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New Klimas Paper- NPY, Stress, HPA Axis and CFS

Messages
61
Willow...look at this link for the history of this field:

http://www.nfnlp.com/psychoneuroimmunology_quinlan.htm

An excerpt:

It is possible then, that when there is stress on the organism, mental or physical, that there is a corresponding link between the two. That is to say, if a person has a mental state of depression, this state can be interpreted by the body to produce lethargy and other corresponding ailments. Conversely, if the body is diagnosed as ailing from a serious disease, i.e. cancer, a negative mental state may ensue. By conditioning the immune system through mental processes a connection in communication has been made. Providing the patient with some feeling of control over their circumstances may create a positive outlook and attitude. Some believe that this may, "Inoculate against disease and act as a valuable supplement to conventional medical care."

Psychoneuroimmunology then is the scientific field of study investigating the link between bi-directional communications among the nervous system, the endocrine (hormone) system, and the immune system and the implications of these linkages for physical health.
 

Angela Kennedy

Senior Member
Messages
1,026
Location
Essex, UK
Man this thread is ridiculous, do you want to learn more about this disease or do you want to selectively hear only what supports your agenda? Its new data and it's interesting, take it for what it's worth. Just because CFS is a physiological disorder with infectious causes doesn't mean there isn't ALSO mental stuff going on (as a secondary consequence) that may be correlated with various biomarkers. For crying out loud.

Yeah, right - have you not seen the mention of causation fallacies on your journey through this thread? Do you not know THIS is a key problem in ME/CFS research? If we accusing others of 'agendas' now - what 'agenda' do YOU have?
 

Angela Kennedy

Senior Member
Messages
1,026
Location
Essex, UK
"By conditioning the immune system through mental processes a connection in communication has been made."

Exactly how does that work???

Well that's the interesting thing - they don't know, and may never. But fallacious special pleading around ME/CFS as a psychogenic illness (by default due to medical uncertainty, by the way) away from other organic illnesses is a key aspect of this approach, and they would rather spend time and money following what is a wild goose chase then study ME/CFS as an organic illness.
 

Angela Kennedy

Senior Member
Messages
1,026
Location
Essex, UK
Well that's the interesting thing - they don't know, and may never. But fallacious special pleading around ME/CFS as a psychogenic illness (by default due to medical uncertainty, by the way) away from other organic illnesses is a key aspect of this approach, and they would rather spend time and money following what is a wild goose chase then study ME/CFS as an organic illness.

By they, I mean governments, psychiatrists, other doctors, the MRC, etc. etc.

Re Klimas - I've noticed a lot of scientists and doctors who people see as 'the good guys' (a way of looking at things which is misguided I think) saying things or taking part in projects which are flawed and psychobabbly. The community faces a lot of cognitive dissonance when faced with this. I would advise the community to stop looking for heroes. These people are mostly working to further careers and research interests. This means they get involved in woefully poor science authored by promoters of psychogenic explanations. I don't hink we can 'trust' Klimas to be painting a bigger picture by this project necessarily - if, by the sound of her email, she doesn't understand what might be wrong with this latest project she put her name to. So, some of us will have to critique work she's involved in - the same goes for Kerr, Weir, Newton, as just a few examples.

I have no emotional ties to any of the scientists and doctors in this field. I don't see them as villains or heroes, just part of a flawed system, which makes it easier to critique their claims and methods when that needs to happen.
 

Angela Kennedy

Senior Member
Messages
1,026
Location
Essex, UK
we want to learn about this disease and we want this disease to be taken seriously. At the moment and for the past 25 years and counting (USA) and much longer (UK), the theory that stress and maladaptive coping causes this disease has prevented this disease and therefore any patient labelled with CFS (correctly or misdiagnosed, doesn't matter) from being taken seriously.

Meaning the patients are ridiculed and fail to get medical care for this condition or any other condition they may happen to have, especially if the other condition has symptom overlap (asthma, for instance). In some cases the patient abuse is even much more serious than this. Patients also have trouble getting social support or disability aids.

Perception of the disease also influences whether any researchers are interested in the disease and how much funding is available (and whether even the small amount of funds will actually be spent productively or whether it will be frittered away and diverted to other things).

How a disease is percieved is very serious, because the consequenses to the patients are very serious.

The question isn't whether there may be secondary stress (there is, just the same as in any other chronic debilitating disease).

The question is: did the paper do a good job of explaining what ME/CFS is (because that explanation is so badly needed) or what they meant by the terms they used? The Discussion was pretty good but the Background was dismal. Since the background comes right at the beginning, this is a problem. Also since the buzzword "maladaptive coping" was used without explaining what the authors meant (they evidently didn't mean the usual; Klimas interpreted it to mean "pushing through"), that's a very serious problem because it won't be interpreted in this way.

Nice explanation Willow.

I wish there was a 'like' function on this forum for posts like these.
 

Enid

Senior Member
Messages
3,309
Location
UK
Thank you for an interesting discussion. I quite agree anything pyschobabbly is not only erroneous but could tempt that lot back in. So much caution I feel should be given to findings and reporting in this type of research. But a biomarker (not the cause) may aid.
 

biophile

Places I'd rather be.
Messages
8,977
Slippery slope on the mountain of speculation

The impression I receive from this paper: NPY is involved in the neurobiological stress system and associated with a range of conditions. Elevated NPY somewhat correlates with "perceived stress, anger, depression, negative thoughts and maladaptive coping" in CFS patients. There is mention of a connection between dysregulation of the immune and neurobiological stress systems, but they do not appear to speculate much about the direction of causation in regard to the psychological symptoms (others will no doubt be doing such speculating though) but they hint that elevated NPY may be due to infection, immune activation and inflammation. I have no idea if hypocortisolism would be more or less of a problem in CCC defined CFS.

