Health Update – Fire Weather…This was supposed to be a hot, fire-ridden summer out in the Western U.S., and it has been.
My pattern of running into issues continues. This is the 6th strenuous episode since I crashed 7 weeks ago.
With three near symptom-free days behind me, I was ordered to move because of the Mt. Ward fire near Ely, Nevada (which was not tending in my direction at all (darn!). (It was a spectacular sight, though :))
Breaking camp is a bear and it set me back. A week later, and following some very hot weather, I’m better but not back to baseline.
The good news is that while I’m still pretty symptomatic, my resting heart rate (which had tanked) finally appears to be back to normal, and my HRV – which zoomed up (not actually a good sign) was normal this morning. Plus, the weather has cooled considerably, so hopefully better times are ahead.
Onto a most interesting blog!
One of the great questions has been where the muscle fatigue comes from – the brain or the muscles (or both)?
One of the great questions in these diseases is where the muscle fatigue comes from. Is the brain somehow clamping down on the muscles, or are the muscles simply pooping out, or are both happening?
The question goes at least as far back as 2004 when Chaudhuri and Behan published their tome “Fatigue in Neurological Disorders” in the Lancet.In truth, there is evidence for both in ME/CFS and long COVID.
Could neuroinflammation be behind all this?
THE GIST
-
- Health Update – a nearby fire forced me to break camp, which inevitably interrupted my recovery. Things are looking up now, though.
- The study “Central origin of fatigability in Myalgic encephalomyelitis/chronic fatigue syndrome revealed by multimodal neuroimaging” is a follow-up of Nath’s 2024 intramural Deep Phenotyping ME/CFS study and used some of the same participants.
- Using a handgrip test in which participants attempted to maintain force as their muscles became fatigued, the researchers measured electrical activity and oxygenation/blood flow in the brain, as well as electrical activity in the muscles.
- The ME/CFS patients were able to produce normal amounts of force at the beginning of the study but then declined quickly.
- The brains of the healthy controls showed a continued increase in brain electrical activity as their brains sent signals to recruit more and more muscle units as their muscles became fatigued.
- The brains of the ME/CFS patients, though, showed a quick uptick in electrical activity and then a quick decline. For whatever reason, their brains did not engage in the muscle recruitment process – resulting in a quick reduction in force and increased fatigue.
- The same pattern repeated itself with the blood flow/oxygenation imaging. While the healthy controls recruited a wide swath of brain regions as they worked to keep their handgrip force up, the ME/CFS patients did not. It was as if their brains were sitting the exercise out.
- A test assessing how well the brains were communicating with the muscles and vice versa suggested that the brains of both groups were communicating OK with the muscles, but the muscles of the ME/CFS group were not communicating well with the brain.
- The strangest finding came, though, when they found that electrically, at least, the muscles of the ME/CFS patients never seemed to be in a fatigued state. When muscles become fatigued and ATP production drops, their electrical frequencies drop.
- This happened in the healthy controls, but despite the fact that the ME/CFS patients’ muscles quickly stopped producing normal amounts of force, this never happened with them. That led the authors to the odd conclusion that their muscles did not enter a state of normal fatigue.
- How to explain that? While the authors emphasized that the process was not conscious or deliberate, they fell back on some old canards: fear, pain, and issues with perceived effort could have all stopped the brain from engaging properly during the exercise and failing to recruit new muscles.
- While they noted that their study could not confirm this, they suggested that fatigue in ME/CFS is caused by the brain, and that centrally acting drugs and/or magnetic stimulation might help the brain engage in exercise more.
- That was the end of the paper, but that’s not the end of the story.
- The muscles send signals to the brain as well, and it’s possible that damaged muscle could be telling the brain to shut down and stop recruiting them. The authors discarded this possibility because their (rather primitive) muscle biopsies did not reveal any problems.
- The biopsies done, though, were examined for gross structural defects and did not assess muscle physiology, which could have been impaired without the muscles showing dramatic structural problems.
- Rob Wust has dug much deeper into long COVID patients’ muscles before and after exercise, and he has discovered exactly the type of physiological problems in them that the NIH team didn’t look for.
- Plus, Wust’s lab work found that muscles that had been separated from the brain were still unable to generate energy. That suggests that an inherent energy problem exists in the muscles.
- His newer work has found significant muscle damage in both ME/CFS and long COVID patients. If Wust is correct, damaged muscles could be telling the brain to shut down and stop trying to recruit them.
