Chemobrain (& CFS): critical review & causal hypothesis [=somatoform via biomed]

[Valentijn]

... contrasting reported perceived cognitive dysfunction with little measured objective cognitive impairement ....

I read one of those studies involving FM. They reached their confident conclusion using a tiny sample, and a single cognitive test. And it wasn't even the normal form of that cognitive test, since they had to explain why the scores were so weird for both patients and controls.

Pretty absurd, since there are many types of cognitive function. I really think Walitt & Company's "disproving" of fibrofog was the intent from the start, with a willingness to deliberately run a bad trial to do it.

 

[Old Bones]

• The authors imply that chemobrain and mecfs/fibromyalgia patients make a lot of their symptoms, contrasting reported perceived cognitive dysfunction with little measured objective cognitive impairement,

Do those symptoms reflect reality?

The authors express great scepticism over whether the problems reported by chemobrain patients are really that bad:

Based on the above theory, does this mean that when I was struggling to keep working post-ME, I only perceived my inability to add three three-digit numbers together with a calculator and get the same answer twice? Or, maybe I had merely developed a pathological psychological response to doing math.

 

[Scarecrow]

In short, he's bat-shit crazy,

Well said!

In this case, you're probably quite right to drop the qualification of "bordering on". You'd only get misquoted anyway.

 

[adreno]

The onset of over-reacting can be triggered by something biological, including genes.

More philosophical bankruptcy. Where does the "over-reacting" reside after the biological anomaly is gone? If it's not in the brain anymore, it must be in the "mind", i.e. a psychosomatic state is created. It's dualistic, magical thinking.

There is no such thing as a mind, or psychosomatic state, existing independent of the brain. A monist acceptable explanation of this phenomenon would be "sensitization", however this would be measurable in the brain. And of course, the evidence we have seen so far does not support the idea of central sensitization.

Basically, he seems to concede that there might be a partially physiological basis for the psychosomatic disorder, but there is no physiological basis for the symptoms being experienced.

Self contradictory, and completely incoherent, meaningless nonsense.

 

[Simon]

Walitt's underlying model of psychosomatic disorders (based on reading 10-12 of his papers), seems to be that basically:

Respect. It's taken me two days to wade through just the one. But I reached several of the same conlusions just from that one.

There is no damage or ongoing pathology....

Physiological differences are associated with the psychosomatism, but are also somehow normal and not indicative of a neurological or other biological disorder.

...Basically, he seems to concede that there might be a partially physiological basis for the psychosomatic disorder, but there is no physiological basis for the symptoms being experienced.

It's all a bit muddled from Walitt, and I'm trying to tease it out..

These quotes from the chemobrain paper

We hypothesize that acute shifts in cytokines related to chemotherapy administration lead to epigenetic alterations. These epigenetic changes persist after the resolution of the chemotherapy-induced immunologic changes and are primarily responsible for creating and maintaining changes in neuroplasticity that underlie the somatoform experience of chemobrain.

So they are pointing the finger at cytokine changes as initiating things. But note

Chemotherapy, or the psychological ramifications of cancer treatment, may simply be one of a variety of “triggers” that ultimately lead to dyscognition.

Also: ...We hypothesize that acute shifts in cytokines related to chemotherapy administration lead to epigenetic alterations.

So maybe they are arguing that both chemotherapy and psych stress trigger a biological cascade, that leads to the "experience" of chemobrain. ie:

chemo => cytokine spike => long-term epigenetic changes => experience of chemobrain
as well as
psych stress => cytokine spike => long-term epigenetic changes => experience of chemobrain

What isn't clear to me is this claim that somehow the long-term epigenetic changes* is non-pathological. (*or whatever, there is mcuh less evidence for this claim than the more traditional and more specific idea of activation of microglia, the brain's immune cells)

They claim these epigenetic changes "create and maintain changes in neuroplasticity", yet are also normal. But I can't see any elaboration on the idea, let alone evidence. It's a black hole at the centre of the paper. There's just this

A somatoform view of chemobrain would consider it as an atypical yet predictable subjective experience that result from the normal functioning of the brain rather than from an injury

But that's just a vague assertion: they don't propose a clear biological or psychological mechanism, or why this is normal and not pathological.

