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The GIST

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Effort what?

Ah, the famous (infamous?) NIH Intramural ME/CFS study. Interrupted by the pandemic and dramatically downsized, the “Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome” study was still one of the most expensive, and certainly the most comprehensive ME/CFS study ever done.

THE GIST

  • Interrupted by the pandemic and dramatically downsized, the NIH Intramural study was still one of the most expensive, and certainly the most comprehensive ME/CFS study ever done. Nancy Klimas said the study was, “As thorough an evaluation as has ever been delivered in any clinical study that I know of in any disease”. Avindra Nath, the leader of the effort which ended up involving over 75 researchers, said it was easily the most complex project he’d ever led.
  • Its findings were gobbled up by the media, and in the media the reports were, in fact, overwhelmingly positive, but many in the ME/CFS community greeted the findings with alarm. Something called “effort preference”.
  • Walter Koroshetz, the Director of the National Institute of Neurological Disorders and Stroke (NINDS), spent much of his introductory talk not on explaining what the study was about but on effort preference. He explained we tend to think of effort as something we consciously assess, but when neurologists use this term, they’re referring to microsecond-by-microsecond decisions by the brain which are below our consciousness.
  • When our muscles just can’t go any further, many times it’s not that they’ve run out of energy but that in a process called “central fatigue”, the brain has told them to stop. The study findings suggest that something has gone wrong with the pathways in the brain that tell the muscles to move.
  • Avindra Nath spoke of his deep commitment to solving this disease, and citing all the controversy, asked for a bit more trust. In my experience, Nath has been open and available and has supported this disease in many ways. We lucked out when we got Nath. 
  • Nick Madian emphasized that effort, as applied to their work, is not under conscious control. The brain evaluates whether to move forward based on the amount of energy spent and the “reward” it sees is available. If the cost-to-benefit ratio of an action is low, the brain will send messages in the form of fatigue, difficulty moving etc., to make sure the activity is not carried out.
  • Most interestingly, this process is carried out in the brainstem, which is the locus of so many other things – from sensory to autonomic nervous system problems – that are at play in ME/CFS. The brainstem regulates movement, in part, by the generation of norepinephrine – which we will see is low in the cerebral spinal fluid (CSF) in ME/CFS. Norepinephrine activates pathways in the “evaluation network”; if the evaluation network says no, it will be very difficult to move. Again, these pathways are not under conscious control.
  • Parkinson’s Disease, stroke, dementia, and brain damage can all affect the evaluation network in similar ways as ME/CFS, and Madian noted that dopamine-enhancing drugs help Parkinson’s patients to “engage with physical tasks more readily”.
  • Since it’s the motor cortex that tells the muscles to move it, the motor cortex was checked out, but both it and the pathways in the brain that engage it were found to behave normally. Activity in the temporal parietal junction pathway, though, which assists in “motor control” and “motor control signaling” was reduced.
  • In the end, reduced levels of norepinephrine, dopamine and serotonin in the cerebral spinal fluid were believed to contribute to the loss of “motor control” and the inability of ME/CFS patients to exert themselves. Norepinephrine, in particular, was signaled out because of the crucial role it plays in movement and in maintaining brain energy levels. In the end, the problems are believed to start in the brainstem and the hypothalamus – two areas that are already of high interest in ME/CFS.
  • In the immune system, multiple check points that are required to activate T and B cells were found, as was T-cell exhaustion. The inability of these later or adaptive immune cells to track down and kill pathogens or pathogen infected cells could be causing the activation of the more primitive, less effective and highly inflammatory innate immune system that is seen in ME/CFS. Dr. Nath suggested drugs that could help.
  • The gut flora of the ME/CFS patients was less diverse and lower levels of butyrate producing bacteria were found. Both of these have been seen before in ME/CFS and work is ongoing to further explore these findings. Interestingly, low butyrate levels were also found in ME/CFS patients’ cerebrospinal fluid.
  • The molecular biology or “omics” studies demonstrated how important it is, in this very important arena of research, to separate males from females. Every time this was done, dramatic differences were found between the healthy controls and the ME/CFS patients even when the sample sizes were very small.
  • Once again, this study validated past findings in ME/CFS, including problems with fatty acid oxidation, mitochondrial functioning, lipids and proteins.
  • The exercise physiology study found that people with ME/CFS were unable to generate normal amounts of energy to the extent that “performing activities of daily living would be difficult”. No increased incidence of postural orthostatic tachycardia syndrome (POTS) was found, in part because similar numbers of the healthy controls tested positive for POTS. (You can have POTS and still be healthy.)
  • Post-exertional malaise is being explored in further studies.
  • Ultimately, the authors proposed that an infection leads to immune dysfunction and changes in the gut microflora, leading to impacting the brain, leading to decreased production of catecholamines (norepinephrine, dopamine, serotonin), which disrupts autonomic nervous system functioning and impacts the ability to exercise. A wonky hypothalamus results in decreased activation of the temporoparietal junction when people with ME/CFS try to move. That results in reduced engagement of the motor system, problems with movement and ultimately, exertion.
  • The dataset from the study is available to anyone. I counted at least 8 ongoing studies within the NIH that have resulted from this work.
  • Several severely ill people who participated in the study spoke, including one person who had to be carried on a stretcher, and another who could not sit upright for 15 minutes without severe symptoms. They all lauded Brian Wallit and his team for their attention and care.
  • Despite all the angst and controversy the study findings first aroused, this study was clearly a significant success for the ME/CFS community. Despite its reduced size, it achieved its goal of providing numerous openings for future research, and it suggested that, if done right, ME/CFS is very amenable to study even when small sample sizes are present.
  • Past findings were validated (B and T-cell abnormalities, T-cell exhaustion, brainstem abnormalities, mitochondrial issues, low HRV, low gut butyrate, low gut diversity, lipid abnormalities, reduced energy output, reduced dopamine, gender effects) and promising ones popped up (temporal parietal junction functioning linked with poor motor performance, reduced CSF norepinephrine and butyrate levels).
  • The reduced CSF norepinephrine findings appear to present a particularly enticing finding as the low norepinephrine production in a potentially critical area in ME/CFS – the brainstem – could affect not only the effort/reward/movement issues found but also brain energy levels.
  • Even the researchers seemed startled by the large separations between healthy controls and ME/CFS patients that showed up once gender was taken into account. These findings suggest that simply separating the genders in future studies (or by reassessing past study results by taking into account gender) could be very helpful indeed.
  • Several panelists at the symposium, including Dr. Nath, declared that it was time for clinical trials to take place.