- Another less likely possibility is that the brain’s inability to recruit enough muscles causes the ones that have been recruited to become overloaded and then damaged. They would then send messages to the brain to shut down.
- The most interesting possibility, though, concerns a paper Health Rising reported on several years ago. Adding infectious factors to the brains of laboratory animals produced neuroinflammation and reduced mitochondrial activity in the muscles (but did not disrupt the muscle fibers).
- This hypothesis neatly ties together infectious onset, neuroinflammation (Younger), and a kind of muscle fatigue that would not show up in the tests the Bedard group did.
- Interestingly, preliminary results from the Open Medicine Foundation muscle biopsy study suggest that the mitochondria are indeed affected in ME/CFS.
- It’s clearly time for comprehensive studies that assess brain activity, muscle metabolism and activity, blood flows, and immunology to see if we can get at the driver of the mysterious fatigue found in these diseases.
Support Health Rising and Keep the Information Flowing!
Health Rising is not a 501 c (3) non-profit
The Study
This small study (15 ME/CFS; 19 healthy controls) “Central origin of fatigability in Myalgic encephalomyelitis/chronic fatigue syndrome revealed by multimodal neuroimaging” came down firmly on the brain side. It’s essentially a follow-up of Nath’s 2024 intramural Deep Phenotyping ME/CFS study and used some of the same participants.
The exertion stressor used – a 30-second handgrip exertion/rest test done 16 times – was pretty simple. The participants were asked to maintain a certain level of handgrip pressure over the 30-second blocks. Because it became harder and harder to do that over 30 seconds, the researchers were able to assess how the brain and the muscles coped with the stress of maintaining the handgrip pressure.
During the handgrip test, they measured:
- Grip force – the maximal force the participants were able to produce over a short period.
- Muscle electrical activity (EMG) – assessed the electrical activity in the muscle to see how the muscles responded
- Cortical electrical activity with EEG – as the test proceeded, the motor cortex should have increased its activity; i.e., it should have recruited more and more muscle fibers in order to keep the handgrip strong.
- Regional brain activity with BOLD fMRI – since BOLD MRI measures blood flow, blood-oxygen-extraction, etc., the authors wanted to know which parts of the brain became activated as the participants strained to keep the handgrip pressure up.
- Directional corticomuscular coherence (CMC) between the brain and muscle and muscle and brain – asks how tightly the brain and muscles and the muscles and brain are communicating.
If their hypothesis that the brain plays a key role in muscle fatigue was correct, then abnormalities should show up in each of these tests – and, in fact, they did.
Results
“ME/CFS did not change their muscular and brain activity” the authors
Initial Grip Strength
Handheld dynamometer (Image by Ashayou_Wikimedia_Commons_Creative_Common_CCO1.0)
Both the ME/CFS patients and the healthy controls were able to produce about the same handgrip force/strength at the beginning. This will be the sole completely normal finding in the study – and it will turn out to be an important one.
The rest of the tests indicated that while the brains and muscles of the healthy controls became activated, neither the brains nor the muscles of ME/CFS patients did. From what we could tell from these tests, it was as if, except during the very beginning of the handgrip test, they never got the message that exertion was occurring. (It’s going to get a lot more complicated than that…)
Not Just Reduced Blood Flows (the Strange BOLD MRI findings)
The handgrip test in the healthy controls resulted in an increased BOLD MRI signal (blood flows, blood oxygenation, oxygen extraction) in a wide swath of the brain (sensorimotor, thalamus, cerebellum, temporal parietal junction, middle temporal gyrus, mid-cingulate, precuneus/cuneus).
The top section shows the places in the brain where activity as measured by the BOLD MRI was greater in the healthy controls during the handgrip tests. (No part of the brain was more activated in the people with ME/CFS). The C and D sections show what happens as the handgrip test proceeds. Note in D how, at the beginning of the experiment, the brain activation is actually a bit higher in the ME/CFS (red). As the test proceeds, though, the brain activation in the healthy controls (blue) climbs, while the activation in the ME/CFS patients’ (red) brains actually drops.
The regions that were activated made sense as they assess sensory input, force production, motor control, movement, effort, pain, attention, and the state of the body.
The fact that so many areas of the brain became activated as the healthy controls strained to maintain their handgrip force indicates that maintaining strength requires multiple areas of the brain to work together.
The BOLD findings in the ME/CFS patients started off normally but instead of increasing, actually declined as the test proceeded; that is, the parts of the brain needed to maintain physical exertion actually became a bit deactivated.
