time would lead to more obvious answers.
The FM study was 48 and the Italian study was just 12. As far as I understood it the authors proposed it the motor cortex excitation was compensating for “altered motor processing” – whatever that means. The motor cortex is aided by the supplementary motor cortex in the planning phase I mean. If I remember correctly, Nath et. al. at one point pinned the motor cortex excitability on the HPJ.
What little I’ve gleaned about the motor cortex and endurance is that endurance is more a function of increased blood flows to the motor cortex allowing it to function better.
Please post if you try it. I am interested as well.
Hi Cort,
Please may I share excerpts of this article on social media.
I would also link to here.
Please is it generally fine to do this for articles I want to share with my friends.
I would always link to the main article.
I would share it on my X account @andybayo_
Thanks.
Of course! Thanks 🙂
I have had FM for more than thirty years. I started taking PEA-LUT at night before bed. I haven’t had any negative side effects, and it is an analgesic that seems to have some lasting power. I feel much better, particularly in the mornings. It may sound silly, but my brain seems more relaxed, and I have a lot less pain and stiffness, even if it does not improve my cognition. Sleep and pain are my biggest issues.
Nice! I’ve heard it can really be helpful for some 🙂
Karen …can you share the name of the product that you’re using?
I use Ultramicronizwd PEA but there’s no luteolin .
Thanks
There are lots of options for PEA-LUT that offer varying strengths online. You try them to find one that works the best for you.
Thanks again for excellent work! Korte and Straub have written about the pathophysiological mechanisms of fatigue in rheumatic disorders. It is som much like ME. Take a look at the figures in https://pubmed.ncbi.nlm.nih.gov/31682277/
Whoa – I hadn’t seen that. I love fatigue hypotheses 🙂 – thanks!
I want to point out a study that I also saw in this blog, it was about the hyperexcitability of the muscles in people with fibromyalgia, too accelerated when doing strength movements, and in relaxation the muscles are still exercising when they should be resting. I also want to emphasize Ativan, which increases GABA activity, and it caught my attention because it is what our friend Withney Dafoe is taking.
I’d advise caution using the benzodiazepine Ativan. It has a short half-life which means it enters the system quickly and in a relatively short time leaves the system. The brain then craves another dose. It’s considered addictive and if you decide to taper-off Ativan, it can take quite a long time.
But not as long as 12 years severe. I’ve been prescribed up to x 2 daily for nearly 12 years. I take none, one or two and they take the edge off the worst of my severity.
My GP actually said if they are used for a purpose addiction is far less likely than if used recreationally.
As long as they relieve the hellish symptoms occasionally I couldn’t care less if I’m on them for 100 years, or double the dose.
I was befuddled by the declaration that ME/CFS fatigue was not central, so I looked into the paper further. It turned out that Walitt/Nath used the lack of post-exercise MEP depression after unsupervised grip test as the indication for it. They went on to say that “this indicates that the primary motor cortex remained excitable for PI-ME/CFS, suggesting reduced motor engagement from this group.”. But Samii/Hallett” paper that they used as the reference for this measured MEP a few minutes after supervised exercise found that “this postexercise MEP depression was similar in all groups.” If anything, Samii/Hallett’s result was the opposite: “the increases (of MEP) in the patient groups, however, were significantly lower than normal” immediately after the (supervised) exercise.
So, the motor cortex remaining excitable for ME/CFS is an artifact of the unsupervised grip test that they did and then attributed the subjects’ failure to pacing. They are in fact attributing the primary motor cortex remaining excitable to pacing (“reduced motor engagement”) as well.
Even if the motor cortex excitability turns out to be true, it’s only a correlation, not causation, as the fibromyalgia paper made it clear. It could well be that an upstream event (neuroinflammation?) is causing the coupling between motor cortex and reward gain anticipation. They’ll have to come up with a test to prove the cause-effect relationship.
The biggest omission in all this is PEM. Why does a minor exertion make it so much worse, including brain fog and light/sound sensitivity? People are still focusing too much on fatigue and not enough on PEM.
Agree 100%. The “causation vs correlation” issue and the ignoring of physical damage shown in PEM (thank you muscle biopsy study for proving that!) are imo the two biggest barriers to ME/CFS science right now.
Why do we get such substandard research? It would never fly in any other field 😭
Motor cortex raising its ugly head again. I have PPS…post polio syndrome. Pem is,front and center! So is motor cortex. Check it out!!! I had polio when four, I’m now 84!! I’ve suffered for years with symptoms just like ME. Tell me they’re not related!! Polio is caused by an infectious virus!
Thanks for digging into that. I agree the motor cortex must be somewhere in the middle of all this – not at the beginning. Nath et al did come up with an overall model which will be explored in a future blog.
Too bad they whoofed on PEM – that shocked the heck out of me. They went to the trouble of including a nice exercise stressor and didn’t use it! I wonder if they took blood before and after…
“people are still focusing too much on fatigue and not enough on PEM”
YES!! I keep thinking this constantly. Where is the PEM? Given how signficant it is in patients lives, and how central it seems to the illness as a whole, it’s insane that there’s so little research that even includes acknowledgement of it, never mind actually focused in on it. I saw that it came up several times in people’s comments on the NIH research roadmap input website. Fingers crossed it changes as a result of it being so highlighted by the community.
