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- The second of a series of blogs on recent findings on the mitochondria in chronic fatigue syndrome (ME/CFS), long COVID, and fibromyalgia focuses on ME/CFS.
- The first ME/CFS mitochondrial study on the docket is “only” a case report – but what a case report! The senior author of the paper was none other than Alan Light, and that deserves a little digression.
- Light attempted to do for fatigue what had been done for pain; that is, delineate the fatigue pathways produced during exercise. Alan and Kathleen Light pioneered a series of studies in the 2010s which showed that ME/CFS patients’ white blood cells were hyper-reacting to metabolites released in the blood during exercise.
- The Lights went on to show that the response to exercise in ME/CFS and another fatiguing disorder was similar and different: both diseases demonstrated a dysregulation of the fight or flight or sympathetic nervous system, but only the ME/CFS patients’ white blood cells went into a kind of frenzy as they searched for signs that the muscles had been damaged.
- The Lights also participated in a pioneering heritability study in 2011 which concluded: a) there was a strong heritable contribution to ME/CFS (i.e. ME/CFS can run in families), b) a group of “high-risk” family lines were present (and should be studied). But the NIH, rather bizarrely, refused to provide further funding for it.
- After about 10 years of steady work on ME/CFS, the Lights last ME/CFS publication was in 2017. Then in 2024, Alan Light popped up in an intriguing case study involving a 75-year-old woman who’d been sick for over 20 years following an Epstein-Barr infection.
- A deep dive into her mitochondrial DNA and her mitochondria, however, revealed that she had several mitochondrial DNA mutations. The authors believed these mutations would be devastating and have “progressive effects on ATP production and mitochondrial functions”.
- They believed the herpesvirus infection triggered the mutations by producing large numbers of reactive oxygen species (free radicals) that already weakened mitochondria were unable to cope with.
- While we don’t ordinarily think of mitochondria as part of the immune defense, they play an important role in mounting the alarm when pathogens show up. In response, viruses produce large numbers of “virologs” in an attempt to disable the mitochondria and turn down the immune response.
- Next, a recent animal model explored how fatigue produced by the brain or “central fatigue” affects the mitochondria. The idea that central fatigue could be a big deal makes sense since ME/CFS symptoms are similar to the flu-like symptoms produced by the brain when we catch a cold.
- The study, which stressed mice but did not make them exercise harder, found that the stress damaged the mitochondria both in the brain and the muscles in several ways. That suggested that changes in the brain could affect the mitochondria in the muscles (!).
- The authors proposed that the fatigue, reduced endurance, and cognitive problems found in the mice with central fatigue were related to mitochondrial damage, problems with energy metabolism, and oxidative stress. Once again, they believed that mitochondrial damage played a key role in producing these symptoms.
- Finally, a very small but perhaps telling Stanford study found that stimulating the T-cells of ME/CFS patients resulted in increased numbers of dead and dying T-cells they believed might have been the result of damaged mitochondria which couldn’t “handle the heat” when they were tasked with getting activated.
- Once again we were back to the mitochondria. Whether in the brain or muscles or immune cells, these studies – all of them small, it should be noted – brought us back to what might very well be the original sin in these diseases: dysfunctional mitochondria.
The first ME/CFS mitochondrial study on the docket is “only” a case report – but what a case report! The senior author of the paper was none other than Alan Light, and that deserves a little digression.
Alan Light is back! He and his wife did pioneering work on ME/CFS in the 2010s.
Alan Light Returns!
We can’t just step over the fact that Alan Light has published again on ME/CFS. For those who don’t recognize them, he and his wife, Kathleen Light, are University of Utah pain researchers who, from 2009 to about 2017, produced a series of promising studies on ME/CFS.
Their 2012 paper produced perhaps the most startling graph I’ve seen in ME/CFS yet. It indicated that exercise produced remarkable increases in the expression of the receptors on white blood cells that detect metabolites associated with exercise. In essence, it suggested that exercise was either inducing a lot of damage which the white blood cells were reacting to, and/or that the white blood cells had become hypersensitive to any signs of damage produced by exercise. (Exercise always induces some damage). In either case, it appeared that an exercise-induced immune activation was in full bloom.
Interestingly, given Naviaux’s emphasis on the purinergic metabolites, the paper particularly plucked out the activation of a purinergic receptor (purinergic type 2X4 receptor). The paper also showed that when it came to exercise, people with ME/CFS and another notoriously fatiguing illness, multiple sclerosis (MS), were similar and different.
Exercise did not provoke the white blood cells in MS to go on high alert for exercise-induced metabolites, but it did trigger a spike in adrenergic receptor activity in both ME/CFS and MS patients (but not healthy controls). That suggested exercise dysregulated the sympathetic nervous system in both diseases.
Elucidating the Muscle Fatigue Pathways
The Lights’ study showed a dramatic increase in white blood cell reactivity to metabolites released during the muscles during exercise.
Alan Light said he wanted to do for fatigue when had been done for pain (i.e., elucidate the fatigue pathways in the body) and in 2015, he and Markus Amann put their findings together in a review paper, “From Petri dish to human: new insights into the mechanisms mediating muscle pain and fatigue, with implications for health and disease“.
The paper asserted that metabolites produced by muscle activity activated both myelinated and unmyelinated neurons (small nerve fibers) which then sent signals to the central nervous system via the nerve located on the dorsal horn of the spinal cord.
They noted that two sets of receptors designed to interact with these exercise-induced metabolites were present: one subtype responded to relatively low levels of intramuscular metabolites (lactate, ATP and protons), as seen during `normal’ (i.e. freely perfused and aerobic) exercise, while the other responded to higher concentrations of metabolites that were produced during ischemic conditions in which the muscle was in a state of hypoxia; i.e. low oxygen levels.