The authors did not give an explanation why this strange pattern occurred but asserted the early normal/later decline pattern likely meant that reduced brain blood flows, i.e., neurovascular coupling, were not solely responsible.
Indeed, the declines seen in the electrical activity in the ME/CFS patients’ motor cortex (see below), which does not depend on blood flows, suggest that something more than reduced brain blood flows is going to play a role.
A number of things could explain this.
- Reduced neuron recruitment – The motor cortex needed to become more and more activated and recruit more and more neurons as the fatigue increased. If it failed to do this, the BOLD readings could remain flat.
- Neurovascular coupling – the ability to send blood to the parts of the brain that need it – might be OK at rest but poop out when the brain is put under strain. If this is true, then reduced brain blood flows could play a major role.
- Reduced cerebral blood flows – blood flows to the brain as opposed to solely within the brain – might not have been sufficient as the test proceeded.
- Signals from the muscles – due to metabolic strain/energy stress, and pain – could be telling the motor cortex to shut down.
Electrical Glitch
The fMRI assessed the electrical signals in the bilateral primary motor cortex, pre-motor, supplementary motor area, and somatosensory cortex (Top image). Note that activation in these areas initially rose in the healthy controls but immediately dropped or rose less in the ME/CFS patients. Note also that the primary motor cortex was not the big problem. Other, more secondary parts of the brain that are involved in exertion were. The finding does not suggest that the
As the muscle gets fatigued, the motor cortex and its supporting areas should light up and recruit additional muscle motor units; increase the firing rates of the muscle, and more. That’s how the muscle is able to maintain strength even as it’s becoming fatigued. Over time, the brain will reach its limit, and the activity will decline.
The EEG findings indicated that electrical activity in brain areas that produce movement and force increased dramatically in the healthy controls but in most cases not at all in people with ME/CFS. Note that the supplemental motor areas were most affected in the ME/CFS patients.
The low motor cortex/supplemental motor/premotor/somatosensory activity in the people with ME/CFS probably prevented signals for muscle activation from reaching the muscles.
Brain-Muscle: Muscle-Brain Communication
The corticomuscular coherence test assessed how well the brain communicates with the muscles and how well the muscles communicate with the brain.
Interestingly, the brain-muscle connection was relatively normal in ME/CFS, but the reduced muscle-brain connection in ME/CFS suggested that the muscles were not sending normal levels of signals to the brain. This finding may gain in significance later.
No Muscle Fatigue !?
The really strange reading. At least electrically the ME/CFS muscles did not show the expected signs of fatigue.
Finally, and quite significantly, there was the Dimitrov Index (DI). The DI measures how the frequency of the electrical signal changes as the muscle works.
As muscles fatigue, the intracellular ATP-dependent Na⁺/K⁺ pump activity loses steam, which causes muscle fiber conduction velocity to decrease, the fast-twitch muscle fibers to drop out, and the slow-twitch muscle fibers to ramp up.
This results in lower electrical frequencies in the muscles and a higher Dimitrov index. This is a normal muscle response to muscle fatigue.
Except it didn’t happen in the ME/CFS patients. Instead of the DI increasing, it remained about the same and even dropped a bit. It was as if their muscles never entered the normal fatiguing process.
Interestingly, the ME/CFS muscle electrical activity was not diminished – it simply didn’t shift as it should have during exercise. Despite being highly stressed, electrically at least, they didn’t look like fatigued muscles. They were kind of inert!
The DI results led the authors to a most interesting conclusion – they couldn’t technically say the ME/CFS muscles were fatigued (!).
“Put together, these results show that the ME/CFS had limited engagement of their neuromuscular system that was substantially less than what was observed in HV. This resulted in an early decline in performance, and thus, an early onset of physical fatigue; although, we should be careful before labeling this as fatigue since their neuromuscular system showed much reduced engagement.”
In the papers conclusion, they again noted
“In healthy individuals, fatigability is the objective decline of performance over time. Fatigability in ME/CFS should be interpreted differently. While our results suggested that ME/CFS fatigability has a central origin, we would argue that… the fatigability process in ME/CFS did not fully take place”
Not Engaging – Brainwise or Muscularly
So, now they had to explain how both the brain and the muscles of the ME/CFS patients simply did not engage. Why did they not pick up? That immediately brings up the effort question; i.e. were the ME/CFS patients trying hard enough? (Here we go again!).
