This is Part 3 of a 4-part article on NIH’s Effort Preference claim.

Part 1 can be found here.

Part 2 can be found here.

In this Part 3, I will discuss the EEfRT as a psychological measure, NIH’s frantic attempt of damage control in response to the firestorm reaction to the intramural paper, the agency’s decades-long obfuscating characterization of ME as merely fatiguing, its reframing of fatigue in ME as being purely subjective, the investigator’s fear of using a second-day exercise test, and NIH’s ongoing research of an allegedly dysfunctional Effort Preference in ME.

The EEfRT as a Psychological Measure

The EEfRT is a psychological measure. The study of motivation and effort-based, reward-based decision-making belongs to the field of psychology, and the EEfRT itself is a behavioral measure that—outside of studying motivation in autism and the impact of factors such as caffeine, tobacco abstinence, age, the indirect dopamine agonist d-amphetamine, and social conformity on the motivation of healthy individuals—has been used exclusively in psychological conditions, such as depression, schizophrenia, bipolar disorder, and binge eating.

The EEfRT was developed by Dr. Michael Treadway, a clinical psychologist with a focus on studying psychiatric symptoms related to mood, anxiety, and decision-making. His TRead Lab—TRead stands for “Translational Research in Affective Disorders”—researches decision-making in affective disorders, e.g., depression and bipolar disorder. The EEfRT was developed specifically for use in psychiatric populations.

Deficits and dysregulation of motivation have been identified as a key contributor to psychopathologies, such as anhedonia and addictive behaviors, and the EEfRT effort valuation has been established as a psychological construct used to understand psychopathology as well as a significant predictor of psychopathology. See for example the paper “Effort valuation and psychopathology in children and adults” (screenshots below).

According to the paper, “Previous research regarding the role of effort valuation in psychopathology has consistently found differences in effort-based decision-making between patients with mental disorders and healthy comparison subjects.”

Another paper states, “Research using the EEfRT across psychiatric populations can identify similarities and differences between [eating disorder] and other psychiatric conditions on effort expenditure….”

Claiming that the EEfRT is not a psych measure is simply untrue.

NIH’s Attempt to Justify the Effort Testing

Since the paper has been published, the Effort Preference part and other aspects of the study (such as the pitiful cohort sizes, which undermine the significance of any findings) have been met with enormous condemnation by researchers, ME advocates, and patients. As a result, NIH has gone into damage-control mode, unsuccessfully arguing that Effort Preference is not a psychologizing or otherwise harmful concept. The agency has also activated surrogates, such as Komaroff—Anthony-of-all-trades and NIH study case adjudicator, manuscript commenter, and paper reviewer—to deliver to the media the seemingly immortal, destructive trope that ME is real as if there is any reasonable doubt about it, thereby creating and/or perpetuating doubt.

NIH-Symposium—Koroshetz
NIH has circled the wagons going as far as involving Dr. Walter Koroshetz in the recent NIH Symposium on the study (at 0:46). Koroshetz spent more than half of his remarks on highlighting the issues of fatigue and effort in ME, trying to make a silk purse from the sow’s ear of Effort Preference. That is extraordinary when you consider that Koroshetz is the Director of NINDS, reporting directly to the NIH Director. Koroshetz promoted none of the other study findings; his main goals of presenting at the Symposium were to sell, and lend a scientific air of legitimacy to, Effort Preference, the primary finding of the intramural ME study, and to tell ME patients to stay tuned for Long COVID research to possibly benefit them. He also heaped high praise on Walitt and Nath.

Koroshetz labored to persuade the audience that effort means something different to neurologists than it does to the lay person. He claimed that the study has shown that there is a computational problem in the brain of the ME patients that leads to them unconsciously overestimating effort and/or underestimating rewards due to no fault of their own. He was emphatic when he said that NIH is not claiming that patients do not want to make an effort, except that that is exactly how the term Effort Preference will be interpreted—the only reasonable interpretation. No intellectually honest person would argue otherwise unless completely clueless.

NIH-Symposium—Madian
Madian’s Symposium presentation followed in Koroshetz’s footsteps (at 2:21:16). Madian is first author of the paper “Repetitive Negative Thought and Executive Dysfunction: An Interactive Pathway to Emotional Distress” on anxiety and depression and senior author of the paper “Non-pharmacological Treatment of Pain: Grand Challenge and Future Opportunities” on mind-body therapeutic modalities for pain.

