US NIH: Responses to NANDS Request for Information: How to advance ME/CFS Research

Research suggestions and ideas

Actimetry and wearables
The key clinical problem in ME/CFS is exertion intolerance. I think we need to be able to measure that objectively. I think there is an analogy with the inability to move rapidly and smoothly in Parkinsonism. The neurologists have made progress in documenting this with actimetry - including describing on-off phenomena. Actimetry in ME/CFS has mostly looked at just quantity of activity but I think it needs to be used to look at PATTERNS of impaired activity so that these can be tracked objectively over long periods. The technical term for this is apparently 'motor fatigue'. That is to say not a sense of fatigue but a behavioural pattern that can be studied objectively. Only when we understand these patterns will we know what we are trying to explain. I think it very likely that if we really knew what the activity deficit was we would know we are not looking for a metabolic defect, for instance. [The most compelling ME/CFS research needs]

Wearables are cheap and the data can be uploaded easily. Patients worlwide are a rich resource and companies making bioharnesses to measure physiology and activity are interested in research and some prepared to donate the equipment. We can put people on the moon and train elite athletes yet can't devise an effective physiologically guided activity program for a person with ME/CFS and its associated exercise intolerance . It is a huge whole in the research that would be extremely profitable to address. [Potential research resources, tools, and/or materials that could help advance ME/CFS research or enable early career investigators and senior investigators new to the ME/CFS field to more easily conduct research]

Modify a Fitbit-like home measurement device that sufferers can use to report data remotely from home in an automated way. [Approaches to reduce barriers that prevent individuals with ME/CFS from participating in research. For example, these might be logistical challenges, such as difficulty traveling to a study site, or might be because of an unwillingness to undergo certain types of research protocols]

Autopsy study
A key resource would be the collection of a series of 20 sequential autopsy brains on moderate to severe patients commiting suicide. A central consistent processing facility with controls should be used and blinded tissue samples sent to three independent neuropathologists. An important aim would be to exclude any so far missed patterns of pathology but positive findings would be of geat help. Such a proposal should be set up prospectively with government funding making use of something like the UK Queen Square RNHND brain bank facility . I think Nacul and colleagues have raised this in 2014. [The most compelling ME/CFS research needs]

A US Data Repository and Biobank
Data Repository and Biobank: Finalize a clearly articulated plan to establish and maintain NIH-funded centralized data and biospecimen repositories, which can store anonymized clinical and research data, including imaging data and biospecimens collected from well-characterized patients in past, current, and future research studies. These repositories should be fully operational within two years and accessible by outside researchers. The repositories can be extensions of existing repositories that are storing ME data and biospecimens or built from scratch. The current efforts focused on just the data generated by the NIH supported CRCs must be expanded to include institutions not funded in the CRC grant, provided they share their inclusion criteria and specifics regarding the manner in which the specimens were gathered and stored. [The most compelling ME/CFS research needs]

One of the most daunting aspects for someone who wishes to enter the field is access to quality samples that are accompanied with detailed clinical data. The UK biobank is helpful but will not be able to supply all projects. I believe that a US ME/CFS biobank is needed, developed by a specific project designed to collect no-strings-attached samples from subjects selected by ME/CFS expert physicians. The number of such physicians is rapidly dwindling as many who entered the fields during the ME/CFS outbreaks of the 1980s have retired or are at retirement age now. I suggest that an RFA needs to be issued for collection of samples that would go into an NIHsponsored repository, from which researchers could request samples by a non-cumbersome application process. [Potential research resources, tools, and/or materials that could help advance ME/CFS research or enable early career investigators and senior investigators new to the ME/CFS field to more easily conduct research]

Many patients would love to participate in research but live too far from a research center and/or are (much) too ill to travel. Establishing a large biobank, maybe following the template of the UK MEbiobank, could help overcome some of these access problems. [Approaches to reduce barriers that prevent individuals with ME/CFS from participating in research. For example, these might be logistical challenges, such as difficulty traveling to a study site, or might be because of an unwillingness to undergo certain types of research protocols]