This is all the evidence for the role of cytokines in chemobrain

Multiple clinical studies have demonstrated that administration of a standard dose of chemotherapy causes increases in cytokine levels such as TNF-α, IL-6, IL-8, IL-10, and MCP-1in cancer patients and that these changes are more prominent in patients who experienced dyscognition

Looking at data where I could find it, the changes generally aren't that big and clearly they occur in all patients not just those who go on to develop chemobrain. So could the extra small increase explain chemobrain? The authors don't explore or explain, but it's hardly compelling.

Bit more on how mecfs is just like chemobrain:

The state of the evidence for chemobrain strongly resembles that which is seen in fibromyalgia and chronic fatigue syndrome. Like chemobrain, patients with these illnesses experience subjective and clinically distressing dyscognition, with attention, concentration, forgetfulness, word-finding, multi-tasking, and organization being the most common complaints. Also like chemobrain, measurements of objective neuropsychologic function frequently fail to demonstrate impairment and what is seen in positive studies is of small clinical magnitude [40–42].

Both of these illnesses have disputed causal triggers, such as trauma in fibromyalgia and infection in chronic fatigue syndrome, whose validity is also not answered by the scientific literature to date.

You'd think they'd read the literature before writing an article that suggests a cause of the illness (see eg Dubbo ref in my last post as good evidence of a causal trigger in some cases of mecfs).

As for the importance of cytokines in inducing chemobrain, it's not that clear

Overall, it looks to me like a bit of a vague hypothesis with little evidence, that somehow the authors decide to attach to a different condition. Maybe if they could nail their hypothesis in chemobrain first, they could then think about clearly explaining why it might be relevant to other diseases/illnesses/"misperceptions".

added more from paper on role of cytokines:

In summary, there is strong evidence that correlates changes in peripheral cytokines with the development of dyscognition in the setting of many if not all commonly used chemotherapeutic drugs for different types of cancer [64,76,78,83]. The changes are typically heterogenous, with small magnitude of change being seen in multiple cytokines simultaneously. However, the mechanisms by which these cytokines elicit change in the central nervous system are still unclear. We speculate that a variety of well-defined neuronal mechanisms enable peripheral cytokines to induce central cytokine changes, which trigger a subsequent cascade of neurological events as described below that lead to the experience of chemobrain [64,76–78,83].

But 'below' is the generic info on epigenetics that adds little of substance: just says epigenetics happens and describes the biochemistry of epigenetics, as well as saying there is some evidence of epigenetic changes being involved in both stress and brain pathologies:

Emerging studies indicate that epigenetic regulation of gene expression is involved in various brain-related disorders, such as addiction, depression, stress, and Alzheimer’s disease, that genetics alone cannot entirely explain [86–89]

But that's a bit like saying gene expression is involved in Alzheimer's, stress etc. So what?

 

[adreno]

What isn't clear to me is this claim that somehow the long-term epigenetic changes (or whatever, there is mcuh less evidence for this claim than the more traditional and more specific idea of activation of microglia, the brain's immune cells) is non-pathological.

Either it's pathological changes causing pathological behavior, or it isn't. You simply can't have non-pathological changes (i.e. normal variations) causing pathological behavior. You (the authors) haven't explained shit. Pathological behavior doesn't exist in some ontological vacuum independent of brain state. It's magical thinking. If the brain state variations are within normal range, then what explains the pathological behavior?

 

[user9876]

It's all a bit muddled from Walitt, and I'm trying to tease it out..

The bit muddled is the think that really worries me. Vague or badly stated theories are not good from someone undertaking a study. I tend to think even if there is a exploratory study of data collection there needs to be some sort of clear conceptual framework for what to look at and why and what different hypothesizes may be explored.

 

[Bob]

I think the muddle in this paper (that none of us can follow) is what you get when you try to fit a biological process into a somatoform framework. It doesn't fit. Everything just buckles and cracks.

 

[barbc56]

@Simon @Bob @Valentijn and everyone else who went through this very confusing study and/or added points to the discussion.. Your time and effort are certainly appreciated!

I had a hard time getting past the title but from what others here are writing, it looks like the author is comparing two things that really aren't comparable. Then to make matters worse, he somehow manages to mess up each health condition? It would have taken forever if I tried to go through this, so again, thanks!