Like Koroshetz, Madian distinguished the layperson’s understanding of effort from effort exertion as the result of the brain’s valuation network that unconsciously computes the cost-benefit ratio of exertion based on weighing energy costs and potential rewards (effort discounting). According to Madian, the inter-variability of that computation is the definition of Effort Preference—as though Effort Preference were a medically accepted characterization. To be very clear, there is no established meaning of the term Effort Preference, and there is certainly no accepted meaning of the term or concept as a defining feature of any disease.

The paper, too, attempts to give the impression of legitimacy of Effort Preference by pretending that it is well established, which it is not:

“[Effort preference] 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.”

“[O]ften seen” by whom? By precisely nobody other than NIH when it comes to ME only.

Effort Preference as a Choice
Koroshetz and Madian talked a good game during the Symposium in their shameless attempt to reframe Effort Preference and pacify the community, but the truth is that there is no discussion of the unconscious nature of Effort Preference in the paper. Instead, the paper focuses exclusively on the behavior of patients during the EEfRT with respect to choosing hard versus easy tasks, clearly referring to conscious decision-making and implying blame.

Nobody is arguing with neurology or neurobiology. However, the invoking of unconscious decision-making is outlandish with respect to the EEfRT, a task that quite literally involves a deliberate, i.e., conscious, choice between hard and easy tasks. The variation by trial in reward magnitude and the probability of a trial being a win trial are intended to influence the participants’ conscious decision-making. In fact, those aspects of the EEfRT regularly result in participants’ making strategic choices. NIH’s argument that decision-making on EEfRT is unconscious is inconsistent with the design of the task.

Linguistically, the term preference strongly suggests a choice—in this case the choice of ME patients, due to some alleged miscalculation of how much they can exert, to invest less effort than the authors claim patients safely could. The American Psychological Association Dictionary of Psychology (remember that effort research is typically done in the field of psychology, see more under “The EEfRT as a Psych Measure”) confirms this interpretation.

In addition, the authors admit that the EEfRT involves conscious decision-making when they claim that patients were pacing by reducing their button-pressing speed on the easy tasks. Pacing is, of course, unquestionably a conscious choice. The authors themselves quote an ME study participant expressly describing pacing as “a conscious choice” as allegedly supportive of their framing of disrupted effort discounting and an “unfavorable” Effort Preference being unconscious concepts, thereby directly contradicting their own claim:

The finding of a difference in effort preference is consistent with how participants describe pacing. One participant describes: ‘You have to make a conscious choice of how much energy [to use and] whether or not something is worth crashing for. It’s hard because no sane person would ever participant [sic] to suffer and … that’s what you’re doing [by choosing] an activity that will make you crash. You are going to suffer… You have to decide what gives you meaning and what is worth it to you.’” [emphasis added]

On the topic of the authors contradicting their own findings, it is worth pointing out that they did not try to explain why they did not entertain the possibility that patients were pacing when they chose slightly fewer hard tasks than controls. The authors were in a pickle and had to settle on an inconsistent analysis of their EEfRT findings and hope nobody would notice. They had no choice than to invoke pacing as the reason for the decline in easy-task button-pressing speed by patients because the only alternative explanation would have been fatigue, which they authors could not concede because that would have refuted their Effort Preference claim since a group difference in fatigue sensitivity on hard-task choices would have ruled out an altered Effort Preference. The pacing claim is a questionable interpretation; it is more likely that patients realized that they did not have to press the button on the easy task as quickly as they did initially because they continued completing easy tasks even after they slowed down. But, in order to protect their Effort Preference claim, the authors had to stay away from considering pacing as the underlying reason for patients selecting slightly fewer hard-task choices than controls because of the conscious nature of pacing, which would have contradicted the effort discounting and Effort Preference claims, which are built on the unconscious narrative.