Over time, studies concluded that protons, ATP, and lactate produced by the muscles induce muscle fatigue and pain, and that neurons with ASIC, P2X, and TRPV1 receptors respond to them. The Lights found that exercise highly upregulated these receptors in ME/CFS. With that, they seemed to be on the road to delineating how muscle activity during exercise could be producing the pain and fatigue in ME/CFS, but the Light’s time with ME/CFS ended in 2017 with Dane Cook’s paper showing that exercise impacted brain functioning.
Inheriting Dysfunction (at the NIH)? The Heritability Study
The NIH funded an exploratory heritability study – and then when it proved to be successful – refused to fund a follow-up…
The Lights also participated in a 2011 paper, “Evidence for a heritable predisposition to Chronic Fatigue Syndrome“, that was remarkable for: a) its conclusion that there was “strong support for a heritable contribution” to ME/CFS (i.e. ME/CFS can run in families), b) its ability to identify a group of “high-risk” family lines, and c) the bizarre fact that it was never followed up on (they tried).
Identifying high-risk family lines was a coup, as researchers typically study families to get clues about what’s going on in a disease. The bizarre part comes from the NIH funding what turned out to be a successful study – and then being unwilling to fund a follow-up. (Why fund the study in the first place?)
What happened to turn off the Lights’ ME/CFS spigot is unclear, but the 2017 paper was the last one from the Lights and ME/CFS until 2024, when Alan Light popped up in an interesting case report.
A Viral – Mitochondria Connection?
The authors believe that an EBV infection probably produced the mutations found in her mitochondrial DNA.
The case report, “The “Mitochondrial DNA Missense Mutations ChrMT: 8981A > G and ChrMT: 6268C > T Identified in a Caucasian Female with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Triggered by the Epstein–Barr Virus“, involves a 75-year-old woman who had been sick with ME/CFS, triggered by an infectious mononucleosis infection about 20 years earlier.
Her symptoms were primarily mainly neurological and cognitive impairment, and included fatigue, severe PEM, severe dysautonomia, unrefreshing sleep, widespread achiness and tenderness, sporadic dizziness with vertigo, severe orthostatic intolerance, and brain fog.
Standard lab tests, of course, were normal. The NASA lean test, though, revealed that she had neurally mediated hypotension (reduced blood pressure upon standing). Despite taking antivirals (valacyclovir, valganciclovir) for long periods, she at times exhibited moderately high titers of EBV antibodies. Still, neither, her antibody nor a PCR test suggested she had an active infection.
But then there were the mitochondria…
The electron chain complexes where ATP is finally produced are mainly encoded by mitochondrial chromosome DNA (ChrMT DNA, or mtDNA) passed down through the mother. The ChrMT chromosome is also where the first half of the mitochondrial energy production process – the Krebs cycle – where oxidative phosphorylation (OXPHOS) takes place. Because ATP generation produces a lot of oxidative stress (i.e., many free radicals) – picture sitting next to a blast furnace – this part of our DNA is highly susceptible to oxidative damage and has high mutation rates.
A deep dive into her mitochondrial DNA and her mitochondria, however, revealed that she had several mitochondrial DNA mutations (ATP6 (ChrMT: 8981A > G Q152R) and Cox1 (ChrMT: 6268C > T A122V)) including one at a site (ATP6) well known to cause mitochondrial problems.
That ChrMT Cox1 mutation was not just any mutation. For one, it was new to the literature. For two, it occurred in a gene (Cox1) that plays an important role in the later stages of the electron transport chain. The authors believed that a mutation affecting those stages would be particularly devastating and have “progressive effects on ATP production and mitochondrial functions”.
One of those effects was large numbers of dysfunctional extracellular mitochondria. These mitochondria appeared to “protrude” or “secrete” vesicle-like structures similar to those that Gram-negative bacteria produce in stressful conditions (!).
The authors proposed that the extracellular, abnormal mitochondria found in her and other ME/CFS and post-infectious illness patients probably resulted when a batch of malfunctioning mitochondria met up with a virus.
Sitting next to the blast furnace that is the mitochondria, it’s no wonder that mtDNA are more susceptible to mutations.
They also proposed that viral-induced reactive oxygen species (free radicals) were at least partly to blame for the mutations in the mitochondrial DNA found.
We’ve seen both of these hypotheses show up. They suggest that dysfunctional mitochondria not only fail to rise to the challenge when a pathogen shows up but break down and start producing large amounts of reactive oxygen species, which then produce more mitochondrial damage.
The authors proposed that people with ME/CFS probably had “dysfunctional mitochondria” that predisposed them to develop ME/CFS after viral infections”. Those dysfunctional mitochondria could either be inherited, or modified by epigenetic changes, and/or by an infection.
With regard to this patient, they believe her mitochondrial mutations probably reflected “accumulated mitochondrial stress” caused at least in part by her exposure to the Epstein-Barr virus at age 52.
Harkening back to the heritability study, they recommended, though, that her family undergo ChrMT DNA sequencing to “help uncover the role that viruses, mitochondrial DNA mutations, and mitochondrial problems play in the disabling fatigue found in post-infectious diseases”.
While we don’t normally associate the mitochondria with viruses, as Dr. Naviaux has explained, and as we saw in a recent blog, the mitochondria play a pivotal role in our viral defenses. Because they do so, they are targeted by viruses which produce large numbers of “virologs” in an attempt to damage the mitochondria and turn down the immune response.
The Brain-Mitochondria Connection
Let’s forget infection for a moment though. Could stressful conditions all by themselves lead to mitochondrial breakdown? A recent animal study suggests they can.
Several researchers have proposed that much of the fatigue in ME/CFS comes from “central fatigue”; i.e. fatigue that’s caused by the brain. In fact, Behan and Chaudhuri’s 2004 tome, “Fatigue in neurological disorders“, which repeatedly cited ME/CFS, was one of the first to make this connection. Their focus on the pathways interconnecting the basal ganglia, thalamus, limbic system, and higher cortical centres still rings true today.