Nancy Klimas said the intramural study was, “As thorough an evaluation as has ever been delivered in any clinical study that I know of in any disease”. Avindra Nath, the leader of the effort which ended up involving over 75 researchers, said it was easily the most complex project he’d ever led.

Its findings were gobbled up by the media, and in the media the reports were, in fact, overwhelmingly positive, but many in the ME/CFS community greeted the findings with alarm. Something called “effort preference” reared its head, and how was it possible that there was no evidence of increased postural orthostatic tachycardia (POTS). How could that be? This, some concluded, was nothing more than an attempt to push ME/CFS back into a psychological corner. Avindra Nath was all over the media stating that the effort preference finding was not a psychological one, but the damage was done.

We weren’t done with the study yet. The Symposium that followed the study gave the investigators a chance to tell the study’s story in their own words – and they told a different story, indeed.

Walter Koroshetz

NINDS Director Walter Koroshetz spent much of his introductory talk explaining that effort preference did not refer to a conscious process.

The Symposium on the Intramural Study

It’s not clear when the Symposium of the NIH’s Intramural Study was planned, but I wouldn’t have been surprised if it didn’t start within days of the study’s publication. The NIH – to its credit – didn’t simply shut up and go away: it took the time and trouble to produce a symposium to clarify the study’s findings.

The study presented many intriguing findings, most of which were in line with what we know about chronic fatigue syndrome (ME/CFS), but the finding of “effort preference” and the way it was (or rather wasn’t) explained overshadowed all. There may be no better example than the “effort preference” finding of how badly the meaning of a scientific term (sickness behavior is another one) can clash with a layman’s understanding of it.