Test off-label treatments
NIH should also leverage all funding opportunities including both clinical efficacy trials for interventions already being used offlabel and for exploratory trials to identify responder/non-responder subgroups and investigate underlying biological variables driving disparate outcomes. To best leverage this opportunity, we recommend NIH issue a targeted funding announcement with set-aside funds to support the establishment of a Clinical Trials and Interventions Consortium to develop the network of clinical sites who participate in trials and to further develop the instrumentation, methods, and trial design to ensure success of these trials. We also recommend NIH institutes prioritize and provide funding for intervention trials already being used off-label in clinical practice. [The most compelling ME/CFS research needs]

Change in vision as objective marker
One possible objective marker could be a change in vision. I often claim to have worse vision when worse - this is something like worsening myopia. Although the change is not a huge scale, it may be true for other people with ME/CFS. REM have been shown to be abnormal in MS patients performing a fatiguing task (Ferreira M., 2017). [Relevant considerations and strategies for clinical ME/CFS research, including the development and validation of data standards and outcome measures]

Adequate vocabulary
One crucial problem is a lack of adequate vocabulary. Most of the common labels used in this disease are unrepresentative and unnecessarily vague. It is unfortunate that “I feel sick” is an inadequate description, but nothing of value was gained by arbitrarily preferring instead the even more inadequate obsession with fatigue, a secondary symptom of ME, a term that is used to provide various meanings from sleepiness to the common “subjective sensation of tiredness”, a completely inadequate and misleading definition of ME. […]It’s likely that a reliable test will require less reliance on language and more on objective measures, but there are clear advantages to creating a common and accurate idiom that actually relates to the lived experience of the disease while carrying proper meaning to researchers and clinicians, as initial clinical consultations will require the proper use of accurate terms to guide the diagnostic process towards a proper (future) test. [Relevant considerations and strategies for clinical ME/CFS research, including the development and validation of data standards and outcome measures]

 

Collecting more data

Lack of longitudinal data
ME/CFS also needs more up to date longitudinal data. I have been sick for 23 years, and I have no idea what this illness is doing to my body, or my prognosis.[The most compelling ME/CFS research needs]

I've read accounts from several patients who say they had minor symptoms years ahead of actually developing ME/CFS. This leads me to wonder if there is a substantial 'incubation' (or equivalent) period where major symptoms are not present but the disease itself is silently or mostlysilently progressing. So, is there an incubation or silent period in the development of this disease. [The most compelling ME/CFS research needs]

Let patient’s pay for theirs tests in research studies
I have had CFS for 36 years. I am financially able to donate to research that has the possibility of applying to me. Let’s say a researcher is working on the prevalence of certain cytokine patterns or metabolomic patterns in people with CFS. I would like to pay to have testing done on myself and if in fact my lab work is consistent with what the researchers are finding, I would want to donate money toward that research because there is a chance that it will help me. I believe there are many other people who have money to donate, and would be more likely to do so if they believe the research has a possibility of helping them. And with people paying to have their own testing done, you would have larger sample sizes and research could be trashed sooner if it appears to not be on the right track, or it could be given the go ahead. [Strategies for overcoming scientific challenges or barriers to progress in ME/CFS research]

Currently researchers tend to use small samples of people with Cfs in their studies. A lot more information could be obtained by allowing people with Cfs to have the same testing done on themselves that the researchers are using. at our own expense. Let’s say an individual study has 30 participants and a researcher was able to get 500 people to self finance the same relevant testing. Let’s say those 500 people with Cfs don’t show the same testing patterns as the researcher is studying. The researcher could move on to the next theory much more quickly! If there is consistency, continued research in that area would be warranted. [Strategies for overcoming scientific challenges or barriers to progress in ME/CFS research]

Doctors could gather more info on their patients for research
I'm a breast cancer survivor. I must have participated in at least five studies, because there always seems to be one going on, and I was always asked to be a part of them by my oncologists (and I always said yes!). ME/CFS patients would be more than happy to participate in any study available, but where are they? I feel that even one or two good studies that involved lots of doctors gathering information from their patients would help a lot. It seems like most of the reports I see about studies being done for this disease have a very small focus and small patient bases. There are so many variables to this disease that it seems studies with lots of patients would be more beneficial. [Strategies for overcoming scientific challenges or barriers to progress in ME/CFS research]