“Oh, what a tangled web [they] weave, when first [they] practice to deceive.” —Sir Walter Scott

Effort Preference is an Overwhelmingly Prejudicial Label
Even when the term preference is viewed as a liking or favoring as opposed to a choice, it is a tremendously stigmatizing label when it comes to preferring something undesirable, such as preferring to perform easy instead of hard tasks, and the authors would have been keenly aware of that. In fact, they characterized the Effort Preference of ME patients as “unfavorable.” As mentioned, the label Effort Preference has never been used in connection with any disease. Not even the creators of the EEfRT have used the term Effort Preference, and neither did any of the subsequent EEfRT studies, but the allegedly unbiased NIH investigators (Walitt claimed to have no bias, no bias at all, about anything) felt it was just fine to debut a stigmatizing label for a disease that has been as disparaged as ME has. They might as well have used the term Malingerers’ Preference. The label Effort Preference makes the term Chronic Fatigue Syndrome seem downright scientific, an extremely high bar. NIH managed to take the defaming of ME patients to a new level, and doing so was obviously intentional.

NIH claims that their effort finding is based in neurobiology. Then why not name it something that sounds like neurobiology instead of laziness? For example, the authors point to a possible connection between the hard-task choices of 15 patients made on one occasion and a dysfunction of brain regions that drive the motor cortex, such as the temporo-parietal junction (TPJ) as if correlation equals causation. Given that NIH made up a new term out of whole cloth, it would have been easy to choose a respectful, scientific designation, such as TPJ Dysfunction, but that would have defeated the purpose of the EEfRT testing. Obviously, the term Effort Preference was chosen for maximum detrimental impact on the reputation of ME patients. The agenda of the NIH authors here is glaring, their contrived rationalization is unabashed, and their gaslighting skills are advanced. Defaming a vulnerable patient population is not science, and it should definitely never be part of government-generated, tax-payer funded “science,” and yet that is exactly what NIH did.

Prior Use of the Term
Again, Effort Preference is not an established term. It has been very sparingly used in a few different, inconsistent ways and never as an established term or concept or in connection with a disease, let alone as the defining feature of a disease.

For example, one study used effort-preference terminology to describe the preference to receive effort information before receiving reward information in choosing to complete a task.

Another study used the term in connection with the finding that participants preferred to exert effort for others rather than themselves.

NIH’s Reframing of the EEfRT
A virtual-audience member asked during the NIH Symposium (at 2:52:19) why NIH used the EEfRT in an unprecedented (non-validated?) way. There was no hint in the paper that NIH was completely reframing the EEfRT as a measure of effort discounting, i.e., as a measure of whether ME patients falsely perceive effort and their ability to exert, instead of following the established interpretation of the EEfRT as a measure of reward motivation, effort allocation, and reward-based decision-making. The reader of the paper would have no idea that NIH was introducing an entirely new interpretation of the EEfRT.

Walitt fielded the question. He referred to Madian’s comments (see above) in terms of “what Effort Preference is for us.” That is an apparent admission of the fact that NIH went rogue with the interpretation of the EEfRT. It is highly unusual for researchers to interpret an established test in a brand-new way with potentially far-reaching consequences without discussing and justifying doing so and without showing that their new interpretation has any validity. Scientists are typically eager to receive credit for novel and unprecedented research findings or interpretations. Instead, the NIH investigators carefully attempted to cloak their bastardization of the EEfRT by pretending that its use to assess effort discounting and identify an altered so-called Effort Preference in a disease is established science. It is not. Walitt continued by saying that the authors chose to frame the EEfRT results as a measure of Effort Preference in order “to reflect the conscious and unconscious aspects that guide the moment-to-moment choices that are made during the effort task.” If that is so, then why choose a term that indicates and even stresses a conscious choice, and why choose the EEfRT?

Both Walitt and Madian were clearly petrified of ad-libbing when they spoke about NIH’s EEfRT conclusions. They had written out in advance the EEfRT presentation and answers to questions from the virtual audience about the EEfRT and were reading both. This indicates an awareness of just how thin the EEfRT findings are and how carefully they have to be framed. Constructing such a vulnerable house of cards as Effort Preference in ME requires extreme discipline when presenting the alleged results. One slip-up, and the authors are exposed. No wonder scrutiny is considered hostile by Nath.

The scarce EEfRT parts of the paper have been written in the same vein: the authors chose to discuss only the absolute minimum of their effort testing and alleged results, leaving out key items, such as limitations, validity issues, potential confounding factors, relevant analyses and graphs, explanations of decisions regarding inclusions and exclusions, etc. Unlike with exclusions in other parts of the study, the data-exclusions spreadsheet (supplementary data 23) does not explain why control F was excluded from the EEfRT analysis; all the spreadsheet says is that his data was invalid but not why.