This study did not answer that question, but they noted that reduced engagement was not conscious: “Importantly, this lack of engagement was not conscious or deliberate.”
Still, they went back to some old canards: the fear, conscious or unconscious, of triggering post-exertional malaise, musculoskeletal/joint pain, or elevated perceived exertion could be responsible.
After noting that central-acting drugs have not proved helpful in ME/CFS, they nevertheless suggested that drugs (or brain stimulation) could help the brain engage more when presented with exercise.
They reported that the most likely explanation for their results was that the fatigue in ME/CFS is caused by the brain, but that the study could not prove that. The explanation wasn’t surprising, though. It was the one they reached in the intramural study.
Taking a broader view in the conclusion of the paper, though, they shifted and stated:
“that a cascade of events affecting the autonomic, neuroendocrine, immunologic, bioenergetic, and physiologic systems… are most likely the source for the lack of engagement of the neuromuscular system.”
Other Explanations
Citing the rather primitive muscle assessments done in the deep phenotyping study, the authors discarded the possibility that damaged muscles might be playing a role.
The authors agreed that damage to the muscles could have prevented them from responding, but they didn’t think this was likely because the muscle biopsies in Nath’s “Deep Phenotyping” study did not show “major” problems with muscle-fiber composition.
The muscle assessments done in that study were quite primitive, however. The one biopsy per patient simply assessed muscle type and relative muscle fiber size. A gene expression analysis of the muscles was unilluminating, but the sample size was very small.
Muscle physiology was ignored. The ability of the muscles to generate ATP, ATP or phosphocreatine availability during or after exercise, oxygen extraction, microvascular blood flows to the muscles, the muscles’ metabolic response to exercise, lactate, pH or other metabolite levels, fatty oxidation and calcium handling, and many more things – many of which have been raised in past ME/CFS studies – were not done.
The muscles could have looked just fine structurally but still had considerable abnormalities.
In the end, the muscle biopsy assessment may have been the weakest part of Nath’s intramural study. The evidence wasn’t much to hang a hypothesis on.
Other Explanations
Several other possibilities exist.
Damaged Muscles?
Wust found significant reductions in aerobic energy capacity and enzyme activity in long COVID.
The 2024 Wust group’s long COVID paper “Muscle abnormalities worsen after post-exertional malaise in long COVID” did dig very deeply. In fact, that paper’s findings make it hard to believe that muscle issues do not play a role in the fatigue and reduced strength that accompany exertion.
Wust’s study, while not large (n=46), was still considerably larger than the Deep Phenotyping study. Unlike Nath’s study, Wust did find a higher proportion of more fatigable type II glycolytic fibers at baseline. He also found reduced aerobic energy production capacity (oxidative phosphorylation), reduced reliance on aerobic energy production, and reduced power output per skeletal muscle.
One day after a strenuous exercise bout, things considerably worsened. Wust found reduced SDH activity, worsening metabolic abnormalities; increased muscle-fiber necrosis; increased muscle atrophy and immune cell infiltration in the muscles (a big no-no).
As noted earlier, the Bedard paper authors banked their conclusions in part on the inability of the ME/CFS patients’ muscles to respond electrophysiologically to exertion. The fact that they never reached the kind of fatigue state expected led them to believe that the motor cortex must be failing to activate them.
If the muscles in the ME/CFS patients were in as bad shape as Wust’s long COVID patients, though, it’s possible that they couldn’t respond correctly.
If that’s true, then the equation potentially flips – the brain asks the muscles to activate (note that they did react normally at first), but as the test went on, they quickly became depleted/damaged and sent a message up the spinal cord to the brain – “Stop that! You’re hurting me”. The brain says “OK- Sorry! (:)) and stopped muscle recruitment (motor cortex) and activating the brain regions (BOLD MRI) needed to keep the force up.
Were damaged muscles telling the brain to stop activating them?
The muscle-brain connection is solidly based in science. The muscles produce over 50 proteins that affect the brain and affect so many processes in the body, that they’ve been called a second endocrine organ.
One result from the Bedard handgrip study – the normal coherence between the signals coming from brain to the muscles and the reduced coherence between the signals the muscles are sending to the brain – suggests that this is what happened.
One of the Wust group’s study results produced quite a challenge to the top-down brain hypothesis. By testing the muscle biopsies in the lab, Wust completely separated them from the brain.
His finding that long COVID patients’ muscles generated less power per unit of muscle than the healthy controls in the lab indicated that the muscles themselves lacked power. Neither reduced effort, conscious or otherwise, nor a balky motor cortex could explain that result.