Does the NIH not have some central database that alerts physicians to certain patient diagnoses that are undergoing studies so that they can inform their patients about them? [Approaches to reduce barriers that prevent individuals with ME/CFS from participating in research. For example, these might be logistical challenges, such as difficulty traveling to a study site, or might be because of an unwillingness to undergo certain types of research protocols]

Engage underrepresented groups of ME/CFS patients
Explicitly encourage researchers to address underrepresented groups in ME/CFS research. Currently, subjects in ME/CFS studies consist of mostly middle-aged (around 50), well-educated, middle-class, Caucasian women who have been sick for years and are able to attend clinic. Yet clinicians know and studies show ME/CFS affects a much wider group. Researchers should address how they intend to recruit men, younger and older people, people of color, poor people, people who have sick only briefly, and severely affected people. Pediatric ME/CFS research must be especially encouraged as onset during the teenage years is common. [Strategies for overcoming scientific challenges or barriers to progress in ME/CFS research]

 

How to get more patients into studies

Social media campaign to attract participants for studies
I would suggest social media campaigns as outreach to locate and hear from more patients living with ME/CFS. I imagine many of us would gladly participate in order to further awareness and research. There is currently no platform (digital or physical) that brings the ME/CFS community together in a way we can share and learn from each other. You can’t solve something without data and that can’t be limited to small control groups but the investigators could learn so much from the masses of patients if there was a publicly advertised call to participate put out on various social media sites. I was only able to access support by searching myself and too many have to work just to make it through the day before they can dedicate time to finding resources online. By blasting a callout on social media you could generate a larger response rate from people that can share their story of how they were diagnosed, what precipitated their initial onset and most importantly what treatments are working for them. We have to be able to talk collectively and share information. With that information patterns and identifying markers could be learned and diagnostic and treatment plans could be built. [Potential research resources, tools, and/or materials that could help advance ME/CFS research or enable early career investigators and senior investigators new to the ME/CFS field to more easily conduct research]

More (financial) incentive for participants in studies
PRovide more incentive for patients to participate. I have to fly from Boston to SLC to participate and spend at least one night in a hotel- and yet i get $50 for participating. It would be far easier for more people to participate if funding to get patients to travel were covered. [Potential research resources, tools, and/or materials that could help advance ME/CFS research or enable early career investigators and senior investigators new to the ME/CFS field to more easily conduct research]

I travelled to Stanford University from San Diego, CA to participate in two research studies. My community raised the money for me to be able to travel with my spouse & for someone to watch out children who stayed behind, as the trip was cost prohibitive to us on our own. There are more studies I qualify for, but I am unable to afford all the expenses we would incur to the there. I am also more severely effected then I was when I did the study. I would probably need medical transport to participate, and would not be able to participate in studies that might further worsen my condition, like exercise studies and spinal taps. [Approaches to reduce barriers that prevent individuals with ME/CFS from participating in research. For example, these might be logistical challenges, such as difficulty traveling to a study site, or might be because of an unwillingness to undergo certain types of research protocols]

MONEY! FUNDING! I LIVE IN LOS ANGELES; THERE ARE SEVERAL STUDIES I WISH TO PARTICIPATE IN BUT ARE EITHER 400 MILES AWAY FROM ME IN STANFORD OR 3000 MILES AWAY FROM ME IN ITHACA, NEW YORK OR BOSTON MASSACHUSETTS. I AM ON DISABILITY AND CANNOT AFFORD THE TRAVEL OR LODGING. [Approaches to reduce barriers that prevent individuals with ME/CFS from participating in research. For example, these might be logistical challenges, such as difficulty traveling to a study site, or might be because of an unwillingness to undergo certain types of research protocols]