What the authors did include in the paper contains significant misrepresentations and misinterpretations of the results. It is obvious that substantial effort was invested by the authors to obscure the improprieties in the EEfRT analysis,

Other Neurological Diseases
Madian claimed that the EEfRT has been used in several neurological disorders. I have reviewed dozens of EEfRT studies and have found none that involved neurological diseases or any other medical context other than mental health conditions. In fact, numerous EEfRT studies have excluded potential participants because of a history of a major/lifetime/significant medical disease, which makes sense given the physically intense nature of the EEfRT.

Parkinson’s Disease Study
Madian equated NIH’s use of the EEfRT in ME patients to a study that measured the impact of dopaminergic medication on the exertion of effort for rewards by patients with Parkinson’ Disease. That study, although it studied effort, did not use the EEfRT. It found that Parkinson’s patients on dopamine medication chose to invest more effort for a given reward compared to Parkinson’s patients off dopamine. Madian argued that the NIH study’s findings and the Parkinson study’s finding are analogous because NIH allegedly found a positive correlation of norepinephrine levels in the cerebrospinal fluid of ME patients and their Effort Preference. Both dopamine and norepinephrine are neurotransmitters, of course.

It appears that NIH had been frantically searching for a justification after the fact for their use of the EEfRT in ME patients. The Parkinson’s study, which the NIH authors seem to have located only after publishing their ME paper, was apparently the inspiration for referring to some alleged neurobiological aspects relating to the Effort Preference claim into Madian’s and even Koroshetz’s NIH Symposium presentations.

However, the Parkinson’s study is distinguishable in a number of ways. First, it designed the experiment in a way that controlled for confounding factors. For example, it calibrated the test requirements to each participant’s maximum performance, resulting in the outcomes actually reflecting the choice to invest effort based on an action’s expected value as opposed to reflecting motoric ability. The NIH investigators, on the other hand, chose not to control for differences in motoric or other ability, and as a result, there was a dramatic difference in the groups’ physical ability to complete hard tasks, invalidating NIH’s effort findings. (see more on NIH’s failure to do so in Part 2 under “Confounding Factors and Validity Issues of EEfRT—Physical Inability of ME Patients to Complete Hard Tasks”).

Further, there was no choice to be made by the Parkinson’s study participants between easy and hard tasks (an invalid metric for the willingness to expend effort in the confines of the EEfRT as explained in detail in Part 2 under “Game Optimization Strategy”), and there was no element of luck; instead, the Parkinson’s investigators instructed the participants to accumulate as many virtual stakes as possible, and if the participants performed the required task, they did win the stakes in all trials as opposed to in win trials only, which was the case in the NIH study. The Parkinson’s study was, therefore, not confounded by participants’ optimization strategies. If the NIH investigators had indeed been influenced by the Parkinson’s study to test effort in ME, why did they not use its study design, which is clearly superior to the EEfRT because it cuts down on validity concerns. To avoid a misunderstanding, I believe that most effort testing is fraught with severe issues, but I want to give the Parkinson’s study investigators credit for at least trying to address some of them, unlike the NIH investigators.

Of course, the Parkinson’s researchers also did not call what they described Effort Preference, nor did they allege that the study results spoke to anything other than effort exertion for rewards. The NIH researchers, however, over-generalized the significance of their findings by claiming that they apply to any and all decision-making by ME patients involving effort (see details in Part 2 under “Confounding Factors and Validity Issues of the EEfRT—Misrepresentation of EEfRT Scope”).

Moreover, the controls in the NIH study showed an inverse correlation between cerebrospinal-fluid norepinephrine levels and alleged Effort Preference (ME patients had shown a positive correlation), so it is entirely unclear what the norepinephrine results mean if anything, especially since the NIH paper also claims that norepinephrine levels in cerebrospinal fluid did not differ between the two groups.