The idea that central fatigue is a big deal in ME/CFS makes a lot of sense in several ways. For one, we know that the symptoms of “sickness behavior” we experience when we have a cold are produced by the brain. Given its typical post-infectious onset, ME/CFS could simply be a cause of chronic, unrelenting “sickness behavior”.
Of course, the big question is how to account for the findings of muscle damage, blood vessel, and mitochondrial problems that have shown up in the periphery in ME/CFS. Does the brain have that far of a reach?
A fascinating study from Daniel Clauw suggested it just might. In another animal study, Clauw found that increasing the activity of the insula – an organ of the brain involved in autonomic nervous system regulation and sensory processing – resulted in the development of small fiber neuropathy and increased pain sensitivity in its limbs (!).
The authors proposed that the fatigue, pain, sleep and cognitive problems caused by putting the mice under stress were due primarily to mitochondrial problems.
A recent animal model, “Replicating human characteristics: A promising animal model of central fatigue“, set out to understand just how far “central fatigue” might go. It first created a state of central, or brain-induced, fatigue via sleep deprivation and alternate-day fasting. Note that no increases in physical exertion were introduced – whatever happened in the periphery was not the result of exertion.
Even though the mice didn’t exert themselves, their muscles were hit hard. They exhibited reduced grip strength, and endurance, increased lactate levels and energy consumption, and muscle atrophy, including a reduction in slow muscle fiber levels.
And then there were the mitochondria. The mitochondria both in their brain and the muscles got hit even harder. Noting that mitochondrial problems have been found in another fatiguing disease – ME/CFS – the authors reported finding reduced ATP levels, increased levels of oxidative stress, irregularly shaped cells, increased heterochromatin in the nucleus, decreased levels of mitochondria in the cytoplasm, broken or disappeared inner cristae, and ruptured outer membranes.
In the end, the authors proposed that they believed that the fatigue, reduced endurance, and cognitive problems found in the mice with central fatigue were related to mitochondrial damage, problems with energy metabolism, and oxidative stress.
We were back to square one with the mitochondria – and a brain that apparently has a long reach.
Microstructural Mitochondrial Abnormalities
Swollen (damaged) mitochondria (white arrows) were greatly increased in the ME/CFS patients. (Image fr. Jingjing-Fan-Xiaoqi-Yang-Jie-Li-Ziyang-Shu-Jun-Dai-Xingran-Liu-Biao-Li-Shaohui-Jia-Xianjuan-Kou-Yi-Yang-and-Ning-Chen-CC-BY-3.0-Creative-Commons-via-Wikiimedia Commons)
A small but perhaps telling Stanford study from Fereshtah Jahanbani (“Phenotypic characteristics of peripheral immune cells of Myalgic encephalomyelitis/chronic fatigue syndrome via transmission electron microscopy: A pilot study“) used transmission electron microscopy (TEM) to dig deep in the microstructures (including the mitochondria) of both unstimulated and stimulated immune cells.
Only four people participated in the study – a pair of identical twins, one of which had moderate ME/CFS, a person with severe ME/CFS, and another healthy control – but the study produced some intriguing results that will hopefully be followed up on.
Immune activation is not a subtle process. It requires a lot of energy, and thus provides a nice way to test a cell’s energy metabolism. Placid-looking monocytes, for instance, turn into hairy monsters called macrophages, and B and T-cells jack up their energy metabolism as they prepare to clone themselves in great numbers.
Researchers have proposed that all that activity is too much for the puny mitochondria found in people with ME/CFS, causing the immune cells to punk out and either become exhausted (T-cells) or fail to reach maturity (B-cells).
The authors of this small study might agree. Once stimulated, the number of dead and dying T-cells in the ME/CFS patients began to pile up, and the levels of swollen mitochondria – indicative of mitochondrial dysfunction – increased significantly. The authors reported that the two ME/CFS patients “showed remarkably higher numbers of swollen mitochondria.”
The Original Sin – Bad Mitochondria?
Once again we were back to the mitochondria. Whether in the brain or muscles or immune cells, these studies – all of them small, it should be noted – brought us back to what might very well be the original sin in these diseases: dysfunctional mitochondria.
- Coming up: Pt. 3 – the Mitochondria in Fibromyalgia Plus Some Treatment Suggestions
Looks like we are really getting closer and closer to a nice story to explain ME/CFS and his main symptoms: PEM and brain fog.
Some people could be genetically predisposed to mitochondria mutations that could be triggered by stress (stressful life events) and/or virus (EBV here but maybe also the highly suspected HHV6-A).
Once ME/CFS is declared, the more stressed you are in your life and the more severe the symptoms you are going to have. This is a vicious circle.
All this would at the same time reconcile the different hypotheses and approaches to fix the problem. A medical solution (genetic, anti-viral, etc) combined to a ‘mental ‘solution like anything allowing to lower the stress (meditation, brain retraining, etc).
Again the ‘mental’ solution part does not mean at all that any of us is crazy neither that this is all in our head.
Like it !!!
I think you laid it out quite well 🙂 Some weakness in the mitochondria that predated the infection I think is the idea.
Cort,
You know what. I am an aerospace engineer and it is probably professional training but I really need to understand things in life. The more I understand things in life, the more I feel empowered and in control of the situation. It is exactly the same thing with ME/CFS for me. The more I understand the potential causes, the more relax I feel, in spite of pretty tough periods evidently, and the less severe the situation is for me globally.
Mind therapy doesn’t work for ME/CFS, many of us have tried it and had no improvement. In fact I deteriorated even though I was doing very good relaxation exercises, body scanning, vagus nerve relaxation etc.
Note: i haven’t had and don’t even have anxiety. I’m a chill person.
I think you are confusing ‘stress’ as the psychological form.
When there’s stress in biology it means things in the environment like food, compounds, toxins, viruses bacteria fungi, exercise, immune responses, hormonal changes etc, that all put a stress cells and cellular signalling. These cells as Dr Naviaux has stated many times are locked in a Cell Danger Response that normally only turns on during infection or injury. For some reason it remains locked on.