Participating in research costs us, both in our health and wallets. For example, I spent $5000 on travel for a Phase 2 drug trial. This required 6 trips back and forth and about 24 hotel stays. The compensation for the study was only $1500. I felt that it was worth the risk to my health and the money, because the drug had the potential to be curative, and this was not a placebo controlled double blind study. Only because I knew for certain I would get the drug, was the risk worthwhile to me. [Approaches to reduce barriers that prevent individuals with ME/CFS from participating in research. For example, these might be logistical challenges, such as difficulty traveling to a study site, or might be because of an unwillingness to undergo certain types of research protocols]

Register patients and ask them questions occasionally
I have no idea. I want to say surveys to gather information about health history and current symptoms, but honestly, as a sufferer of CFS, it's just so hard for me to concentrate most of the time so filling something like that out would be difficult. Maybe registering patients, and then sending one question at a time, say once a week? [Potential research resources, tools, and/or materials that could help advance ME/CFS research or enable early career investigators and senior investigators new to the ME/CFS field to more easily conduct research]

Reach out to health services with experience with homebound patients
Reach out to health services providers who have experience with disabled/ homebound/ bedridden patients may reveal new technologies or methods that have not been considered in ME/CFS. For example, home-based blood draws, physical therapy visits, Skype physician follow-ups, and portable chest x-rays/ ultrasound/ EKGs have long been used in home health care. Funding to provide such services is essential to recruit severely ill subjects. [Approaches to reduce barriers that prevent individuals with ME/CFS from participating in research. For example, these might be logistical challenges, such as difficulty traveling to a study site, or might be because of an unwillingness to undergo certain types of research protocols]

 

Diagnostic criteria and questionnaires

Stricter diagnostic criteria
The absolutely essential first thing to advance research at the NIH and elsewhere is to stop mixing the distinct disease myalgic encephalomyelitis, ME, with various fatigue-based conditions that are not ME under the obfuscatory term "ME/CFS." Use of the hybrid name "ME/CFS" makes explicit the main impediment to productive research in the field-combining the differentiable neurological disease ME with ill-defined fatigue-based conditions as a single heterogeneous group. Using the existing ICC to select research subjects with ME by far would have the greatest impact on the productivity, reproducibility, and usefulness of research for people with ME. The logical way to research a disease is to use subjects who unequivocally have the disease being studied. This commonsense approach has worked with other diseases, but is yet to be tried significantly with ME. [The most compelling ME/CFS research needs]

How to assess post-exertional malaise
Post-exertional malaise - PEM is a hallmark of ME and according to some people in the field also occurs in other illnesses though it manifests differently. It seems that in ME , the triggers, onset, severity, frequency and duration are different than in other diseases/conditions. However, there doesn’t seem a thorough scientific characterization of PEM which means that health care professionals and researchers may be missing patients with it or mislabeling patients without it. Therefore PEM needs to be carefully characterized in order to facilitate diagnosis, educate healthcare professionals (and stakeholders) and to elucidate what is same/different about PEM in all conditions in which it occurs. A thorough understanding of the physiology of PEM, the cognitive and physical impact of PEM in ME and of the cognitive and physical triggers of PEM is essential. This characterization should also be done by an NIH sponsored project of ME expert clinicians and researchers as well as researchers in the other conditions said to have PEM. This should be done immediately so as to ensure that the research definition and methods decided upon by ME expert clinicians and researchers will incorporate this characterization of PEM to accurately adjudicate ME patients. [The most compelling ME/CFS research needs]

It would be useful to develop a questionnaire for detecting postexertional malaise that yields results that closely align with the objective 2-day CPET protocol. If overexertion in the early stage of the illness does worsen the prognosis as many patients suspect, then it would be important to develop a tool to identify patients early on. [Relevant considerations and strategies for clinical ME/CFS research, including the development and validation of data standards and outcome measures]

There are too many symptoms and variables
Limit the number of common issues. There are too many symptoms and variables. There has to be a range that connects to the nervous system, the brain neurons, the digestive breakdown. Use those most commonly found, stay away from the hundred different symptoms, I have a different issue every other week, facial muscle spasms, weak limbs, itchy legs. Those don't matter, the number one is WHY can I not walk up and down the stairs like a normal person, why do I need to decline long trips, why do I need to sleep during the day regardless of stimulant treatment?, Sleep all day, all night? What are the common denominators, what are the main cases? [Potential research resources, tools, and/or materials that could help advance ME/CFS research or enable early career investigators and senior investigators new to the ME/CFS field to more easily conduct research]