The reference to the Parkinson’s study by Madian felt desperate. Surely, if that study had been the NIH authors’ motivation to study effort in ME patients—if they had hypothesized that neurotransmitters have an impact on the willingness of ME patients to exert themselves—they would have mentioned that in their paper; they did not. Instead, by the authors’ own admission, their “primary objective” of the intramural study was to show “the existence of EEfRT performance difference” between ME patients and controls (see Part 2 under “Effort Preferences as a Defining Feature of ME”).

Moreover, the NIH paper itself tells us that the Parkinson’s study was assuredly not why NIH investigators chose the EEfRT. The real reason was that they were hoping that it would give them an opening to claim that ME patients only believe they cannot exert themselves when they actually can. We know this because the NIH paper’s Supplementary Results (page 9) expressly tell us the investigators’ reason for including the EEfRT testing in the study:

“Alterations in the “sense of effort” have been reported in the literature.”

The citations for that statement are three papers asserting that ME patients suffer from a disturbed or elevated sense of effort:

• “Is the chronic fatigue syndrome best understood as a primary disturbance of the sense of effort?” (citing several papers by Wessely and cognitive-behavioral-therapy and graded-exercise-therapy cheerleader and Wessely soulmate, Sharpe)

• “Perception of cognitive performance in patients with chronic fatigue syndrome”

• “Elevated Perceived Exertion in People with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia: A Meta-analysis”

Here are some claims and suggestions from those papers:

• There is no muscle weakness in ME patients.

• “It has been empirically established that the clinical course of CFS can be modified by cognitive-behavioral therapy … to correct the reduced physical fitness resulting from excessive rest and ‘dysfunctional attitude to exercise'” (citing Sharpe). The authors celebrate that the alleged “benefits [of cognitive-behavioral therapy] continue to accrue after stopping formal treatment.” (Remember that the NIH authors claim that what allegedly defines ME, Effort Preference, is what leads to deconditioning and functional capacity in ME patients.)

• Re-education of ME patients in the area of motor function was suggested. (This gives definite Lightning Process vibes.)

• ME patients suffer from “cognitive distortions” by having an “impossibly high standard of … performance”—both their own performance and what normal performance should look like.

• “[A} nagging sense of insufficiency over what patients feel they should be accomplishing may indeed contribute to an overestimation of exertion and fatigue.”

• “People with ME/CFS and [Fibromyalgia] perceive aerobic exercise as more effortful as healthy adults.”

• “People with ME/CFS and [Fibromyalgia] exhibit elevated [perceived exertion] during exercise.”

These psycho-babble papers, which align perfectly with documented beliefs of NIH’s biopsychosocial disciples, are what inspired the NIH investigators, by their own admission in the paper, to test ME patients’ effort exertion. As you can see, there is no mention of a correlation between neurotransmitters and effort. Madian seems to have used the Parkinson’s study as a fig leaf after the fact for the utterly indefensible decision to use the EEfRT in the intramural study and to declare a dysfunctional perception of patients’ ability to exert a defining feature of ME.

NIH’s Obsession with Fatigue in ME, Reframing of Fatigue, and Denial of Established CPET Science

The authors used their new Effort Preference concept to reframe fatigue in ME:

NIH’s Historical Obsession with Fatigue
There is a well-documented history of NIH’s obfuscation of the true nature of ME by falsely reducing ME to fatigue. One of countless examples is the following image in a slide used by Nath; look at his emphasis of the word fatigue.

(Also note the preposterous stock photo used in this slide supposedly illustrating the severity of ME: a sad boy resting his head on his forearm.)

NIH’s culture of misrepresenting ME goes back decades, all the way to the late Dr. Stephen Straus, NIH virologist, who was involved in renaming ME Chronic Fatigue Syndrome and redefining ME with the Fukuda criteria, an overly broad definition centered around fatigue, thereby capturing many who do not have ME. The late ME advocate and author of The CFS Report, Craig Maupin, obtained, though a Freedom of Information Act request, a letter written by Straus to the lead author of the Fukuda criteria. In that letter, Straus went on record with his plan to reframe ME as “Chronic Fatigue,” with the stated goal of causing ME to cease to exist as a recognized disease, which Straus called a “desired outcome.”