There’s been decades of nonsense about the mind therapies for ME/CFS. If it worked I’d be cured and everyone else would be cured now too. But it’s only a few improved who i believe either had recovered and we’re deconditioned, so can pull out if that/ or had psychological fatigue that improved with mind therapy.
Us (the ones with actual ME/CFS) have a biological disease.
The cure will be biological too. Not psychological, not ‘dualism’, just biological.
Like other diseases the mind only helps cope with living with the disease. It doesn’t improve it. If you look at studies on cancer outcomes with will power and optimism, they made no difference to the outcome of these physical diseases.
All mind therapy does is help reduce the emotional suffering of having to deal with such a vile physical disease. I support it being used for only that
I’m truly sorry that you got worse. That said I’m really disappointed with part of the community discrediting other people’s experiences.
If someone says that mental approaches were a part of their recovery or improvement, don’t minimize that just because it doesn’t work for everyone!
I’m not saying mental approaches are a cure-all for ME, they obviously aren’t. But we aren’t doing the field any good if we dismiss the cases where it helped by just saying they didn’t have ME in the first place. There may well be different subtypes of ME and each trajectory is so different due to genetics and all sorts of environmental factors before and after developing the disease.
We should be interested in WHY it helps for some and not for others. Then we could better figure out how to help each and every patient individually. And especially, we would finally fix this divide in the community, which does nothing for it.
I believe a component of ME/CFS impacts the central nervous system. I also believe that mental stress is a trigger for a crash and puts extra burden on the body. For instance, on vacation my ability to exercise and physically exert myself without a crash increases dramatically. For me, meditation and relaxation helps dramatically. I’m normally a pretty chill person, not particularly stressed or nervous, or so I thought, but a few minutes of meditation before bed helps me sleep better and seems to energize my body the next day. Breathing techniques help me fall back to sleep when I wake up feeling wide awake at 3am, which occurs almost every night. I call feel the breathing and relaxation calming the fight or flight response my body seems to be going through.
As an aside, I was diagnosed with ME/CFS by Dr. Systrom who also gave me a small fiber neuro test – positive.
It seems these techniques don’t help everyone, but some might find relief.
Well said, Nuria. Thank you. It astounds me that people who have suffered the pain of being discounted, discredited, gaslit, and judged feel no hesitation to deliver that same harm to fellow patients. There is no single option that helps everyone. Even something as basic as pacing isn’t helpful to all. Neural approaches are NOT appropriate or useful for everyone but for those they are, they can be a game changer. My point, though, is not to promote neural approaches. Instead, it is to promote change in how we treat each other. It is helpful to share what works and doesn’t work for us so we can learn from each other and decide what to implement based on what is appropriate for our individual circumstances. It is harmful to discredit, discount, gaslight and judge others because their experiences do not match our own. We are not all the same. Mutual support and respect will go a long way to healing the harm that we’ve all experienced. If we aren’t willing to do that among ourselves, how can we expect it to come from others?
I said “… it’s only a few improved who I believe either had recovered and were deconditioned…” (what I mean here is they genuinely had ME/CFS but their bodies recovered (i.e. PEM had previously gone without them knowing). But because they were so weak from years of being unwell they remain deconditioned. People could be in that state for many months. (It happened to a friend of mine).
Then they use mind therapy and start finding they are able to push through. That’s because there was no PEM to block their recovery).
That is exactly happened to Prof Paul Garner. Back on the 5th October 2020 He replied to my email, to tell me he “didn’t have problems with pushing through” and was “doing 5km daily walks”
Note: That was before mind therapy. Yet he now he is on a campaign falsely claiming it was mind therapy that cured him.
The important issue here is he and others whose PEM had ‘gone prior’ will recover with mind therapies. But if you have severe PEM after exertion then using their techniques a crash will occur.
If someone has a psychological problem on top of ME/CFS then yes that will help tone down exacerbation of symptoms. I think it’s fine to do meditation and other stress relief exercises if a person is constantly on edge as is energy consuming so reducing that energy use for them can reduce a flare. but my comment was in reply to someone saying that to do mind therapy with medication will help people recover. I’m saying that’s not true and there’s no evidence of that either.
I am talking about people who don’t have mental illness but do have ME/CFS. It’s not true that it’s rare. Some people with ME/CFS don’t have anxiety and some do. You lot are adding a ‘psychological comorbidity’ onto ME/CFS. Which is a separate issue.
This is a biological disease, not a psychological one.
For decades those with mental illness induced fatigue ‘without PEM’ ended up in ME/CFS clinical trials due to misdiagnosis, and that data muddied the waters in the results. Which is a big reason why this disease hasn’t progressed in biological research. And is because it was suggest that ME/CFS was psychological, was a huge reason why government funders have have shied away from biomedical research.
It’s also a reason why the psychiatric community (Simon Wessely and his goon squad) hijacked the disease with their fake GET and gaslighting CBT mind therapy to challenge one’s sickness belief nonsense. That therapy actually harmed people.
There is so much to unpack here, I don’t know where to begin and I’m not going to try other than to say quite emphatically that neural approaches do NOT, and let me say that again, do NOT suggest ME is psychological or a mental illness or a psychological comorbidity. Neural retraining goes well beyond CBT or GET or meditation and is very much related to biology. Autonomic nervous system dysregulation, which is biological and which neural approaches help regulate, is not being ‘anxious’ or having a mental illness that ‘muddies the waters’. Those of us using these approaches are as educated, experienced and knowledgeable about ME as everyone else. We are not confused about PEM and deconditioning. We know what helps us and what doesn’t. Improvement comes in different ways for different people. Can we not accept and respect that?
Hi Michele,
I have learned for a very long time in my little career (I am just a not very educated and knowledgeable aerospace engineer who can not understand complex concepts because I am working in such an easy field) that it is very hard and not very useful either to argue with people with such a rigid attitude.