The picture of the black hole certainly sums up the worth of this study. Visual aids are always appreciated,

In short, he's bat-shit crazy, just like all the other psychobabblers

So succinct yet so accurate.

ETA
Oh dear, I seemed to have missed page two. Hopefully, the above still makes sense.

This paper could be used as a bad example in any study design or related course.

 

[Sea]

Based on the above theory, does this mean that when I was struggling to keep working post-ME, I only perceived my inability to add three three-digit numbers together with a calculator and get the same answer twice? Or, maybe I had merely developed a pathological psychological response to doing math.

When someone rings wanting to speak to my husband and I can't tell them where he is or when he'll be back, is that a subjective experience of forgetfulness?
I can pull it together and pass a neurocognitive test on a reasonable day with hyperconcentration like you would for an important difficult exam, but I can't live like that. The aftermath of such concentration is terrible payback. I would certainly fail a longer test.

Oh for researchers who would actually listen to what we're saying our difficulties are and devise tests that would capture them properly instead of giving standard tests and saying everything is normal

 

[Old Bones]

I can pull it together and pass a neurocognitive test on a reasonable day with hyperconcentration like you would for an important difficult exam, but I can't live like that. The aftermath of such concentration is terrible payback. I would certainly fail a longer test.

@Sea Here's an example. Pre-ME, I was quite an accomplished pianist (before I "lost my brain"). However, I had never taken music theory exams. No longer working, and with lots of time on my hands, I decided it was an opportunitiy to make my theory credentials match my practical abilities. I started a self-study program -- Theory Grade 1 -- and prepared by doing practice exams. Unfortunately, I consistently went from getting every answer correct, to every answer incorrect, without realizing it, at about the 20-minute mark -- a definite problem for an exam that would last an hour. The work-around I devised was this -- lightly penciling "cheat" notes at the top of the page (to be erased before handing it in) while I still had use of my brain, and practicing over and over again until I could quickly complete the exam in 20 minutes or less. This strategy worked. I got 100 percent. But the broader problem is this . . . One can't rehearse every action involved in day-to-day living, whether required for employment, managing a household, or even socializing. Here lies some of the disability associated with our illness. Those who see us behaving "normally" for certain tasks, and for short periods of time, don't realize what we have to do to accomplish this, and that it isn't sustainable.

 

[Snowdrop]

Pretty absurd, since there are many types of cognitive function. I really think Walitt & Company's "disproving" of fibrofog was the intent from the start, with a willingness to deliberately run a bad trial to do it.

Does he than have published papers that might warrant a retraction?

 

[Valentijn]

Does he than have published papers that might warrant a retraction?

Probably, but it never happens.

 

[Mary Schweitzer]

What concerned me the most was this sentence: "The discordance between the severity of subjective experience and that of objective impairment is the hallmark of somatoform illnesses, such as fibromyalgia and chronic fatigue syndrome.” Note he just accepts as common knowledge that CFS and fibro are "somatoform."

 

[deboruth]

I've finished rereading this study and found it very hard to comprehend, not least because the authors seem to be avoiding clearly stating their beliefs. Here's what I came up with

Commentary (summary first)

• The authors imply that chemobrain and mecfs/fibromyalgia patients make a lot of their symptoms, contrasting reported perceived cognitive dysfunction with little measured objective cognitive impairement,
  
• They propose the well-known hypothesis that temporary spike in cytokines related to chemotherapy treatment could lead to long-term changes in the brain responsible for chemobrain
• What's novel about their hypothesis is the assertion that all this is in the range of 'normal' ie this is a natural 'physiologic' process rather than abnormal patholgy (thanks, @Bob).
  
• They suggest that the psychological stress of chemo (and cancer) may play a role too
• They argue the long-term changes may be epigenetic (many long-term changes in the body are), but emphasise the mind and brain are intertwined ie explicitly avoid arguing for a biological driver

But the biggest concern I have is they take an unproven hypothesis about chemobrain, and effortlessly equate it with mecfs (and fibro) - then assert that studying chemobrain could reveal what causes mecfs. As opposed to, say, studying mecfs as it emerges.

They suggest the 'post-infectious' trigger of mecfs could be down to recall bias and seem unaware of the numerous prospective studies eg of glandular fever that track the development of mecfs, eg the Dubbo studies (below). Perhaps that's why they ignore the possibility that such postinfectious studies are both practical and a much more approrpiate, direct approach.
(Dubbo study: Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study | The BMJ)

Notes (work in progress)



Do those symptoms reflect reality?