Straus’s agenda is as strong as ever at NIH. In fact, there is a push at NIH and other federal health agencies to promote all diseases it views as post-infectious as a monolithic entity—thereby misdirecting and hampering research and treatment for these complex diseases—by identifying them through a single shared symptom, fatigue, which is common in a prodigious number of health issues. Nath asserted, during the May 28, 2024 NIH Advocacy call, that it would be more appropriate to use the term Post Acute Infection Syndromes for ME, Long COVID, and Post-Ebola Syndrome instead of allowing the continued use of their distinct names. Nath proposed to put “a whole slew of diseases” under that umbrella term. He wants to include Gulf War Illness and Sick Building Syndrome; never mind that they are not necessarily triggered by an infection.

Of course, Walitt has been promoting the lumping of ME and Fibromyalgia for many years (see Part 1).

There is a pronounced difference between studying effort in ME, which has been maligned by NIH and other federal health agencies as merely fatiguing for decades, and diseases such as Cancer, Multiple Sclerosis, or Rheumatoid Arthritis, which are not at risk of being distilled down to fatigue.

NIH’s reductionist focus on fatigue is tantamount to grasping the tail of an elephant and insisting one is holding a snake. There is a vast body of ME research on which NIH could have built in lieu of testing for effort if it had not been for NIH’s pathological and deceptive fixation on fatigue. ME is a complex disease that presents with many disabling symptoms. It is not mainly characterized by fatigue but rather by the persistent expression of the profound and often severe, complex dysregulation of multiple bodily systems, including, but not limited to, the immune, neurological, cardiovascular, and endocrine systems; energy metabolism, production, and transport systems; the Hypothalamic-Pituitary-Adrenal Axis; and other systems. Fatigue is a symptom, not the symptom.

As fatigue is not at the driving factor or core symptom of ME, curing or treating fatigue in ME would leave patients still disabled just like curing or treating fatigue in cancer would still lead to the death of most cancer patients in the absence of a treatment that stops the abnormal growth of cells. The following signs and symptoms have been well established in ME. This non-exhaustive list is based mainly on the ME:ICC and the Myalgic Encephalomyelitis International Consensus Primer for Medical Practitioners authored by expert clinicians and scientists in the field of ME.

With respect to issues with muscle strength after exertion, they are much more likely a protective downstream response designed to keep the body from being damaged by further exertion than they are the result of a miscalculation of effort. And if that is the case, then treatment with medication that affects neurotransmitters, such as dopamine and norepinephrine, in an attempt to impact the valuation center in the brain that deals with effort-based decision-making—the unconvincingly purported impetus of NIH’s effort inquiry in this study (see above under “NIH’s Attempt to Justify the Effort Testing—Parkinson’s Disease Study”)—are likely to be harmful as it will cause patients to override their limits. That is why treatments with stimulants such as Ritalin (affecting dopamine and norepinephrine levels) or caffeine tablets (impacting dopamine, glutamate, and GABA) tend to have horrid long-term outcomes in the ME population not unlike modalities such as the Lightning Process that indoctrinate patients into ignoring their limits.

NIH’s Escalating Reframing of the Fatigue Narrative
In this paper, NIH has reframed and, thereby, escalated, its ME fatigue narrative. Although greatly diminished muscular strength and work capacity, i.e., fatigue/exhaustion and fatigability, are obviously part of the ME presentation, NIH claims to have found them only in controls but not in ME. Apparently, the agency went from insisting that ME is nothing but fatigue to the even worse narrative of asserting that there are no objective fatigue or issues with muscle strength in ME, but rather that any fatigue patients experience is subjective, i.e., the result of a false perception of effort and fatigue (i.e., an altered Effort Preference) that leads to deconditioning and functional disability. That is what NIH purports to believe, and falsely claims, defines ME.

The paper has laid the groundwork for reframing ME accordingly:

“[E]ffort preference, not fatigue, is the defining motor behavior of this illness.”

and

“Fatigue is defined by effort preferences….”

In NIH’s press release for the study, Walitt claims:

“We may have identified a physiological focal point for fatigue in this population. 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.”

Nath describes the allegedly altered Effort Preference in patients as relating only to pacing whereas according to Koroshetz, Walitt, Madian, the paper itself, and the NIH press release, the alleged dysfunctional effort discounting in ME patients results in a general false perception of effort and fatigue without any limitation of the Effort Preference claim to pacing. The more inconsistent and confusing the narrative, the less subject to scrutiny and criticism it will be, or so NIH hopes.