Indeed, they have a hard time to understand the concept of discussion : to exchange ideas on a open mind basis in order to end up with a better comprehension of a situation.
Generally, they just want to have the last word because THEY KNOW. I am always very wary of people who know because they tend to jump to conclusion before the full job is completed.
By the way, in case this could be useful to someone, anxiety needs to meet very very specific criteria of circumstances and severity to be diagnosed as a ”mental illness” in the DSM5-TR.
You are so right and I only occasionally engage on this topic because it is so fraught with misinformation, disinformation and emotion. With what recently happened to Dr. Eleanor Stein, though, I am less inclined to say nothing. Doing so is giving a group of anti-neural training people a louder voice than what is healthy for the community. It is causing harm.
https://www.eleanorsteinmd.ca/blog/canmebecuredwithneuroplasticity
As I’ve said elsewhere in this blog and in other places, I am not here promoting neural training. While it can be very helpful, itis not a cure. It is not appropriate for everyone. As with every other option for ME/LC, results are mixed.
What I am calling for is for us to come together as a community. To listen to each other and respect that we are all different in what works and what doesn’t. Our individual experiences are valid and deserve respect. At the same time, none of us has the right to claim our version of ME is the only right version or that what works or doesn’t work for us applies to everyone else. I’m going to continue to call for mutual respect because I believe it is long overdue and essential for our health.
No, I am not confused about the stress definition. I perfectly know the difference between biological stress and psychological stress.
I fully agree with the explanations of cells being latched on in an emergency or danger state. Of course ME/CFS is a biological problem and any relaxation technique, brain retraining or whatever you want to call them are absolutely no cure to this physical disease.
I am not saying at all that psychological stress is the cause of ME/CFS. I am only saying that that emotional stress, if you have some, induces a second vicious circle layer to the base physical problem and then, the more relax you are in your life, the better you are able to cope with the base physical problem. We are saying exactly the same thing.
Good for you if you are a chill person and if you never had any anxiety related to this disease (you are a very rare and lucky one because I personally find this disease extremely stressful on all aspects of my life). I am also very surprised that you deteriorated because being more relax, even if you already are, can normally do no harm but this is your personal experience with these techniques, so be it.
In fact, B Rob, many of us HAVE improved with neural therapy. To date, there is no cure for ME. There are, though, different strategies and different treatments that lead to improvement in some, but not all, people. Neural therapy is one of many options that may or may not lead to improvement. Discrediting the experience of others is not helpful. In fact, it is harmful to all of us.
Show the scientific evidence with Peer reviewed Randomised Controlled Trials. And studies that were able to repeat the same outcome
It would be wonderful to have this kind of evidence for every treatment or approach for ME. We can only hope that someday it is the norm. Sadly, evidence like this is in very short supply and is very expensive to achieve. If we condemn everything that isn’t supported by repeatable peer reviewed RCTs, our list of options will be very limited. I don’t personally know of any patients who are willing to do nothing to help themselves while science takes it’s time to catch up to us. Can we not show respect for people who have experiences different from our own?
There’s millions of people in the world with ME/CFS and Long Covid. Neural brain training has been around a long time now. If worked beyond placebo we’d see tens of thousands of patients recovered or vastly improved by it. We don’t
I’ve been to these brain training websites and read the testimonials, and I see only a few dozen people claiming it worked. Even if it was a few hundred people that’s still so tiny compared to the millions with ME/CFS, or thousands that have tried it.
I’ve seen far more people in online forums and social media saying it didn’t work than did.
If it works then why aren’t there any decent studies showing it works? I can’t find any. Yet they charge big bucks to do the course, lots of money being made yet not put into proving it works. Thats a red flag. I also see the practitioners of these courses coming into online forums as bunched claiming it works, but of course they will as they are motivated by money.
I can accept that people who did recover actually were on the cusp of improving anyway because there’s plenty of recovery without mind therapy. Had they tried a certain supplement at the time they recovered they’d be adamant it was that specific supplement.
I’m not saying to people don’t try it. I did. I’ve tried so many different things.
On the issue of money, why are these brain training therapies all behind paywalls? Surely if mind therapy worked there’d be someone so excited to guide people in a YouTube video for free.
Virtually every trade and skill is shown in ‘How To’ videos by someone on YouTube for free. If you have a link to a video on it id be interested to see if it’s similar to what I did. And if you are sure it works you will be helping others at the same. Or do they have to pay?
Fluge, Mella and Tronstad (very biomed oriented people) might be able to explain why some patients benefit from mind-body techniques:
«In our model, clinical symptoms of ME/CFS are related primarily to the inadequate autoregulation of blood flow yielding tissue hypoxia on exertion, but are also influenced by the compensatory adaptations from increased sympathetic output and from metabolic shifts.
We speculate that cognitive techniques, which are reported to help subgroups of patients, might act by modulating the sympathetic output. If so, one would expect a greater benefit for patients with less ongoing immune activation and less vascular dysregulation, but with main symptom contributions from the secondary autonomic adaptations.
Conversely, patients with active immune disturbance and ongoing vascular dysregulation as the main symptom generators would have less impact from cognitive intervention, although psychosocial support and coping strategies may still have a beneficial impact on their quality of life.»
Ir the mitochondria has less oxygen, it will die more often, regatdless of the mutations. If some of the lack of oxygen is caused by an over-active SNS, calming the SNS through e.g. mind-body could in theory be beneficial. For some, that’s enough to get better. For others (probably most), it’s not enough.
Thanks! That’s in line with what I’ve been proposing for years. 🙂
Fluge, Mella and Tronsta Had a massive difference between their first trials compared to their big RCT trial. It was an utter flop. The last trial was so profoundly different I suspect they manipulated the data in the first ones to get funding.
I have no trust in those researchers whatsoever
@B Rob
It’s completely normal to have different results between phase 1, 2 and or 3. Probably more normal than not – most drugs don’t make it to phase 4. That’s also why they stopped, because they trusted the results and want to focus on finding an actual cure. How is that a bad thing?
