“One takeaway is It’s a disease that comes from the brain” Nancy Klimas

Avindra Nath

Avindra Nath called the project the most complex he’s ever led.

It was one of the most expensive ME/CFS studies ever done. The brainchild of former NIH Director Francis Collins, the unusual study was designed to give the NIH solid footing to move forward in a controversial disease.

The study was not designed to determine the cause of ME/CFS. Instead, the $8 million study, with its achingly rigorous patient selection process, was designed to look at a very wide array of factors and come up with solid avenues for future research.

That prospect seemed in doubt when the NIH shut down the study during the pandemic and never reopened it, leaving it about 50% shy of its initial target of 80 participants.

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.  Nancy Klimas said  it was “As thorough an evaluation as has ever been delivered in any clinical study that I know of in any disease”

The stakes were high. A null study finding might very well have tanked interest in the disease at the NIH. On the other hand, a positive study finding would boost ME/CFS’s lowly position at the biggest medical research funder on the planet – the NIH.

Prestigious Journal

The small study size led to concerns – that ended up being overblown – about the ability of the paper to get published in a prestigious journal. The “Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome” study was published in Nature Communications – a multidisciplinary journal with a high impact factor that emanates from the prestigious Nature Publications group. One review reported that the “journal’s rigorous peer-review process and high editorial standards have contributed to its strong reputation among scientists”.

The publication of the study in this journal means it will go out to a “vast audience of researchers, scientists, and scholars from various disciplines across the globe”. In other words, everybody is going to read it.

Indeed, media outlets from the New York Times, “Study of Patients With a Chronic Fatigue Condition May Offer Clues to Long Covid“, to Science, “Sweeping chronic fatigue study brings clues but not clarity to mysterious syndrome“, to Stat News, “NIH study of ME/CFS points to immune dysfunction and brain abnormalities at core of long-dismissed disease“, to Medical Express, “Study offers new clues into the causes of post-infectious chronic fatigue syndrome“, to the Scientific American, “People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome May Have an “Exhausted” Immune System, to the Guardian, “Scientists find link between brain imbalance and chronic fatigue syndrome“, covered it.

The Group

different group

With almost a quarter of the group recovering, and no evidence of increased rates of orthostatic intolerance, small fiber neuropathy, sleep problems, or cognitive impairment the ME/CFS group seemed a bit different.

One thing to keep in mind is that this was a select, and in some ways odd – in ways the researchers could not have known – group of patients. The patients had to have come down with the disease after being triggered by an infection within the last five years.

In its search for rigor, the study excluded 190 of the 217 patients who underwent a detailed case review by a group of ME/CFS experts. Four people who went through the first weeklong hospital stay were excluded because they were found to have something else (cancer, atypical myositis, primary biliary cholangitis, Parkinsonism).

The patients had to be well enough to make it to the Baltimore facility and tolerate 2 week-plus studies which included at least one exhausting exercise session; i.e. they were better off than most. Several common findings in ME/CFS that have been well validated (small fiber neuropathy, orthostatic intolerance/POTS, sleep problems, cognitive impairment) were not increased in the ME/CFS group.

The strangest outcome, though, was that almost a quarter of the group (4/17) ME/CFS patients “spontaneously recovered” after the study – indicating that a substantial subset of patients may have, in some crucial way, been different from you or me.

Not Psychological – Check!

The authors stated that the participants underwent substantial neuropsychological testing which indicated “that their symptoms were reliable and a true representation of their disease”, and concluded that “psychiatric disorders were not a major feature in this cohort and did not account for the severity of their symptoms.”

Autonomic Nervous System Dysfunction – Check!

Increased sympathetic nervous system/ reduced parasympathetic nervous system activity during the day (HRV) and at night (night-time heart rate) driven, the authors thought, by central nervous system problems.

Effort Preference (Effort Preference?)

A test I’ve never seen used before in ME/CFS, the “Effort-Expenditure for Rewards Task (EEfRT)” took a rather prominent place in the paper. This test consists of a series of repeated trials in which the participants choose between performing a “hard task” or an “easy task” in order to earn varying amounts of monetary reward.

A low EEfRT means that a person tends to choose the easy task over the hard task more often, regardless of the reward or probability. This could indicate a lack of motivation, a high sensitivity to effort, or a low sensitivity to reward.