How does an altered Effort Preference explain objective signs and symptoms such as the objectively measurable exacerbation of ME symptoms as the result of exertion (PENE, often referred to by the less specific and less scientifically accurate term and concept Post-Exertional Malaise or PEM), susceptibility to viral infections with prolonged recovery periods, reactivated viruses, low-grade fevers, enlarged lymph nodes, orthostatic intolerance (POTS and Neurally Mediated Hypotension), elevated resting heart rate, elevated heart-rate during and after eating, low heart-rate variability, abnormally low body temperature, etc.? It cannot. NIH is, of course, fully aware of that, but it has sacrificed ME science on the biopsychosocial altar.

The decision to study effort in ME is clear evidence that the investigators refuse to accept the findings of ME expert researchers, who have amassed over 10,000 published, peer-reviewed papers documenting the biomedical abnormalities of the disease, as well as the reported experience of ME patients. There was an overwhelming confirmation bias at play here: the investigators were motivated to claim that ME is defined by a particularly prejudicial form of fatigue that they made up, i.e., Effort Preference, in direct contradiction to the ME expert clinicians and researchers.

NIH’s new focus on Effort Preference constitutes a continuation and intensification of the agency’s misrepresentation of the nature of ME and a misdirection of its efforts and the efforts of other researchers by gatekeeping extramural research, continuing the indefensible decades-long practice of rejecting nearly all grants for biomedical research into ME with contrived reasons. How many more “Fatigue Self-Management” or “Biofeedback and Hydrogen Water as Treatments for Chronic Fatigue Syndrome” studies by Dr. Fred Friedberg will NIH fund? Will NIH now approve grants only for those extramural researchers who toe the Effort Preference line? The NIH researchers and bureaucrats are nowhere near as subtle in their institutional bias as they seem to think they are.

NIH’s Relentless Misnaming of ME
NIH broadcasts its persistent bias by repetitively and nearly exclusively using the trivializing and inaccurate terms chronic fatigue (a non-specific symptom in a large number of health issues) or Chronic Fatigue Syndrome when referring to ME as well as labels such as condition or disorder. They also like to mix and match medical entities, such as ME and Chronic Fatigue Syndrome (ME/CFS). Koroshetz added a new twist to this during the NIH Symposium when he repeatedly referred to ME as “this problem” or “this general problem.” Ongoing institutional refusal to use appropriate nomenclature perpetuates the misperception and discounting of this severely disabling neuro-immune disease.

NIH’s Denial of Well-Established Two-Day CPET Science
A major symptom of ME is PENE. Without PENE, an ME diagnosis is a misdiagnosis. The only way to objectively confirm PENE is with a cardiopulmonary exercise test (CPET) performed on two consecutive days. The dramatic drop-off on day two on this test, during which maximum effort is objectively confirmed ruling out cheating, is incontrovertible evidence of the severe limitations of capacity in ME. That being the case, both things cannot be true: (a) that patients are objectively unable to repeat on day two (or whenever they are in PENE) their day-one CPET results (or their baseline performance) and (b) that patients think that they cannot exert on day two (or whenever they are in PENE) as much as they did on day one (or at their baseline) due to an altered perception of effort and/or rewards resulting in a misperception of their capacity to exert. The authors agree with that dichotomy:

“as fatigue develops, failure can occur because of depletion of capacity or an unfavorable preference.” [emphasis added]

The two-day CPET results of ME patients, without fail, demonstrate that there is a depletion of capacity, ruling out the “unfavorable”-preference alternative. The way the authors get around this fatal contradiction in their claim is by ignoring, if not denying, the extensive body of well-established CPET science in ME. Without even trying to look into the capacity issue in the patient group by including a second-day CPET, the authors allege that ME patients have “an unfavorable preference.” Their proof? The debunked results of the EEfRT, an unreliable behavioral measure.

The investigators seem to have been terrified of including a two-day CPET—the gold standard for confirming PEM or PENE—in their protocol and at the direction of Walitt did not. The purported rationale for not using a two-day CPET given by Walitt during the Symposium (at  3:59:08) is that the physiological measurements of the CPET (“further collapse of metabolic activity”) do “not measure the experience of [PEM]” but rather cardio-respiratory performance. Moreover, Walitt claims that a second-day CPET was not necessary in light of a brand-new instrument, Qualitative Interviews, that was developed by NIH, for use in the phenotyping study, as the result of a focus-group PEM study. Walitt asserts that the investigators were able to induce PEM with only a one-day CPET allegedly shown by the Qualitative Interviews. Never mind that only eight ME patients participated in the CPET (although the Supplementary Information of the paper, on page 14, inconsistently states that it was nine patients). Finally, Walitt said the researchers did not want to risk harming patients by asking them to do a second CPET.