The authors express great scepticism over whether the problems reported by chemobrain patients are really that bad:


They go on to doubt that methodological issues are behind the failure to find cognitive problems, which implies the issue is one of perception by pateints who don't really suffer from what other people would regard as problems.

So let me fish out that Susan Cockshell study finding one more time, that hints at a more appropriate way to measure cognitive problems


Contrasting pathogenic "neuronal injury" with "somatoform" normal functioning




Now with added epigenetics!
I'm not sure invoking epigenetics adds anything.


In a recent talk, George Davey Smith described epigenetics as 'the confused researchers friend': can't explain something? Just say it's epigenetics... It could be, but basically we still have a black box of a brain: changes in cytokines in the body somehow leads to changes in the brain, that leads to 'cognitive dysfunction'. But what's driving it?

Here is the now-familiar 'mind/body dualism is simplistic and wrong' cliam:


More later.

Maybe. I find this all rather demoralising; it seems a step back rather than forward.

 

[deboruth]

I think we should put together all of the incompetent and inappropriate government employees with evidence of their incompetence (including new Tuller proof on fraudulence of GET and CBT endorsements), point out that all must be eliminated and follow up with communication to Congress as appropriate (certainly for Walitt) pointing out that these people are not serving the interests of the US and its citizens as they swore to do and that they must be dismissed from the government payroll as there is no justification for taxpayers to continue supporting do-nothing lazy bones. E.g., Walitt in one of his studies slandering "cfs" perhaps chemobrain, used only one source on cfs -- 1988 Holmes. Unbelievable. We need a short background of what Tahoe really was -- ME-- and the true history of ME as most often pathogen initiated. And we should get decent scientists to call for retraction of all the dumb papers and notify the public as to the effort. We are sick of being victimized by this garbage; every American taxpayer is sick of paying for garbage.

 

[deboruth]

I agree. Not only did the "paper point in two contradictory directions", Walitt's interview seemed to as well. I watched the entire video, and found the content to be a confusing, jumbled mess. My opinion of what he was saying repeatedly switched from agreement (that he was "on our side"), to indignation (that his views were "way off base"), and back to at least partial agreement. In the end, I was left wondering if even he knew what he thought.

That's not bad news, that's good news: makes it easier to explain what we are complaining about.

 

[barbc56]

@

That's not bad news, that's good news: makes it easier to explain what we are complaining about.

So funny and yet so true!

It can be so hard to remember there are good people out there. We need them.

 

[Ecoclimber]

Also consider the fact that changes could be made to the ICD codes which means it would be harder to file for SSDI

This was mention on a possible coding change on the dxrevsionwatch blogsite
http://dxrevisionwatch.com/2015/08/...ssification-of-chronic-pain-in-icd-11-part-2/
On May 5, 2015, the ICD-11 Beta draft category, Fibromyalgia, was deleted from the “Diseases of the musculoskeletal system and connective tissue” chapter and relocated under “Symptoms, signs, clinical forms, and abnormal clinical and laboratory findings, not elsewhere classified”.

The inherent issue with misinterpretating epigentics research
"New age gurus such as Deepak Chopra cite epigenetics as a way of changing your life, under the false supposition that genes are destiny, and epigenetic changes brought on by lifestyle choices such as meditation “allows us almost unlimited influence on our fate”. Well, no: that sandwich you just ate has changed the expression of your genes too."

The NIH has already conducted extensive research on chronic fatigue, fibromyalgia, chronic pain, cancer and ms fatigue. They found no abnormalities that would be classsified as biological pathophysiology. This is not only with Wallit but Catherine Bushnell postions as well. The interpretation of the results is the key. Biomedical reductionism is a huge concern.

 

[RustyJ]

The NIH has already conducted extensive research on chronic fatigue, fibromyalgia, chronic pain, cancer and ms fatigue. They found no abnormalities that would be classsified as biological pathophysiology. This is not only with Wallit but Catherine Bushnell postions as well. The interpretation of the results is the key. Biomedical reductionism is a huge concern.

Bushnell looks to be a key puppet-master of this study.