Use more specific questionnaires
Stop using questionnaires that primarily assess a single vague symptom, such as fatigue (like the Chalder Fatigue Scale) and questionnaires that make a value judgment about the cause of symptoms, such as the HADS. If questionnaires are needed, try to use questionnaires with specific questions (including questions related to everyday functions) like the PROMIS Physical Function, Cognitive Function, Ability to Participate in Social Roles and Activity questionnaires, or the Short Musculoskeletal Function Assessment. [Relevant considerations and strategies for clinical ME/CFS research, including the development and validation of data standards and outcome measures]

 

Other suggestions

Collaboration with EDS and POTS research
There needs to be more collaboration between ME researchers and other specialty disease research. There is symptom overlap with those who suffer from Ehlers-Danlos Syndrome, POTS, disautonomia, and other diseases. Maybe there is a connection? We need more collaboration to find out. [Strategies for overcoming scientific challenges or barriers to progress in ME/CFS research]

Patient input
Patient input - Lenny Jason had 1500 patients working with him on his PEM survey and he ended up with a robust survey document that captures the essence of the disease. So much research lacks patient input and the researchers go off on their own tangent that misses the bulls eye and often provides incomplete or misleading info as they don't know how to interpret the data in light of patient's lived experience. [Potential research resources, tools, and/or materials that could help advance ME/CFS research or enable early career investigators and senior investigators new to the ME/CFS field to more easily conduct research]

Need to incorporate detailed data from both subjective client outcomes and objective biological measures. People with ME/CFS should always be consulted in the development of data collection methods and outcome measures, because we WILL be aware of flaws in the protocols designed by people without ME/CFS. So much of this illness is counter-intuitive, that real input from real people with the illness MUST be included and incorporated in development. [Relevant considerations and strategies for clinical ME/CFS research, including the development and validation of data standards and outcome measures]

Enabling the patients to better inform the experts is crucial to moving this field forward. Doctors know medicine. Researchers know testing methods. Only patients really know their own illness experience. [Strategies for increasing ME/CFS research collaboration and communication between relevant stakeholders]

Need to incorporate detailed data from both subjective client outcomes and objective biological measures. People with ME/CFS should always be consulted in the development of data collection methods and outcome measures, because we WILL be aware of flaws in the protocols designed by people without ME/CFS. So much of this illness is counter-intuitive, that real input from real people with the illness MUST be included and incorporated in development. [Relevant considerations and strategies for clinical ME/CFS research, including the development and validation of data standards and outcome measures]

Stop the double standard towards mind-body interventions
A major barrier to progress is that there is a double standard where claims of biological mechanisms and drugs are held to a high standard, while claims concerning CBT, mind-body interventions, exercise and similar are held to a low standard. So low that claims of efficacy concerning the latter are accepted even if based on unblinded clinicial trials with primary subjective outcomes and inadequate control groups. Such a design make it a trivially easy to obtain positive results for almost any intervention, even if that intervention is in reality ineffective. These claims about successfully treating ME/CFS with psychotherapy and exercise have created misunderstanding and convinced society that ME/CFS is not really a disease. It is therefore unsurprising that there is a lack of researchers investigating ME/CFS. Society needs to be told clearly that this view of ME/CFS was an error and harmful to patients. The double standard also needs to be eliminated. [Strategies for overcoming scientific challenges or barriers to progress in ME/CFS research]

Teach ME/CFS at medical schools
The biggest barrier may be simply not never being exposed/ educated about ME/CFS ever. Since less than a third of medical school even superficially mention ME/CFS, the chances medical or scientific students/ trainees have ever heard of ME/CFS are are slim-to-none. If NIH were able to put together a short brochure/ e-fact sheet introducing the condition and share it via their numerous contacts, that may be helpful. A multi-prong approach is likely needed, e.g. having the brochure at tables during conference, sharing it via NIH Intramural Newsletters, etc., so that students/ trainees are exposed to ME/CFS repeatedly via different methods. [Overcoming challenges or barriers to establishing a career in ME/CFS research for early career investigators and those new to the field]