Since ME/CFS is, by definition, effortful, one would expect people with ME/CFS to have low EEfRT scores, and indeed they did. Their decline in button pressing speed over time suggested to the authors that the PI-ME/CFS participants were pacing themselves to limit exertion and associated feelings of discomfort”; i.e., they were exertion challenged.  One wonders if the patients could have simply been tapped (no pun intended) out. A fibromyalgia finger-tapping study found that FM patients faded quickly as well.

Resting State – Fine

No differences in “ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, basal mitochondrial function of immune cells, muscle fiber composition, or body composition” suggested that a low resting energy state was not present.

Note, though, the emphasis on the “resting state”. The condition of the ‘resting state” has never been the key concern in ME/CFS. The major issue is exertion and post-exertional malaise and that’s why physical or mental exertion stressors have been so helpful in unlocking what we know about ME/CFS.

The Hand Grip Test

Who would have thought that a simple hand grip test would have resulted in the major finding in this study?

While a low resting energy state did not appear to be responsible for ME/CFS, the authors reported that “substantial differences were noted in PI-ME/CFS participants during physical tasks“. This is almost the very definition of ME/CFS – a disease that displays more physiological abnormalities during times of exertion than during rest. That’s why so many researchers use physical/cognitive stressors in their studies.

That physical task was as simple as a maximum grip test.  These tests are designed to estimate the muscle strength generated by the muscles of the hand and forearm. The people with ME/CFS were able to generate normal grip strengths.

Hand grip test results

See how the responses diverge in the Dimitrov index of fatigue resistance in [b], in the TMS test in [c], and the bold brain scan in [e], as the ME/CFS patients failed to maintain a strong hand grip over time. ME/CFS patients – red line.

The authors used the Dimitrov index to assess “fatigue resistance”; e.g. the ability of the participant to maintain a strong grip strength. It does this by assessing the number of non-fatigued “blocks” present during the test. A non-fatigued block occurs when the grip strength is above 50% of the maximum grip strength. A fatigued block occurs when the grip strength remains below 50% of the maximum grip strength.

This simple test seems like a nice way to assess the presence of post-exertional malaise. If the grip strength remains normal, the participant can maintain the exertion. If not, they cannot. Note that this all appears to be taking place during anaerobic energy production. No, or little, aerobic energy production is required and its not clear how any conclusions drawn during a hand grip test could apply to aerobic exercise test results.

While the ME/CFS patients’ grip strength at the outset was normal, their grip strength rapidly declined. The fact that they exhibited a significantly lower number of “non-fatigued blocks” indicated that they lacked endurance, and suggested they had reduced “fatigue resistance”. That didn’t happen in the healthy controls.

This pattern – a normal maximum grip strength but an inability to maintain it for long, suggested to the authors that the reduced “fatigue resistance” was not due to problems with the muscles themselves but was caused by the brain.

Hand grip strength has been found to be reduced several times, however, in past ME/CFS studies. In fact, hand grip strength was so reduced in one study that the researchers proposed that it be diagnostic for ME/CFS.

Bad Motor? The Mortor Cortex Takes Center Stage

A transcranial magnetic resonance stimulation (TMS) done during the handgrip exercise suggested that problems with the motor cortex were to blame. The motor cortex is responsible for activating the muscles during exertion.

motor cortex

Not only does the motor cortex tell the muscles to activate during exertion, but a fibromyalgia study suggested it may also play a role in pain.

When we engage in any physical task, the primary motor cortex in our brain activates the motor neurons in our spinal cord, which then sends a signal to the neuromuscular junction of the muscle telling the muscle to move. As a muscle fiber becomes fatigued, more muscle fibers are recruited. So long as new, fresh muscle fibers remain to be recruited, the exercise can continue.  If no muscle fibers are left to be recruited, or if the brain has a problem recruiting new muscle fibers, fatigue sets in.

In TMS magnetic fields are used to assess the effectiveness and integrity of the connection between the motor cortex and the muscles. (They do this by assessing the amplitude of the motor evoked potentials (MEPs). In healthy people, and in people with depression, the amplitudes fall over time during exertion, but in the ME/CFS patients, the motor cortex remained activated, resulting in, in the author’s words, “reduced motor engagement”. It was as if the motor cortex kept pushing the ‘on’ button in an attempt to get the muscles engaged. In the ME/CFS patients’ case, the overactive motor cortex exhibited what is called increased “corticospinal excitability”.

This was an interesting finding because one might have expected the opposite. Increased corticospinal excitability is more often associated with increased endurance. People who expect to experience high amounts of pain, and people with a fatiguing and painful case of multiple sclerosis, exhibit reduced corticospinal excitability.