How big of a problem was the effort preference issue? Walter Koroshetz, the Director of the National Institute of Neurological Disorders and Stroke (NINDS), spent much of his introductory talk not on explaining what the study was about but on effort preference. If you were upset about the finding – and most of us were – your voice was heard.

Director Koroshetz reported that the word “effort” has connotations in the press that don’t apply to neurology. We think of effort as something we consciously assess, but when neurologists use this term, they’re referring to microsecond-by-microsecond decisions by the brain which are below our consciousness. The whole thing is happening too fast for us to be aware of any of it.

Every time we move, that brain computes – based on a number of factors including the potential reward gained and the effort required to get that reward – how it will deal with the muscles. You would think that if, say, during a handgrip test, you got to the point where you couldn’t go any further, that would indicate that your muscles had pooped out. If you electronically stimulate the nerve at the muscle, though, the muscle will start to contract again. This indicates that a significant part of the fatigue we experience is “central fatigue”; i.e. something in the brain is stopping the muscle from exercising (contracting).

It’s a computational problem that involves reward and effort than anything. We’ll be getting into how terribly important and intertwined the reward system is and how it appears to be impacted in ME/CFS and similar diseases in another blog, but suffice it to say that the whole idea of “reward” is determined by microsecond-by-microsecond calculations in the brain, below our level of consciousness.

The findings suggest something has gone wrong in the circuits of the brain that have to do with reward, effort and movement (and there’s quite a bit of evidence to suggest that).

Avindra Nath

Avindra Nath spoke of his deep commitment to solving this disease and asked for a bit more trust.

For his part, the leader of the project, Dr. Nath, bared his soul a bit in his introduction, stating that:

“we’re deeply committed and have a strong conviction to treating this illness and finding cures for this disease…(that) we’re your partners and have the same shared goals”. However, “when you doubt our intentions and pick apart every single word, you also tear us apart. It causes pain and suffering on both sides and demoralizes us and shatters our goals.”

This is the second time that Nath has alluded to the demoralizing effect that attacks can have on researchers. (The first had to do with efforts to remove Brian Walitt, even though Walitt was administering the study – not doing the research.) Researchers may be analytical in the extreme, they may love to play with numbers and concepts – but they are still humans.

Certainly Nath has earned our respect and trust. Nath, who is involved in many different efforts besides ME/CFS, has been as open and available as anyone I can remember. He has gone above and beyond by repeatedly advocating for more ME/CFS research and has made every effort to link ME/CFS with long COVID in the press. We could have gotten a wallflower who disappeared into his office. Instead, we got a good communicator and supporter. We lucked out when we got Nath.

Still, on the ME/CFS side, the words “effort preference” were bound to raise hackles – there was just no way that was not going to happen in a patient population that has been fighting against being psychologized for decades. It’s unfortunate that the NIH couldn’t somehow find a way to get the word out ahead of the paper.

The Effort and Central Nervous System Findings

A recently retired Dr. Hallet led the discussion of the central nervous system results. Hallet was a senior, highly respected researcher and just happened to be an expert in one of the main findings of the study – problems with “motor control”, as well as movement disorders. Three of the other presenters – Dr. David Goldstein, Dr. Horowitz, and Dr. Snow – were described as “senior researchers”.

Effort!

Nick Madian covered the touchy effort topic. Echoing Koroshetz, Madian emphasized that effort, as applied to their work, is not under conscious control. Yes, during exertion we can gin up our effort, but in the final rung, it’s ultimately the brain that decides how far an effort will go. The brain makes that decision based on the amount of energy spent and the “reward” it sees is available. If the cost-to-benefit ratio of an action is low, the brain will send messages in the form of fatigue, difficulty moving etc. to make sure the activity is not carried out.