Create a curriculum for a college class seminar on MECFS, it’s history, efforts at treatment, and ongoing research, in partnership with the institutions of and or relevant researchers at the MECFS centers of excellence in Cornell, Harvard, and Columbia. This class outline can be made available freely online and can serve as an object lesson to potential doctors and researchers of the relationship between research, treatment, and society in a poorly understood disease. Two such versions of the course can be created: one which focuses on the biology and medicine while touching on the societal, gender, and economic issues of having a and this chronic illness, and one which focuses on the societal, gender, and Economic issues while touching on the biology and medicine. Creating both versions will widen the catchment population of those exposed to the disease, and the latter version can be rolled out sooner then the more biology focused one. The courses may best serve if they are outlines rather then whole courses: this will help professors engage with the material making it their own and will take up less resources. Create a dedicated graduate fellowship/ scholarship position at each of the me/cfs centers of excellence so as to train researchers specializing in the field; creates opportunities for me/cfs centered research by students, even if students don’t go on to specialize in this work after completion of their graduate or doctorate degree and they go on to work in another field they can expose other research fields and organizations to the research being done towards a cure for mecfs. [Approaches to strengthen research and career training for ME/CFS investigators.]

Career training should start in medical school with basic instruction in curriculum. Unfortunately, in a recent survey of 132 medical schools, only a third of them included ME/CFS in their curriculum. (Source: https://tinyurl.com/y5u4cg2c) The study also pointed out that only a third of medical schools treated patients in a clinical setting, and 15% had research programs. When students are not exposed to information or given access to patients, it’s difficult to attract young investigators or get them started on career paths. [Approaches to strengthen research and career training for ME/CFS investigators.]

 

Segregate gradual and rapid onset patients.

It is so easy no one can do it.

 

Thanks for summarising the good comments @Michiel Tack - a massive undertaking given the volume of feedback.

I'd just like to add that there were many many comments that reflected the need for biomarker research - that seemed to be the most common theme in the feedback.

 

In my case what I perceived as exercise-induced muscle stiffness and weakness was assessed as motor fatigue only after I had provided a video documenting my temporary strange gait. My neurologist as well as diverse physiotherapists even think my occasional flares of muscle spasms in other parts of the body are caused by motor fatigue.

But as I said elsewhere on the forum, I am not entirely sure whether my ME diagnosis still stands up to rigorous assessment.

I have no clue, but I guess what pwME perceive as faulty power supply could originate in other structures or systems of the body than those primarily responsible for metabolism.

I think it's interesting that some pwME, in particular so called 'mildly' to 'moderately' affected, might experience impairments in different ways or in a different order and to a different extent. Some seem to have primarily difficulties with cognitive fatiguability, others with walking, standing, sitting upright while using their fingers or hands or entire arms works well or better or for a longer period of time.

Again others seem to primarily have issues with gut motility or sensory sensitivities. In my case, almost all of the mentioned symptoms both accumulated and sometimes changed in a remitting-relapsing way.

If there are metabolic factors involved only affecting some parts of the body or some parts of the brain, I guess these could only occur secondary to other disturbances in these regions (in regions of the brain responsible for steering diverse body functions or in regions in the periphery, i.e. the affected body parts as such.)

The primary issues might be related to blood flow or communication processes that for some reason don't work properly in a or between particular body systems (e.g. nerves), thus consuming an abnormal amount of energy that can't be sufficiently supplied by a normal metabolism.

I'm sure this could be put in a simpler way, but don't find better words at the moment.

I hope others will provide a more substantial answer.

 

The problem for me and also for mitochondrial researchers like Mike Murphy is that the time pattern of difficulty with activity in ME does not follow what we know about the way metabolic processes control energy supply.

We know about short term depletion of energy stores within cells during exercise. We also know about longer term depletion in starvation. But PWME find that their exercise tolerance is impaired for some time after muscle usage. I don't think we know of any metabolic condition that has the time pattern.