Electricity must have something to do with a lot of this…they’ve already found no electricity between our cells.
When I enter a room with high voltage circuit breakers and panels I begin to become very dizzy and disoriented.the longer I stay in this electrical environment, the worse I become.
As a side note, my nephrologist has admitted that the 1.5 years of
Tetracycline caused my health decline
Buckey,
That is very sad to hear about your antibiotic reaction. For what it is worth, check out the information on this website about Faecal Matter Transplants. That might be worth talking to a doctor about.
This is at least partly crazy, but there has been a persistent folklore amongst farmers here in Australia about post-Ross River Virus syndrome (which probably intersects significantly with ME/CFS) being cured by a shock from an electric stock fence (e.g. cattle). Most likely a big shock. Anyway, I’m not suggesting trying this, but it is interesting given your comment.
Very interesting, yes, I’ve always wondered about if a shock of some kind would do anything. I’ll have to try digging up some info.
I was like many others in that I would sleep in a tent because if I entered my home I would instantly break out in a total body rash and feel my health decline…upon leaving the home my health would return instantly…then, when winter came I had to stay indoors, that was when my health went down and I’ve been stuck ever since. Heck, even when I would use an electric drill or other appliance, the electrical field would effect me negatively…my eyes would have that blackened look to them, like no sleep.incidentally, I awake at exactly 3 a.m. every day…WIDE AWAKE. There is definitely one missing piece to my puzzle, and I’ve always thought that one change of SOMETHING would pull me out of this nightmare..
Thank you lono
…..in addition to the above post….I also get many, many shocks off of mostly car doors but other items as well.
Can someone tell me how to edit a post?
I used to work in Port Hedland in far the north of Western Australia. Ross River virus is fairly common there. I spoke with at least two people who said they tried the electric fence approach and it cured them.
Stewart,
At the risk of things being far too weird, is there any chance either of those folks are well enough known to you to ask about the specifics of the shock? How far from the energiser were they, shoes or barefoot, wet or dry, what energiser make and model type (I’m mainly interested in the stored energy in Joules)?
Cheers,
Lono
sorry Lono – I remember who the people were but I lost contact with them over a decade ago. I presume they would have to be barefoot or their shoes would stop the circuit completing. The fence would be whatever is used up North to stop cattle roaming too far.
It is beyond common for people with Ehlers-Danlos and others on the hypermobility spectrum to ‘be clumsy.’ It’s called poor proprioception and the best paper I read about it theorizes that everywhere on the fascia, covering the muscle groups, there are ‘sensors’ which sent signals to the brain (motor cortex?) to tell the mind where the body is in space. In EDS these are abnormal and therefore disrupted. People with EDS have a high representation in folks with energy problems. POTS (and other dysautonomias) are also very common with EDS. Both of these issues probably consume more energy navigating the world than people who fall within normal ranges.
I do wonder if these fatiguing factor may not be accounted for because of the fragmentation of the medical system.
I’m doing taxes right now (too many medical bills!) so am not inclined to look up the before mentioned research.
And before I go, beware the Lyrica! It can do a number on one’s brain processing (thinking) and can be devilishly difficult to get off of (brain ‘zaps’ and other unpleasant side effects).
Nancy B, that’s very interesting about proprioception. I remember learning about that when I was younger, and thinking how amazing bodies are.
Or is ROUNDUP*
finally showing its toll
I found this article interesting because with my 20 year history of CFS, I’ve always had what I call my “Red Alert” feeling. Over the last 20 years, my energy has improved tremendously, such that I could exercise and not get PEM. (By exercising, I mean I could do a 9 mile hike and hike above 12,000 feet elevation and do okay.) BUT, on December 1, 2023, I got the pnuemonia vaccine for the 65 and older people and all my peripheral neuropathy symptoms that had for the most part disappeared, came roaring back 3 weeks later! I also couldn’t exercise much and I had thoughts about what if I go downhill again?
In addition to increasing the antiviral drug I’m on, my doctor put me on Gabapentin, 100 mg twice a day. Surprisingly, my “Red Alert” got tamped down. I never thought I was anxious about anything (as Gabapentin can be used to treat nerve pain and anxiety), so maybe it’s helping to increase the GABA in my brain and helping me to feel better. (I gave this article to my doctor and my pharmacist!)
I’m also trying to do things to help my parasympathetic nervous system be in control more than my sympathetic nervous system (which is probably what is contributing to my “Red Alert” feeling.
Hopefully I won’t spiral downwards to where I was before. I’m hopeful that my nerve pain issues will pass and with the help of Gabapentin and trying to work on my parasympathetic nervous system, that my Red Alert state will become a thing of the past, and I’ll find myself in a better place than I was before I got the vaccine!
Wishing everyone better health in 2024.
Whoa! Good luck with Gabapentin – it can be very helpful.