Locus coeruleus

Low levels of norepinephrine in the cerebral spinal fluid may turn out to be important. Norepinephrine is produced in the locus coeruleus in the brainstem. (Image – Diego69 WIkimedia Commons)

The brainstem (once again, the brainstem) regulates movement, in part, by the generation of norepinephrine – which we will see is low in the cerebral spinal fluid (CSF) in ME/CFS. Norepinephrine then activates pathways that are involved in evaluating the cost/benefit analysis: i.e. is movement or activity called for or not? If the evaluation network says no, it will be very difficult to move. These pathways, again, do not appear to be under conscious control. Parkinson’s Disease, stroke, dementia, and brain damage can all affect the evaluation network.

Madian used a test that’s used to study effort in neurological diseases and found differences in something called “effort discounting” in ME/CFS. Effort discounting refers to the process by which rewards seem less rewarding the more effort we put into them. While the people with ME/CFS put as much effort into the tasks as the healthy controls, the rewards dimmed more quickly for them.

The most significant thing about that finding was that the increased effort discounting was strongly positively correlated with the low cerebral spinal fluid norepinephrine levels found. The lower the norepinephrine levels the more strongly the rewards dimmed for the ME/CFS patients – and the more effortful the task became. (Note that norepinephrine levels in the body; i.e. the plasma were normal.)

Madian took us even further from a psychological interpretation of the effort preference finding when he reported that the same pattern is found in Parkinson’s Disease. He noted that dopamine-enhancing drugs help Parkinson’s patients to “engage with physical tasks more readily” and reiterated that none of this is taking placed at the conscious levels. He proposed that the disrupted effort discounting may be related to post-exertional malaise.

Motor Cortex

motor-cortex

The motor cortex directs the muscles to move. It is not the problem in ME/CFS, though. Something in the pathways leading to the motor cortex is.

Dr. Bedard explained that the motor cortex in the brain sends messages to the muscles to move.  At some point, the muscles will get tired or fatigued. He used magnetic stimulation of the motor cortex to determine whether the fatigue was coming from the brain or the muscles during a hand exercise test. If the fatigue was coming from the brain, the response to the stimulation should die over time. If it was coming from the muscles, the muscles should show an increase in low-frequency electrical activity.

Both groups – ME/CFS and healthy controls – showed a similar maximum generation of force, but the ability of the people with ME/CFS to maintain that force declined over time. The declining excitability of the motor cortex in the healthy controls, combined with few changes in the electrical signals in the muscles, indicated that the central fatigue was driving the fatigue in their muscles.

The increased excitability of the motor cortex over time in the ME/CFS patients – but no changes in electrical signals coming from their muscles – presented a very different situation. The hyped-up motor cortex should have been driving more signals to the muscles, and their muscles still appeared able to generate force, but the people with ME/CFS’s ability to maintain that force dropped dramatically.

Silvina Horowitz took it from there. Seeing the increased motor excitability – but no signs that it was helping people with ME/CFS exercise their muscles – she used a functional MRI (fMRI) to check out what was going on in the pathways of the brain. The pathways in the brain that engage the motor cortex were normal – it was being normally engaged – but the temporal parietal junction pathway, which assists in “motor control” and “motor control signaling”, was reduced.

Later, we heard that more work was being done to combine the different brain modeling data points to understand what’s going on. More “connectivity analyses” to understand what’s going with the norepinephrine production involved are being done as well.

Dave Goldstein, the Director of the Autonomic Section, was up next. He did not find evidence of increased postural orthostatic tachycardia (POTS) in ME/CFS – in part because he found fairly high levels of it in the healthy controls. (It’s possible to have POTS and be completely healthy.) The neurotransmitter tests were, however, quite revealing. As noted earlier, norepinephrine levels (measured using DHGP) were “quite decreased” in the cerebral spinal fluid of the ME/CFS group.

Dopamin-norepinephrine-serotonin

Norepinephrine, dopamine and serotonin levels were all altered. Hallet suggested that low norepinephrine levels could be reducing brain energy levels. (Image Nippapag Wikimedia Commons)

In his summary of the session, Dr. Hallet reiterated that the central fatigue problem in ME/CFS was not coming from the motor cortex but from other “drivers”. He pointed a finger at the reduced levels of dopamine and norepinephrine, and also noted altered serotonin levels found in the cerebral spinal fluid.