The best known example of fatiguability is myasthenia graves. MG is not a metabolic problem. It is a problem with depletion of a neurotransmitter signal. Another example would be chronic dermatomyositis - where the problem is muscle cell wastage from inflammatory damage, not metabolic.

Moreover, fatiguability in MG is not associated with discomfort, let alone pain. Pain is not an expected feature of a metabolic problem unless lactate builds up. But then for lactate to have built up there must be ongoing energy production - the system must be working full tilt.

I am not a muscle physiologist but I worked in the department at UCH where muscle physiologists studies all these illnesses in the 1980s and 1990s. They did not find any evidence of a metabolic problem in ME. They might have missed something but it is quite hard to see how they could have missed something producing severe symptoms.

I would be very interested to have someone come up with a metabolic story that fits but I have not heard it so far. Meanwhile, I agree with Murphy that the problem sounds more like a signalling one - discomfort has to come from some form of distress signal.

The other thing that occurs to me is that the problems PWME have with continuing high level activity seem in some ways more like the problems we get with sleep deprivation. The major limit to activity informal people is the sleep cycle. After eighteen hours of physical exertion like sea sailing or cycling most people cannot go on. That is not a metabolic problem but a top down brain signal switch-off.

 

Wow took the words out of my mouth

Which, I assume is why driving for long periods is utterly physically as well as mentally exhausting, despite being sitting comfortably the whole time.

 

that is exactly how I experience ME. Like someone flips a switch in my brain which just brings the entire system to a grinding, & often quite abrupt, halt. Power failure across the entire grid, from making one's limbs/fingers go where I ask them to, to executive function, to making speech come out coherently.
It is so reassuring & encouraging to me, that at least you, seem to have a good grasp of the problem.
Do you think that similarity with the sleep deprivation phenomena could provide any useful clues?​

 

That PEM preferentially kicks in overnight is I think a clue that it's related to housekeeping processes that occur during sleep.

 

Yes, but I don't think I know what they are!

 

Im intrigued because I never heard of it described/pointed out in that way. Perhaps this might be a more fruitful avenue than we've been following so far.
Who might know or be in a good position to investigate what those clues could be? what kind of researcher/expert might know/ or be capable of finding out?

 

Years ago I travelled for 2hrs in the car (as a passenger) and literally couldn't lift my arms for the next 2 days. The motion and rapid eye movements exhausted me.

 

Not sure. So many researchers seem to be chasing bandwagons these days.

Which makes me realise I have no idea where the term bandwagon comes from.

 

That seems to presuppose that we all feel discomfort, or perhaps pain, and I am not sure that it can be true for all. It isn't for me. The damn things just stop working. There is no particular discomfort.

 

Interesting. I am going by what people have said on the forums over the last five years. The overwhelming impression I get is that exertion is unpleasant.

 

yes it has that effect on me too, it makes me so ill I cant get out of the car & takes at least 24hrs before I can get out of bed.
But even as a healthy person I meant (in response to @Barry's comment about expending energy) - I used to spend long hours on the road for my job & loved driving, but the level of concentration needed is exhausting & i'd feel as exhausted as if i'd been standing up all day after driving for 6hrs.

 

Unless i'm in PEM already then it doesn't feel unpleasant initially (unless I stand upright for too long) it only gets unpleasant afterwards. So when well rested I can exert gently happily for a short while - walk slowly from room to room, sit in reclining chair & talk etc, it only gets unpleasant if I do it for too long - at which point it does become unpleasant - feel faint dizzy sick etc- if I don't stop immediately when I feel like that & push on through regardless.. then after a while the 'off switch' will kick in & then a little later the real punishment in PEM with pain & bad flu-like etc will arrive. Attempting to do necessary exertion while in PEM - getting to toilet etc - that's ruddy unpleasant then.
That's where the crossover with @Andy's 'reasonable descriptive model' comes in - it's only if I go over the SEL that it gets unpleasant.

ETA actually that's not strictly true, I do have some symptoms even when well rested & not in PEM, but you get used to living with a certain amount of continuous discomfort same as you get used to tinnitus, & it's all pervasive & 'normal' after this long that I forget to comment on it. All that to say that yes you're right it's unpleasant, but in degrees.