• 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.
Avindra Nath’s big ME/CFS NIH study recently found increased motor cortex excitability and issues with effort preference and “reward” in ME/CFS. Reward is kind of a weird but important term in neuroscience. The “reward system” is actually crucial for our survival as it motivates us to do “rewarding” things – like get food, engage in work, experience pleasure, etc.

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 Nath ME/CFS Intramural Study Pt. I: “It’s a Brain Disease…”

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.

GABA brain pathway

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.

Fatigue – the Japanese Way: A Chronic Fatigue Syndrome Perspective

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.


transcranial magnetic stimulation

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.

Novel Chronic Fatigue Syndrome (ME/CFS) Brain Stimulation Clinical Trial Begins

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.

The PEA Proposition: Can PEA Help Long COVID and ME/CFS/FM?


bad motor

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.


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