Diagnosing PEM after the one-day CPET performed in only eight patients through subjective assessments is exactly why a quarter of the patient cohort “spontaneously recovered.” Anybody who knows just the basics of ME understands that a quarter is a recovery rate that is well beyond what credible expert clinicians or researchers in the field have found. The generally accepted recovery rate is 5%. There is no explanation for the outlandish “recovery” rate in this study other than that at least some if not all of those “recovered” patients were misidentified as having ME, which then begs the question if any of the other patients also did not actually have ME.

We do not know how many individuals in the patient group were misdiagnosed because of the lack of the second-day CPET. The fact that adjudicators agreed on the diagnosis is a self-serving NIH talking point, but consensus does not equal objective confirmation. The existence of PEM is not a popularity contest subject to a vote. The authors did not explain why they did not feel it necessary to exclude the data of the “recovered” individuals from their analysis, thereby tainting the entire study.

The results of the second-day CPET would not only have ensured that NIH would be studying the correct cohort—something that would have resulted in very different outcomes as it would have weeded out the misdiagnosed individuals in the patient group—but they also would have dominated the paper as the objectively measured drop-off on day two would have been dramatic. This was something that some of the investigators wanted to prevent from happening at all costs because it would have made it impossible to claim that there is a problem with how patients perceive effort and rewards and with their perception of their abilities.

The authors imply that their Effort Preference claim is confirmed by the fact that patients needed “strong encouragement during CPET” in order to reach a respiratory exchange rate of 1.1. That is, frankly, embarrassing. Strong encouragement is typical with CPETs, even with healthy individuals. There is nothing unusual about it. It is not a sign that ME patients can perform at higher levels than they think. The authors were shamelessly grasping.

NIH’s Inability to Explain Outbreaks and the Efficacy of Serious Medication
The investigators owe the ME community an explanation of how Effort Preference could possibly explain the numerous outbreaks of ME over decades. It disrupted effort discounting contagious? It would also be interesting to hear the NIH authors explain how serious medications such as Ampligen (an immune-modulator and antiviral), IVIG (a blood product), Mestinon (a Myasthenia Gravis drug), Low Dose Naltrexone (an anti-inflammatory agent improving sleep, pain, inflammation, and autoimmunity), antivirals such as Vistide and Valtrex, Rituxan (a monoclonal antibody used to treat cancer and autoimmunity), anti-Tumor Necrosis Factor biologics such as Enbrel (used to treat autoimmunity), or even just B12 shots or normal saline, etc. could possibly improve the patients’ perception of effort and of their capacity for exertion to the point of providing relief for patients, often significantly so.

Ongoing Intramural ME Research

NIH is not done “studying” “ME.” The phenotyping study was only the first of three phases of intramural ME research.

What is particularly concerning is that NIH will continue studying what the agency calls, in the case of ME only, Effort Preference. During the NIH Symposium, Madian said:

“Further research on valuation-network damage or dysfunction as a possible contributor to these symptoms is also warranted. A closer investigation of valuation-network functioning in people with ME/CFS is already underway.”

NIH’s obvious goal is to establish Effort Preference as an accepted medical concept, which it currently is not. A few years from now, that will likely have changed, unless NIH is stopped. NIH’s ultimate objective seems to be to blame all ME symptoms on deconditioning secondary to an alleged disorder of perception.

In Part 2, I have shown, without a doubt, that the intramural study does not provide a basis for the further study of effort or of any “valuation-network damage or dysfunction” in ME patients. In fact, the EEfRT testing demonstrated clearly that there there is no such damage or dysfunction. It is crucial that the community shut down this line of inquiry by NIH; otherwise, harm is guaranteed.

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Open Access: I shared quotes, data, images from the paper “Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome” under the Creative Commons license, a copy of which can be found here. I indicated how I re-analyzed the data.