These researchers found increased corticospinal excitability, however. Increased corticospinal excitability has been found in diseases like migraine – a common comorbidity in ME/CFS – and epilepsy. A recent study found that hyperventilation – an common problem in ME/CFS – can be associated with increased corticospinal excitability as well.

The authors proposed that:

“the fatigue of the ME/CFS participants is due to dysfunction of integrative brain regions that drive the motor cortex, the cause of which needs to be further explored. This is an observation not previously described in this population.”

Past Motor Cortex Findings

While most studies have not assessed the drivers of motor cortex dysfunction in ME/CFS, the motor cortex has shown up in ME/CFS and fibromyalgia before.

A 1999 study, which found a reduction in “premovement” brain activity and slower reaction times, concluded that the “central motor mechanisms” that lay the groundwork for an accompanying movement were impaired in ME/CFS.  A 1999 study came to the remarkable conclusion that “an exercise-related diminution in central motor drive” was present; i.e. the brain was having trouble driving the muscles in ME/CFS.  A 2001 study found it was harder to get the brain to cause the muscles of people with ME/CFS to react. Another study (2003) suggested that problems in “motor planning” are present.

A 2003 study, “Deficit in motor performance correlates with changed corticospinal excitability in patients with chronic fatigue syndrome“, suggested that reduced muscle recruitment due to reduced motor cortex output might be the cause of the fatigue in ME/CFS. That study suggested that “… changing motor deficits in CFS have a neurophysiological basis [which] … supports the notion of a deficit in motor preparatory areas of the brain“.

In a fibromyalgia study, the motor cortex activity (oxyhemoglobin content) was similar between the people with FM and the healthy controls at rest, and during slow tapping, but when asked to tap rapidly, the activity in the motor cortex of the FM patients faded (and so did their tapping ability). It didn’t seem to have the metabolic wherewithal to keep up with the healthy controls.

The motor cortex issue, then, makes sense with what we’ve seen before. In a way it’s a perfect explanation for ME/CFS.

The Weird Temporoparietal Junction 

(This is a long and difficult section where I struggled, sentence by sentence, to understand what the authors meant. You might want to skip to the GIST :))

Temporoparietal junction diagram

The temporal parietal junction showed up for the first time in ME/CFS in this study.

Seeking to get at what was happening during the hand grip test, the authors then assessed blood oxygen levels in the brain. In contrast to the healthy controls (whose blood oxygen levels increased), the blood oxygen levels decreased in the ME/CFS patients in three parts of their brain – the temporoparietal junction (TPJ), the superior parietal lobule, and the right temporal gyrus.

The TPJ – the part of the brain they focused on –  has never shown up in ME/CFS before – but then again, no one has ever imaged the brain while doing a handgrip exertion – and here’s where it starts to get a little weird.

The TPJ is a rather bizarre organ the authors had to try to make sense of. It has been associated with things like disembodiment, self-conscious emotions, others’ beliefs, and socially guided decisions. It is also, though, an organ that “makes predictions on states of the environment with actual outcomes”.

That little effort preference finding – which made total sense – why expend effort when the cost is high? – got looped into the temporal parietal junction finding – and one had the sense the authors either had a difficult time making sense of it or had a difficult time explaining it.

The effort preference finding showed up early and prominently in the discussion section. The first sentence states: “Effort preference is how much effort a person subjectively wants to exert.” While the paper has been focused on the brain, now the authors are referring to how much a person subjectively wants to exert, as in, what you, a thinking human being, decide you can do. We just seemingly moved out of the brain and into psychology. It goes on:

“It is often seen as a trade-off between the energy needed to do a task versus the reward for having tried to do it successfully. If there is developing fatigue, the effort will have to increase, and the effort:benefit ratio will increase, perhaps to the point where a person will prefer to lose a reward than to exert effort. Thus, as fatigue develops, failure can occur because of depletion of capacity or an unfavorable preference.

So is it a depletion of capacity? The answer is no – the authors believe the muscles have the capacity to do the work. Why do they think that? Because the muscles were able to produce a suitable maximal grip strength, muscle mass was normal, and they found no evidence of changes in muscle twitch fibers. Plus, they found no evidence of problems in “ventilatory function, muscle oxygenation, mechanical efficiency, resting energy expenditure, the basal mitochondrial function of immune cells, muscle fiber composition, or body composition”. Note, though, that quite a few other studies, including a recent one, have found evidence of muscle dysfunction in ME/CFS and two major muscle biopsy studies are underway at the Open Medicine Foundation.