His latest ME/CFS/long COVID study, “Skeletal muscle properties in long COVID and ME/CFS differ from those induced by bed rest“, suggested that skeletal muscle issues such as reduced capillary supply and mitochondrial impairments characterized both ME/CFS and long COVID patients. Neither of those factors, of course, were assessed in the Bedard or Nath studies.
Wust’s findings don’t mean that the brain isn’t playing a role – the handgrip study suggests that it is – but that it’s probably more complex than the brain simply shutting down muscle recruitment.
It’s still possible that the brain is driving the whole thing – just not in the way that Bedard proposed.
The Brain-Muscle Whack Possibility
Is it possible that the reduced brain activity shown in this study could have damaged the muscles by not supporting them when they tried to work? As the fatigue proceeds, the brain should be recruiting new muscle units. What if that doesn’t happen and the same block of muscles gets “tortured” again and again?
Presumably some damage could result. The fly in the ointment in this idea is that the overworked muscles should still have entered a fatigue state characterized by a high DI. In fact, the ME/CFS patients’ muscles – now really struggling under the load – should have had screamingly high DI ratios. Instead, they had a low DI index.
Because DI only reflects the electrical properties of the muscles, though, it would miss problems with ATP production, metabolic stress, microvascular problems, etc.
In this conception, the ME/CFS muscles become stressed and send signals to the brain asking it to recruit more muscle units, but it fails to do so, placing more stress on the muscles ( which the DI is unable to pick up) and leading to the exertional damage that Wust found.
Infection/Neuroinflammation – the One Hypothesis to Rule Them All?
Perhaps the most comprehensive explanation (but also the newest) is that infection induced neuroinflammation damages the energy processes in the muscles, leaving the muscle fibers largely intact, but preventing them from producing normal amounts of energy.
The last possibility may make the most sense of all. A 2024 study prompted by the coronavirus pandemic produced neuroinflammation in the brain by introducing a variety of infectious factors into laboratory animals.
Oddly enough, it found those factors reduced muscle mitochondria activity while preserving the muscle fibers that the Nath intramural/deep phenotyping study looked for but failed to find.
The senior author of the study stated:
“This is more than a lack of motivation to move because we don’t feel well. These processes reduce energy levels in skeletal muscle, decreasing the capacity to move and function normally,” Dr. Aaron Johnson
He proposed that neuroinflammation may shut down the muscles on purpose in order to save energy. The study found that even after an infection is cleared, the process can become chronic.
Johnson’s results are based on animal studies, but he pointed out that the process is evolutionarily conserved – suggesting that the same process is probably seen in humans.
This scenario potentially ties together the Bedard brain and Wust muscles findings, Jarred Younger’s neuroinflammation findings, and Systrom’s preliminary muscle findings (see below) into the mix to boot (!).
The authors proposed JAK/STAT inhibiting drugs – which are being assessed in long COVID – and IL-6 inhibitors be trialed.
Conclusion
While the authors’ conclusion that the fatigue in ME/CFS is “central; i.eis caused by the brain, is supported by their study, other long COVID and ME/CFS studies suggest that muscle abnormalities will end up playing a major role. The big question now is which one is driving the muscle fatigue and ultimately PEM.
With Wust continuing his work and the Open Medicine Foundation digging deep into ME/CFS we will be learning a lot more about the role the muscles play. The Open Medicine Foundation’s muscle biopsy study, which is using an exertional stress, has been underway for a couple of years and should be nearing completion.
With the study about 2/3rds done, a year ago, Dr. Systrom provided some preliminary results of the 50 ME/CFS person study. Thus far, it appears that people with ME/CFS have an “acquired” (not genetic) mitochondrial problem, which results in reduced numbers of mitochondria and impairs the muscles’ ability to produce energy.
Some people also have reduced activity in the last step in producing ATP – the electron transport chain (:() – while others, apparently trying to compensate for the reduced mitochondrial levels – have increased ETC activity.
Note that reduced muscle mitochondrial activity is what Johnson found occurred after he produced neuroinflammation by introducing infectious factors into laboratory animals.
In the end, this study opens up a lot of intriguing avenues. It’s clearly time to merge brain imaging studies with muscle metabolism, brain and muscle blood flow and immunological studies. Using exercise stressors would be critical to understanding how PEM develops.
Let it be so!
Support Health Rising and Keep the Information Flowing!
Health Rising is not a 501 c (3) non-profit