They also work with Ron Davis’ ME/CFS Collaborative Research Center at Stanford University. If Davis trusts them, I’m inclined to do so as well.
Furthermore, Fluge and Mella (I’m not sure about Tronstad), were cancer researchers before they stumbled upon an ME patient that fully recovered due to chemo. They mostly left the most lucrative and prestigious field for ME – the exact opposite.
They are known for doing a lot with very little funding, and they are currently trying to develop a more gentle way of measuring PEM (text in Norwegian, but you can see the method they propose): https://www.facebook.com/100064524226847/posts/pfbid0ihusHZ1w24Ybc1s2YQ6LpbzTpafxVBoiuNZ3yQPFSVJYu4UUsbzjKQZFG7ALMgiBl/?app=fbl
I agree that many people who have tried mind/body approaches have not met with success – but for me this goes too far: “Mind therapy doesn’t work for ME/CFS, many of us have tried it and had no improvement. ” We’ve had lots of people who said they at least received some benefit from it.
For me, I was one of these people who were highly critically of the mind/body approach. I considered it not only a not very helpful tool (beyond normal stress reduction, healthy for everyone) but I did find its promotion to be counter productive.
First of all because ME is not in the mind. But more so because I feared that (poorly designed) studies looking into the benefit of eg brain training for ME would take money away from needed biomedical research and would serve as a cheap cop out for insurances and other providers.
I still see this danger. With LC we see that big insurance companies in Europe are conducting studies that “prove” that exercise and mindfulness can cure LC patients. The ones not cured have nothing in their hands to claim social security etc.
That said, I began incorporating regular mind body techniques this year as my health has dramatically declined and I really saw a lot of benefits (no cure or drastic improvement). One of the most important and often overlooked ones: Mindfulness helps me with pacing!
Did you read the part that explained that fatigue can be generated by the brain? And how they found that Small fiber neuropathy (A common comobordity of MECFS) can be also caused by stress on the brain?
It doesn’t mean that the disease is psychological but that mental stress can be the detonator with real biological consequences.
If all of this is true, it makes sense to me that some people are cured after brain retraining.
Our organization sponsors the National Birth Defect Registry and we collect data on health, genetic, prenatal and preconceptual exposures in the children of both parents.
Our data include structural birth defects like spina bifida and cleft palate as well as functional birth defects that include immune, endocrine and neurodevelopmental problems like autism.
The online questionnaire for the registry which was developed by a team of scientists has hundreds of questions, but a place to write in a condition or exposure not currently on the survey. We currently have have nearly 6700 cases in the online registry and another 3-4000 in the original booklet format.
We were surprised to have over 539 cases of ME/CFS reported, 422 of these in the children of Vietnam veteran fathers exposed to Agent Orange.
Our hypothesis on the conditions that are increased in the children of Vietnam veterans is that dioxin (toxic component of Agent Orange) has a negative impact on the development fetal immune system making the children vulnerable to autoimmune disorders, cancers, immunological, neurodevelopment problems and more.
https://birthdefects.org/wp-content/uploads/2024/07/Vietnam_Veterans_2024.pdf
There are many other exposures that could also impact fetal immunity.
Maybe we are not going back far enough to understand who is most vulnerable to ME/CFS and Long Covid. Since World War II and the splitting of the chlorine atom, there has been a proliferation of new chemicals in our environment.
Hi Betty,
Very interesting data. Of course chemical pollutants of all kinds may well be a cause of genetic dammages. Indeed, with time going by, I guess we will understand more and more that genetic dammages are not a purely random effect but rather often related to human causes (Irene Brokovich story, etc). AI will probably help a lot soon to investigate such huge databanks. As anyone so far (doctors, research centers, etc) requested your databank for in-depth investigation ?
Dear Canada and Terry,
First, Terry thank you for your kind comments.
Canada, rather than ramble on about what we have done with our data, I thought you might want to read this report about the registry and the scientists involved.
https://birthdefects.org/wp-content/uploads/2024/06/Registry-doc.pdf
Our data have been presented to government agencies, congress and in national media forums.
Thank you for your extraordinary work!
Looking forward to Part 3 – treatment suggestions.
Where there’s smoke there’s fire. Clearly something is wrong with the mitochondria. But are those problems contributing significantly to symptomology, or not? Or are the mitochondria just unfortunate ‘collateral’?
I suspect’chicken and egg’ – a feedback loop. Will effectively treating the mitochondria effectively address the feedback loop?
Is rapamycin part of the answer?
Is viral reactivation the issue? Might PolyBio’s antiviral clinical trial address the mitochondria by addressing viral reactivation?
Praying for meaningful treatments
We have a lot of arrows pointing at the mitochondria, and in some ways we are in the same fix we have always been in – lots of small studies. Hopefully, the smaller studies will add up and we’ll get some nice big ones.
After careful consideration of all the studies that were available at the time my son got sick with EBV-CFS in 2020, I focused on the mitochondria and had him take a full complement of mitochondrial supplements, with the aim of reducing PEM in particular. I believe treating the mitochondria (using PEM as the measure of success) allows the body to recover, allowing the use of neural therapies to seal the deal and the individual to recover to almost normal, as others in this thread have suggested. Interestingly, one of the therapies that helped was low dose naltrexone, which has since been hypothesised to be of use to mitochondria. The mechanism proposed is calcium ion channels, which are within the mitochondria. https://pmc.ncbi.nlm.nih.gov/articles/PMC8313851/
My son recovered after 18 months of fatigue and is living a normal life now. His supplement/medication regimen was D-ribose, CoQ10, Vitamin D/K, curcumin, LDN, methyl B12/Folate, quercetin, high dose B1, magnesium, melatonin, fish oil and methylphenidate. We also tried a number of other supplements with no or little effect. Other things that helped were pacing, Mickel therapy (a neural approach that emphasises doing what one intuits is right based on the messages one’s body is sending) and the Covid-19 vaccine. I hope my little contribution synthesises the approach to treatment of someone here reading this. Good luck to all!