Dr. Hallet then suggested that the altered CSF catecholamine levels may be affecting brain metabolism and energy production. Noting that neurons need lactate and that norepinephrine helps transport lactate to the neurons, he proposed that the low norepinephrine levels found in ME/CFS could be reducing energy production in the brain, causing problems with cognition and autonomic nervous system functioning (!). The norepinephrine/energy connection was entirely new to me.

(Interestingly, in the end, it comes down to poor mitochondrial functioning – not because the mitochondria are broken – but because they’re not getting the energy substrates (lactate) that they need to function properly. The problems with fatty acid oxidation, and the switch to using amino acids to power the mitochondria in the body, suggest that a similar process – an inability to properly feed the mitochondria – may be going on in the body.)

Hallet then proposed that it all starts in the brainstem and hypothalamus. What caused those two brain organs to fail in this manner was not clear, however.

Immune System Exhaustion

Multiple set point defects on B-cells resulted in problems with switching from IgM (the early responder) to IgG antibody (the later responder) production – a problem that can result in T-cell exhaustion – which was found. (Checkpoints of T-cell activation were disrupted as well). This isn’t the first-time immune system exhaustion has been found, and with Nath’s proposal that immune clinical trials get started, it may be that enough evidence has been found.

Exhaustion

Immune cell exhaustion was found again. Is it time for clinical trials?

With the adaptive immune system (T and B-cells) reeling, the early or innate immune system jumps in. The innate immune system, though, is designed to hold the fort for the adaptive immune system – not to get rid of pathogens. It’s highly inflammatory and non-specific; i.e. it can’t really hone in on specific pathogens or pathogen-infected cells and is destructive when over-used. An overactive innate immune system could be causing a lot of mischief in ME/CFS.

The low levels of the less abundant gut bacteria that were found in ME/CFS (reduced microbiome diversity), and the low gut butyrate levels, aligned with the results of past ME/CFS studies. The person presenting noted this is just the beginning of the gut analyses that are underway. Three more papers are underway which will link the gut findings to other findings from the study. Importantly, they will attempt to determine if the gut is influencing other parts of the body or vice versa.

The Omics Studies

Gender

Again and again, we saw huge separation in the omics studies when men and women were assessed separately.

It was in the molecular biology, or OMICS, studies that the importance of separating males from female really stood out. In some ways, this was the most impressive part of the study because even though the study numbers were generally quite low, once the researchers separated the male from the female patients, the contrasts between the ME/CFS patients and healthy controls were remarkable. This indicates that, despite its vaunted heterogeneity, ME/CFS is actually VERY amenable to study once it is studied correctly.

The presenter referred to the “enormous separation” found in an immune analysis which found, rather remarkably, the same cells – B-cells – being altered in ME/CFS but in different ways in men and women.

When it came to the proteomics analysis, the presenter stated, “when we separate by men and women, wow, that’s a lot of separation!”. The same exclamation came with the muscle analysis, “When we separate by the men and women, wow, that’s a lot of separation!”, and, “We see again wonderful separation in men and women”.

Even in very small studies, we see evidence of a large difference between the genders.

“Separation” is what researchers live for. A lot of separation in the results between people with a disease and controls suggests they’re really onto something. Many times, we see results with a lot of overlap, but not this time. The OMICs research group was surely jazzed by what they found.

With regard to metabolomics, they saw downregulation of the beta oxidation network and mitochondrial processing, and in the women, beta oxidation upregulation and down regulation of fatty acid processing in the mitochondria.

The same pattern – a dramatic difference between patients and healthy controls when gender was taken into account – showed up in the metabolomics study of the cerebral spinal fluid. (All ME/CFS patients also showed alterations in glutamate, polyammine (???), and TCA (aerobic respiration) metabolites, implicating the arginine pathway and branch chain amino acids.) Nath noted that getting more ME/CFS cerebral spinal fluid was critical, and there are many analyses that can be done on it.

The gut got more interesting when we found that butyrate was low in both the gut and in the cerebral spinal fluid (CSF). Because butyrate is only made in the gut, and because it has anti-inflammatory and anti-demyelination properties in the CSF, the low butyrate levels in the gut could be making way for increased inflammation in the central nervous system. Butyrate is now being studied in neuroinflammatory diseases like Parkinson’s and Alzheimer’s.