Exercise Causes Muscle Damage and Energy Depletion in Long COVID

The Muscle ME/CFS Connection – Could it Tell the Tale?

So, the problem has to be – according to the authors – “an unfavorable preference” – which the authors linked to a recent hypothesis regarding the activity of the temporal parietal junction. Besides all the other bizarre things the TPJ has been associated with – which have nothing to do with ME/CFS – it is also an organ that “makes predictions on states of the environment with actual outcomes”.

The “actual outcomes” when it comes to exertion are, of course, really problematic when it comes to ME/CFS. Since ME/CFS patients themselves don’t know how to assess the effects of their exertion – sometimes they can tolerate it and other times they can’t – it seems to make sense that a brain organ that “makes predictions on the states of the environment” might be having problems. Perhaps a damaged TPJ doesn’t know what to do when it comes to exertion.

Finding balance

Could the effort preference and TPJ findings reflect the difficulty people with ME/CFS have in making their way through an uncertain environment?

One hypothesis concerning the TPJ (and there are many) suggests that decision-making “is an optimization problem aimed at minimizing the variational free energy”. Minimizing free energy implies selecting actions that reduce uncertainty about future outcomes (a big, big problem in ME/CFS) while maximizing the desired outcomes. Given their uncertainty about what will happen, people with ME/CFS have tremendous problems deciding whether to go for the “desired outcome” (i.e. a trip to the store, seeing friends, going on a walk, going to a doctor’s appointment) while minimizing uncertainty. The best option often is simply to discard the desired outcome.

Then came this bizarre sentence. “Greater activation in the healthy volunteers suggests that they are attending in detail to their slight failures, while the ME/CFS participants are accomplishing what they are intending.” (???)


  • The 8 million dollar NIH-funded study was perhaps the most important ME/CFS study for one simple reason – if successful, it would give the biggest medical research funder in the world the confidence to devote more resources to the disease.
  • The study involved two week-long stays at the NIH’s clinical center where participants got just about everything the NIH could throw at them. The projected 80-person study, however, was curtailed by the pandemic. By the end of the study, 41 participants (17 ME/CFS patients and 24 healthy controls) made it through the study. Plus, sometime after their participation in the study, 4 of the ME/CFS patients spontaneously recovered – suggesting that, in some crucial way, they may have been different from you or me.
  • A simple hand-grip test where the participants were asked to squeeze and hold a hand grip while the researchers assessed brain functioning turned out to play a major role in the paper. The ME/CFS patients had normal handgrip strength, but they faded quickly and their grip strength rapidly declined.
  • The authors proposed that the problem was not in the muscles but in a part of the brain called the motor cortex. During exertion, the motor cortex stimulates the nerves to recruit more muscle units as a muscle becomes fatigued. The motor cortex in the ME/CFS patients was abnormally activated – indicating perhaps that it kept trying, to no avail, to activate more muscle units and stave off fatigue.
  • The authors asserted, “the fatigue of the ME/CFS participants is due to dysfunction of integrative brain regions that drive the motor cortex”. Motor cortex dysfunction could, then, explain a lot of the problems with exertion in ME/CFS. While motor cortex dysfunction has not played a prominent role in ME/CFS research, at least four studies/papers have proposed that it’s present.
  • Seeking to get at what was happening during the hand grip test, the authors then assessed blood oxygen levels in the brain. In contrast to the healthy controls (whose blood oxygen levels increased), the blood oxygen levels decreased in the ME/CFS patients in a part of the brain that’s never shown up in ME/CFS before – the temporoparietal junction (TPJ).
  • The TPJ is a rather bizarre organ the authors had to try to make sense of. It has been associated with things like disembodiment, self-conscious emotions, others’ beliefs, and socially guided decisions. It is also, though, an organ that “makes predictions on states of the environment with actual outcomes”.
  • The “actual outcomes” when it comes to exertion are, of course, really problematic when it comes to ME/CFS. Since ME/CFS patients themselves don’t know how to assess the effects of their exertion – sometimes they can tolerate it and other times they can’t – it seems to make sense that a brain organ that “makes predictions on the states of the environment” might be having problems.
  • An effort test (EEfRT) – which also has never been done in ME/CFS – found that people with ME/CFS tended to choose the easy task over the hard task more often, regardless of whether the reward was high or whether it was likely to occur. Since ME/CFS is, by definition, effortful, one would expect people with ME/CFS to have low EEfRT scores, and indeed they did.
  • The TPJ finding, combined with the effort finding, combined with the lack of findings suggesting that the muscles were damaged suggested to the authors that “effort preference” was the defining cause of the “motor behavior” in ME/CFS – the motor behavior being the inability of the motor cortex to activate the muscles.
  • It was hard to understand exactly what the authors were thinking, but it may have been something along the lines of: when faced with effortful tasks such as exercise, the motor cortex stops signaling the muscles, thereby inducing fatigue. This would work on a subconscious (brain shuts down motor cortex) and possibly conscious (avoidance of effort) level.
  • Not surprisingly, some of the media articles on this part of the study sound a bit psychological while others did not. On the whole, the media response to the study was quite good.
  • There’s much more to come, though, and part II of the blog series is coming up.
Trying to wrap it all together in one nice bow, the authors said, “Together these findings suggest that effort preference, not fatigue, is the defining motor behavior of this illness.” – a crazy-making statement for sure and hard to interpret. Effort preference simply may mean choosing to expend one’s effort in certain ways. Add in the “motor behavior” part and maybe you have a brain that both consciously and subconsciously shuts things down – like the motor cortex’s connection to the muscles.