Congratulations and thanks for sharing 🙂 Very good you got after your sons illness quickly. I imagine that helped.
So, I guess this explains why you get this from your mother?
If you’re in the heritable group it could explain that. Of course, there may be other things going on. Nobody else in my family has had ME/CFS – including my twin (!) – but my mother did have a lengthy autoimmune illness
Wow Cort, that’s very interesting. I am sure it’s more complex than that but when we look at celiac 30% of the population have the gene and only 2% have celiac. So almost always there has to be a trigger. So maybe even when mothers have ME that doesn’t necessarily mean much?
If the mitochondria is the “energy” part of the cell, and if it is not functioning as it should (or not at all) and if this ‘faulty mitochondria causes all the parts of the body not to function as it should; or ‘slower’ than it should, then it makes perfect sense that the brain, the muscles and even the gut would be ‘fatigued “ or work extremely slow i.e. brain fog. I say this because I had shingles at the same time I had a 9 hour surgery on my spine in 1997. Although I had undergone 6 previous long spine surgeries since the age of 15; this one was different. Since that surgery in 1997, I immediately knew something was terribly wrong. I knew what post operative pain felt like-but this was different. Since that surgery, I have experienced excruciating pain 24/7 even with opioids. I have fatigue that caused me not to be able to take care of my younger children. I have had two different types of cancer, undergoing surgeries, chemo, radiation, etc. I also continued to have ‘shingles’ break out on my stomach and around to my back anytime I am under extreme stress. Interesting, my digestion is so slow that I only go to the bathroom every 10-12 days. Still, I must use an enema to empty my bowels. I have tried many prescriptions to help me have a bowel movement, but it only results in the most intense cramping and stabbing pain but does not end with the desired results! Not sure if this has anything to do with the studies on mitochondria, but I would be interested to know the story of other ME/CFS patients and how their illness started and did it progressed ? Or did their symptoms stay the same? How many patients have had times of ‘remission’? How many suffered with severe ME/CFS and now are free from all symptoms?
I might add that I have been in therapy for a long time due to growing up in a very dysfunctional family. Abuse that I won’t explain here~but it was severe and my case study has been written about in 2 books from 2 Therapists who have treated me. I was diagnosed with severe PTSD, childhood trauma and serious neglect; physical and ‘other’ abuse as well as having a mother in and out of Psychiatric hospitals and a father who would leave me (at 5 years old) at home to care for my 14 mo old brother every day while he went to work and my mother was hospitalized; leaving no food, formula or instructions. My Oncologist found it odd that my extensive bloodwork done before any cancer treatment showed that my cortisol was as low as he (or the Endocrinologist) had ever seen. My Psychiatrist said it was probably due to my adrenal gland putting out so much cortisol for so long during these ‘fight or flight’ episodes , that it just doesn’t work.
I wish all ME/CFS patients were given extensive health histories to be filled out and all sent to ONE research group. Finding out all the symptoms, personal histories, etc. might open the eyes of the researchers as well as us, the patients. Sadly, I still deal with physicians who have no clue about ME/CFS. When I tell them what the long name is~ I always get “oh. We ALL have chronic fatigue these days. You should just get more exercise and good sleep”. Ugh! Why are we STILL getting these responses? I’ve had this disease since 1997. It took 12 years, 61 physicians in 8 States before I got a diagnosis! And yet nothing has changed.
This would go some way to answering the oft ignored issue of wherefore post-exertional malaise?
I would think so…The more stress put on the mitochondria the more they break down. I could see an ioxidative stress cascade that results from that as the “fire” feeds on itself. There are also the studies showing that the body at a molecular levels is just not responding to exercise – because the mitochondria have gotten whacked (?) – and muscle repair mechanisms are not kicking in either.
I’m tired of these studies. More, blah, blah, blah..some contradicting, each other… I don’t what..l’m not a phd
I mean want..
Has anyone tried the ginseng supplement HRG80?
https://pmc.ncbi.nlm.nih.gov/articles/PMC8777686/
Ginseng made me nervous..too much energy, and for me, didn’t seem like the good kind of energy.
But try it if that’s an instinctive thing to do, and let us know. Maybe it will work fine for you. Not meaning to dissuade..
Take care everyone!
Yes with no benefit. But I have been feeling better drinking hydrogen water (not hydrogen capsules).
May I ask what symptom benefits from drinking this?
The symptoms of this illness vary so much from person to person, it’s hard to know what might work best.
By far the main symptom for my daughter is mental fatigue and lethargy. Trying to find things that might help that a bit.
Increased energy, less weakness in my legs. Just a better feeling of overall wellness. I started out low and built up to 3 bottles a day (company recommends 5 per day). At first drinking before bed kept me up but now that I’ve adjusted, it doesn’t mess with my sleep. The biggest help for me (which is also proving to me it is helping) is I am no longer getting any (genetic) Hailey Hailey Disease flares. When my cfs symptoms started, my genetic HHD worsened. I’ve found over the years anything that is mitochondria focused, also helped this genetic mutation. For me it feels like a two for one win. My skin is healed and my strength is slowly coming back. It’s only been 4 months so far. I’ve been struggling since 2008.
I really get it Elaine. I also tire of the endless studies that don’t really seem to take things forward much. Yet, at the same time, I do feel that we may finally be on the cusp of some meaningful progress.
I am hopeful that some treatments such as BC007, or rapamycin, might offer meaningful help for a significant number of people. Of course, I am cautious with that hope. We have all been burnt many times by false hope.
I also find some of the new players like PolyBio energising. And Dr Iwasaki at Yale, who PolyBio are collaborating with. We really need that new blood. Some of the old blood have stagnated, without mentioning names, and haven’t delivered on the promise. It’s going to be these young, energetic and funded entities that will get us the answers. Most certainly not the bureaucrats in their massive, slow moving bureaucracies.