When asked, the presenter could not say that butyrate supplementation would help. The gist was it’s probably far better to find a way to induce the gut to produce butyrate than in trying to supplement it.

These findings suggest that when get to the molecular level, it indicates that men and women are quite distinct, and makes one wonder how many problems have been hiding in plain sight that could have been uncovered by separating out the men from the women.

The presenter concluded, “everywhere we looked (the gender split appears) to be of profound importance in understanding the nature of ME/CFS”, and pointed to the cerebral spinal fluid metabolomics results which highlighted the central nervous system.

BioEnergetics

Exercise physiology – the exercise study found widely variable results, with some people with ME/CFS performing well and others not performing well. In general, people with ME/CFS were unable to generate normal amounts of energy to the extent that “performing activities of daily living would be difficult”. They did not find problems with low CO2 or oxygen saturation of the muscles but did find a lowered heart rate response (chronotropic incompetence).

The metabolic chamber did not show problems with CO2 or altered energy expenditures while resting or sleeping.

Body fat – Sam Love presented on the DEXA scan, which measures the whole body fat, lean body mass and the amount of visceral fat around the organs. This is potentially important because of the inflammatory nature of the visceral fat found around the organs, which can lead to numerous health problems. People who seem lean can still have high levels of visceral fat. It’s something you really want to avoid and, in this case, the news was good. While there was great variability – which was expected – people with ME/CFS did not differ significantly with regard to whole body fat, lean body mass or visceral fat levels.

Paul Hwang spoke about the WASF3 finding which Health Rising reported on earlier. In a complex study, Hwang found increased WASF3 production, which may be able to disable the mitochondria, and which suggests a treatment strategy.

Autonomic Nervous System

Mark Levin, a cardiologist, found a trend toward reduced sympathetic activity with increased heart rate during the day and a reduction in parasympathetic activity at night in people with ME/CFS.  A decrease in baroslope and longer blood pressure recovery times after the Valsalva maneuver in PI-ME/CFS indicated decreased baroreflex-cardiovagal functioning.

Post Exertional Malaise

One of the critiques of the study was that it didn’t do much to understand post-exertional malaise, but Nath said the team is still working on its measuring of it in “multiple ways”. Indeed, one of the participants in the study reported that cognitive testing, blood tests, the Seahorse mitochondrial test, a functional MRI, and transcranial magnetic stimulation were before and after the maximal exercise test.

Expect much more on PEM to come out.

Big Picture

The grand hypothesis

The grand hypothesis. (Image from the study)

At the end of the paper, the authors proposed that an infection leads to immune dysfunction and changes in the gut microflora, leading to impact the brain, leading to decreased production of catecholamines (norepinephrine, dopamine, serotonin), which disrupts autonomic nervous system functioning and impacts the ability to exercise.  A wonky hypothalamus results in decreased activation of the temporoparietal junction when people with ME/CFS try to move. That results in reduced engagement of the motor system, problems with movement and ultimately, exertion.

Data Sharing

Nath’s team reported that they “bent over backwards” to make sure that the study data is available in a new database developed by NINDS. Because it’s CCBY4.0 available through Creative Commons, anyone can use it. It can be shared, copied, made use of by companies, built upon, etc. They didn’t do much with sleep microarchitecture or circadian rhythms, but that data is all there waiting to be mined. Nancy Klimas has expressed great interest at merging all that data with her present data into the supercomputer. (The more data, the better the computer likes it.)

Ongoing Studies 

The intramural study findings have prompted a bevy of further studies. A Veterans Administration / intramural NIH study on ME/CFS has begun. The team doing the modelling work on immune signaling is using a “drug targets selection process” to look for potential drugs that could return the immune system to normal. The exciting low brain norepinephrine finding is being explored further. Further gut studies that aim to understand the cause of the gut issues are underway. Hwang is following up on his WASF3 finding. Comparisons between the ME/CFS study findings and Nath’s long-COVID study will be made.