In that context, motor behavior” could be something like “sickness behavior” – a brain-derived condition that produces all sorts of symptoms and problems in an attempt to keep the body as well as possible.  Suffice it to say that motor behavior is a broad and general term that “includes every kind of movement from involuntary twitches to goal-directed actions, in every part of the body from head to toe”.

It’s no surprise, given how hard it is to understand what the authors meant, to see the interpretations of that part of the paper get muddy.

The Media Response

We can make too much of this part of the study.  The media response to the study was positive and did not dwell on it. It’s more an issue for us as a community given our history.

That was good because even Brian Walitt, the lead researcher of the study, spoke inartfully about this part of the study. The NIH Press Release started off fine stating “This suggests that fatigue in ME/CFS could be caused by a dysfunction of brain regions that drive the motor cortex, such as the TPJ” and so did Wallitt “We may have identified a physiological focal point for fatigue in this population”, before he unfortunately opened the door to a psychological interpretation by bringing “thinking” into it, stating, “Rather than physical exhaustion or a lack of motivation, fatigue may arise from a mismatch between what someone thinks they can achieve and what their bodies perform.”

One would have thought Walitt would have been more careful with this topic. In my experience, this is a brain issue – not a thinking issue. The fatigue, pain, etc., signals come so fast that they must come from the brain. Two media outlets thus far have picked up Walitt’s maladroit statement. It’s quite ironic how often people with ME/CFS think and feel they can do something only to find out midstream that they’re in real trouble.

The Medical Express got it right:

“The study found that as they did the hand grip test the ME/CFS showed decreased activity in their right temporal-parietal junction, a brain region involved in self-agency. This is a part of the brain whereby the brain predicts an action before one becomes consciously aware of it.”

So did Nath in the Scientific American

“Nath hypothesizes that this dip in activity suggests the brain is cautioning people with ME/CFS against exerting force during the grip test, which he says makes sense because ME/CFS symptoms often intensify if people with the condition overwork themselves. The finding is preliminary, however, and further experiments are needed to corroborate it.”

Jonathan Edwards, a rheumatologist at UCL, got it right in the Science article

“The researchers suggest brain signals may flash stop signs to prevent physical activity—similar to how a bout with illness forces rest. “When we have a bad flu, [we] can’t get out of bed,”  “It’s a central signaling problem” in the brain, he says. “There’s nothing wrong with your muscles.”

And Tony Komaroff hit the nail on the head in two media outlets:

“ME/CFS patients also had abnormal functioning in a part of their brain that governs effort. When they are asked to exert themselves, it doesn’t light up as much. It’s like trying to swim against a current.” and “That brain area, the right temporal-parietal junction, is involved in “telling the legs to move, telling the mouth to open and eat — it sort of says do something, When it doesn’t light up properly, it’s harder to get the body to make that effort”

As it turns out, in the paper’s proposed model for ME/CFS, the TPJ doesn’t appear to play a prominent role. The authors believe the TPJ dysfunction is caused by other factors but that’s for the next blog. There’s a lot more in this study to chew on.

  • Next up – Pt II: Exercise, the Immune System, and the Really Big Picture


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