🙂 Unfortunately, its science and lots of studies that will prove out in the end. I agree it’s a long road….
In the Gist, 3rd and 5th bullet points include the name White. Should that be Light?
🙂 Yes! Thanks
Stress, in medical terms, is talking about physical demands on the body, not emotional issues, although mental health can have some effect on how we “feel” or experience and interpret our physical symptoms. The best one could hope for in cognitive therapy is learning to cope with the losses caused by ME/CFS, such as anxiety or depression.
I am emotionally healthy and have no history of mental health problems. My symptoms have gradually worsened over time even though I no longer have to push my energy envelope and my life has become a fairly comfortable routine. The PEM is obvious when I push too much, but that’s temporary worsening, not the day to day symptoms that have me far less active than I used to be when life was harder physically and mentally. Is there a mind/body connection? Of course, but it’s not the kind that we can change with magical thinking. I look forward to more mitochondria discoveries.
I was originally diagnosed with adult-onset mitochondrial disease, because I am heterozygous for a few mitochondrial defects. It didn’t explain the severity of the onset though. I had PEM but didn’t understand what it was until 10 years later when I learned of ME/CFS. Because I didn’t know better, I exercised myself into full disability in 6 months, and couldn’t understand how I could catch “the flu” over and over again. My only symptoms from the mitochondrial defects before ME/CFS were mild. I would go hypoglycemic if I ate a large amount of protein at once, and I ran 2miles every other day, but couldn’t run a 5k without bonking. So I carried a candy bar and didn’t run 5ks. Otherwise had a very active life. I think Epstein Barr virus probably triggered me. So I’m believing ME/CFS is an acquired mitochondrial disease. Am interested in treatments, though standard mitochondrial disease treatments have only helped a little.
Chris, can you tell us what the “standard mitochondrial disease treatments” are, specifically? That would be very interestiing to me and I suspect others, as well.
There is a table in this article. https://pmc.ncbi.nlm.nih.gov/articles/PMC4067597/ The two that work best for me, especially reducing muscle pain and cramping, are riboflavin and acetyl-l-carnitine. Acetyl-l-carnitine crosses the blood brain barrier to help with brain symptoms and doesn’t make you smell fishy like the l-carnitine version. I didn’t notice much difference with brain fog. Low dose Abilify helped me a lot with brain fog. Cort said his next article on this topic will include treatments. If you have a genetic defect, you might have to be on a specialized diet, like low fat for a fatty acid oxidation disorder, or low protein or low carb for other specific gene defects.
Hi Ann,
A good deal of what I address in my posts is based on “standard mitochondrial disease treatments’ but in the context of the big picture and my own experience as a scientist recovering from Long COVID.
About half way through the following post is a link to a peer-reviewed paper on “Feeding Mitochondria”. There is a diagram in my post from this open-access paper that shows (for example) the various vitamins and other molecules used by mitochondria to make ATP.
https://longcovidjourney2wellness.substack.com/p/tackling-mitochondrial-dysfunction
My posts are freely available.
Kind regards,
Mardi Crane-Godreau, PhD
Cort you have written a very detailed, complex and overlapping story here. This took a lot of time and effort on your part. This is a superb summary of the research on this topic. I commend you.
You are such a good writer, concise, clear, and understandable. I believe you have gotten better at this over the years, too. When I look at your earlier blogs, they are good but not as good as the recent ones.
This is hard to do and you are an excellent example to all who attempt this kind of summary. Journalists who write for national health publications could learn a lot from you.
You could have a full career somewhere else, but I’m glad you are right here. Cheers.
Hi Cort,
Nice job on this important and complex topic!
It seems likely to me that viral-infection-induced mitochondrial DNA (mtDNA) damage is central to ME/CFS as well as Long COVID.
Educating patients about the nature of mitochondrial biogenesis (repair and replacement) and mtDNA damage are first steps. Understanding the relevance of dietary choices and which supplements are vital to mitochondrial function is the next step.
Recovery from Long COVID seems linked to mtDNA biogenesis happening at a more rapid rate than ongoing damage and degradation.
Taking care of our mitochondria is a primary focus of my Substack posts, Insights on a journey back to wellness. Posts are freely available.
https://longcovidjourney2wellness.substack.com/p/long-covid-tlc-for-mitochondria
Thank you again for a really nice job.
Kind regards,
Mardi Crane-Godreau, PhD
So how could the DNA mutations be fixed if it’s even possible? I don’t get it. How can a stressor change your DNA, if that is possible then it should be possible to change it to a correct state, right?
Please, somebody explain it to me, I am not well versed on biological and medical science.
My disease started after the HPV vaccine on January of this year. Little did I know that MECFS, POTS and Small Fiber Neuropathy were linked to it and that there was already documented.
After spending the last 10 months researching this illness and after reading this post, it made sense to me.
It seems that the vaccine is too strong. So much that the stress induced by it damages the body and the mitochondria which causes all of the problems as pointed on this article.
Small fiber neuropathy being triggered by brain stress blows my mind but it make perfect sense after reading the experiment in the paper.
I just hope there is a way to reverse this. I don’t get how this disease has existed since ever but it’s so unknown and under researched. I also don’t get how drugs well known to be harmful are legal and kept in the market, this should be an incentive to understand this disease as people are always at risk of developing them. It should be unacceptable.
Angel…
It’s called the biggest cover up known to man
The truth is coming out
I think this is why “they” keep changing the name(s)
They called this Yuppie flu in the 70s and the list of names goes on from there
Gulf war illness….the soldiers all got vaccines prior to battle…lots of vaccines
I’ve been vaccine injured my entire life and I’ve been lied to my entire life by the medical mafia
I am sorry it also happened to you. I am also sure there is a cover up, vaccines are a bussines after all.
I just want to get out of this nightmare, I don’t want to live like this forever. There should be something that can be done.