The Participants

Many people have proposed that the fact that no increased incidence of postural orthostatic tachycardia syndrome (POTS) was found in the people with ME/CFS meant that the group was healthier and not representative of the ME/CFS patient population, or perhaps didn’t even have ME/CFS. The study requirements – two weeklong stays at the NIH hospital – did indeed seem to call for a healthier study, but reports from the study participants indicated that many severely ill people did participate.

It should be noted that all the patients in the study went through extensive screening which included being assessed by a group of ME/CFS experts, and the ME/CFS experts had to unanimously agree that the participant had ME/CFS. In short, they were easily the most well-defined and heavily scrutinized patients to engage in any ME/CFS study.

Increased heart rates upon standing were commonly found in the ME/CFS group, but they were also found in similar levels in the healthy participant group. This may seem strange, but just as people can be hypermobile and be perfectly healthy, people can meet the biological criteria for POTS (increased heart rates) without being ill. (Increased heart rates, by themselves, are clearly not the core problem in POTS).

Participant Stories

Sanna said it was difficult to process the criticism the study received

Sanna said it was difficult to process the criticism the study received.

The courage and the determination that participants showed to move the science forward for their illness was nothing short of incredible.

In a video, Sanna related that she’d become ill in 2014 and by 2018 was essentially bedbound. She used her wheelchair and cane to get around during the study but was so crashed after one test that she had to be carried on a stretcher, needed a bedpan, and at one point was too weak to raise her hand and was unable to participate in the CPET exercise test or metabolic chamber. Stating that the study was “very tough”, she still said it was absolutely worth it and lauded Brian Walitt, in particular, and the team for care and attention they gave her.

Another person called participating in the study one of the most difficult she had ever had to make, but she was determined to contribute. Despite being an active person who regularly worked 60-80 hours a week, after coming down with ME/CFS, at one point she was unable to walk, shower or speak above a low whisper.

NIH study participants

This participant was unable to be upright for more than 15 minutes without suffering severe symptoms. She praised the staff for their support.

At the time of the study she was unable to be upright for more than 15 minutes without suffering severe symptoms. Referencing Brian Walitt several times she said she’d never experienced “such devoted care” as she did in the study. Everyone, she said, “was so very careful”. It took her 8 months to return to her prior level of functioning but she said “ME/CFS patients need answers” and that she was “grateful to have participated”.

David Remer, a former doctor, enjoyed challenging himself with outdoor activities, wilderness canoeing and running before he came down with a virus. On a functional scale, David dipped to a low of 15 out of 100 in the year after the study.

His healthy sister, Susan, also participated in the study but then came down with long COVID herself after catching the virus (!). She participated in the Nath long-COVID study that’s underway – giving them a great before and after picture. She called the opportunity the study gave her to contribute a “blessing” and thanked Nath, Walitt and the staff for their “compassion and sound guidance”. (By the time this is all done, she’ll have spent about a month in the intramural hospital getting tested!)

Health Rising reported on the experiences of two ME/CFS participants in the study: Robert and Brian Vastag. Another former doctor, Robert reported that on a functional scale of 1-10 he was a 2, and that the occupational therapist on the study registered shock at how few activities he was able to still do. She had apparently never seen that before.

Brian Vastag’s severe ME/CFS problems are well known but he also referred to other patients in the study who were sicker than he was, and who said they “were absolutely annihilated by it” and took months to recover.

Four Weeks at the Clinical Center: Brian Vastag on the Soon-to-be-Published NIH ME/CFS Intramural Study

Panel Impressions

Next, it was over to a panel who gave their impressions of the findings.

Dr. Komaroff – noted that the most intensive study of ME/CFS ever done had confirmed many past abnormalities and uncovered some new ones. It suggested that “ME/CFS is a brain disease” induced by exhaustion which may result from deficiency of norepinephrine in one part of the brain.  The immune exhaustion found, he predicted, will provide targets for potential treatments.

Ian Lipkin intramural symposium

Ian Lipkin emphasized how critical it is to subset patients (gender/duration) and believed it was time for clinical trials.

Ian Lipkin – seemed quite taken by the B-cell immune exhaustion findings and spent some time asking, if an infection is driving them, how to find it. (Previous efforts have failed). He also noted that the turned-on innate immune defense system could be whacking the mitochondria, and asserted that the time has come for clinical trials of drugs to inhibit the innate immune system as well as trials to improve gut butyrate levels.

At the end, though – noting the need for effective advocacy when it comes to the NIH – Lipkin said, “if I learned anything at 40 years of doing this work, we need better advocates”. (I would say we need more advocates (I was the only one in the 5 staff meetings in the recent advocacy week), and we especially need more money for advocacy.)

Vicky Whittemore (NINDS) – highlighted the need to subset patients according to gender and duration and to stop throwing everyone into the same basket, citing the Roadmap report in the need to move as quickly as possible to clinical trials.

Joe Breen (NAIAD) – citing one study participant’s desire that her grandkids wouldn’t have to experience what she has – said, “I hope we don’t have to wait that long”, and noted the suffering that many have and continue to undergo. He highlighted the immune exhaustion and brain imaging findings.

Nancy Klimas

Dr. Klimas said studies like this help get ME/CFS to clinical trials and called for them to start as well.

Dr. Klimas – was not disturbed by the small numbers. She called the study “very special” and talked of how excited she is to get all that data into her computer modelling work to help understand and find treatments for ME/CFS. Her computers, she said, are “never cowed by more data”. Dr. Klimas has been chomping at the bit for clinical trials for years and she said, “Let’s get to clinical trials”, and those clinical trials should be quite long.

She said her group is modeling ME/CFS patients as a whole, breaking them into gender subsets, and modeling each person as well and this “highly granular data” will help them to do that.

Avindra Nath (NINDS) – Then it was back to Dr. Nath to give his final thoughts. It was Avindra Nath who most explicitly laid out the case for clinical trials. You can study the physiology forever, he said, but if you keep waiting for “the answer”, you’ll never get to clinical trials.

Nath said the study identified “multiple targets for intervention” (i.e. multiple possibilities for clinical trials), and asserted that “combination therapies” will be required. He highlighted immune exhaustion and check point inhibitors, B-cell and T-cell activators, and non-specific immune modulators.

These should be done using platform studies, where a number of drugs are tested against one placebo-controlled group. Crossover studies where patients are put on one drug, then another, then placebo, etc. can help as well.

He said there’s light at the end of the tunnel and that if we all work together, we’ll find cures for this disease.

Conclusion 

Puzzle

The study – which involved 75 researchers – validated past pieces of the puzzle and added new ones. It was a success.

Despite all the angst and controversy the study findings first aroused, this study was clearly a significant success for the ME/CFS community. Despite its reduced size, it achieved its goal of providing numerous openings for future research, and the small size may have produced a silver lining: it suggested that when done correctly, ME/CFS is very amenable to study even when small sample sizes are present.

Past findings were validated (B and T-cell abnormalities, T-cell exhaustion, brainstem abnormalities, mitochondrial issues, low HRV, low gut butyrate, low gut diversity, lipid abnormalities, reduced energy output, reduced dopamine, gender effects) and promising ones popped up (temporal parietal junction functioning linked with poor motor performance, reduced CSF norepinephrine and butyrate levels). The reduced CSF norepinephrine findings appear to present a particularly enticing finding as the low norepinephrine production in a potentially critical area in ME/CFS – the brainstem – could affect not only the effort/reward/movement issues found but also brain energy levels.

The effects that assessing gender on the results of the molecular biology or “omics” were nothing short of remarkable. Increasing study size is often a key to achieving statistical significance, but in this case, decreasing the sample size by dividing the study by gender dramatically improved the omics studies results. Even the researchers seemed startled by the large separations between healthy controls and ME/CFS patients that showed up once gender was taken into account. These findings suggest that simply separating the genders in future studies (or by reassessing past study results by taking into account gender) could be very helpful indeed.

The study has already spawned at least 8 follow-on efforts, and Nath – a senior NIH official – has proposed that a variety of clinical trials take place.

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