However, the lack of clarification on "symptoms" is disappointing because in the Background section text there is talk of "CFS symptoms" and "clinical symptoms", but as others have already pointed out the results focus is on psychological and psychosocial measurements. It is possible that physical symptoms help to explain the reported correlation of NPY with "general health" and "fatigue disruption rating" but these measurements are probably influenced by psychological symptoms as well. They talk about hypocortisolism in CFS, but we don't know if this actually relates to psychological symptoms and the elevated NPY, and they failed to emphasize enough that hypocortisolism is far from being a universal finding in CFS.

It is unclear how useful or helpful a "stress related NPY elevated" subset would be, it seems problematic, especially without knowing the cause of elevated NPY, with significant overlap of NPY levels with healthy controls, and questionable relevance to CFS, as well as the usual issues with measuring or interpreting "stress". Suppose a CFS patient with normal NYP goes through a rough stressful year so their NPY and negative psychological symptoms are elevated, then the rough year is over and things returns to baseline. Are we supposed to believe that such a patient temporarily had a different subset of CFS? Suppose another patient has elevated NPY and is therefore told they fit into the "stress related" subset even if they don't feel stressed, are we supposed to believe they need stress reduction techniques anyway?

People with temporary influenza who are otherwise healthy often appear irritable and more "vulnerable" to psychosocial stresses, probably because they feel terrible and may also have immune-mediated changes to cognitive function etc. CFS is often described as feeling like a permanent influenza, and the prolonged duration of years or even decades as opposed to mere days or weeks would have additional downstream consequences. Using that comparison, I don't have a problem with the possibility that CFS partly involves an immune-related dysregulation of neurobiological stress system which worsens the effects of the psychosocial stresses imposed on patients by the devastating effects that CFS has on their lives.

What I am uncomfortable with is how related research and speculation typically get simplistically generalized to justify hypothetical "mind over body" mechanisms in all CFS patients by default even when the findings are far from universal and the supposed relationship with "stress" is still unclear. Hypocortisolism for example is frequently employed to help explain so-called "effort/stress intolerance" and other symptoms in CFS (eg like Van Houdenhove et al 2009 as cited by this new Fletcher/Klimas paper), but as far as I know such HPA axis abnormalities reported in the CFS literature are usually relatively mild and non-uniform, usually found in a minority of patients, don't usually exist until years into the illness, and are possibly related to reduced activity. Also note that, like elevated NPY, HPA axis disturbances are also found in infectious and auto-immune diseases, they are not restricted to so-called functional illnesses and mental disorders as some people may have you believe.

There are so many unresolved issues relating to CFS criteria, the concept of stress, and so-called psychoneuroimmunological mechanisms, it is an interesting but extremely slippery slope which must be approached with great care.
 

Angela Kennedy

Senior Member
Messages
1,026
Location
Essex, UK
The impression I receive from this paper: NPY is involved in the neurobiological stress system and associated with a range of conditions. Elevated NPY somewhat correlates with "perceived stress, anger, depression, negative thoughts and maladaptive coping" in CFS patients. There is mention of a connection between dysregulation of the immune and neurobiological stress systems, but they do not appear to speculate much about the direction of causation in regard to the psychological symptoms (others will no doubt be doing such speculating though) but they hint that elevated NPY may be due to infection, immune activation and inflammation. I have no idea if hypocortisolism would be more or less of a problem in CCC defined CFS.

However, the lack of clarification on "symptoms" is disappointing because in the Background section text there is talk of "CFS symptoms" and "clinical symptoms", but as others have already pointed out the results focus is on psychological and psychosocial measurements. It is possible that physical symptoms help to explain the reported correlation of NPY with "general health" and "fatigue disruption rating" but these measurements are probably influenced by psychological symptoms as well. They talk about hypocortisolism in CFS, but we don't know if this actually relates to psychological symptoms and the elevated NPY, and they failed to emphasize enough that hypocortisolism is far from being a universal finding in CFS.

It is unclear how useful or helpful a "stress related NPY elevated" subset would be, it seems problematic, especially without knowing the cause of elevated NPY, with significant overlap of NPY levels with healthy controls, and questionable relevance to CFS, as well as the usual issues with measuring or interpreting "stress". Suppose a CFS patient with normal NYP goes through a rough stressful year so their NPY and negative psychological symptoms are elevated, then the rough year is over and things returns to baseline. Are we supposed to believe that such a patient temporarily had a different subset of CFS? Suppose another patient has elevated NPY and is therefore told they fit into the "stress related" subset even if they don't feel stressed, are we supposed to believe they need stress reduction techniques anyway?

People with temporary influenza who are otherwise healthy often appear irritable and more "vulnerable" to psychosocial stresses, probably because they feel terrible and may also have immune-mediated changes to cognitive function etc. CFS is often described as feeling like a permanent influenza, and the prolonged duration of years or even decades as opposed to mere days or weeks would have additional downstream consequences. Using that comparison, I don't have a problem with the possibility that CFS partly involves an immune-related dysregulation of neurobiological stress system which worsens the effects of the psychosocial stresses imposed on patients by the devastating effects that CFS has on their lives.

What I am uncomfortable with is how related research and speculation typically get simplistically generalized to justify hypothetical "mind over body" mechanisms in all CFS patients by default even when the findings are far from universal and the supposed relationship with "stress" is still unclear. Hypocortisolism for example is frequently employed to help explain so-called "effort/stress intolerance" and other symptoms in CFS (eg like Van Houdenhove et al 2009 as cited by this new Fletcher/Klimas paper), but as far as I know such HPA axis abnormalities reported in the CFS literature are usually relatively mild and non-uniform, usually found in a minority of patients, don't usually exist until years into the illness, and are possibly related to reduced activity. Also note that, like elevated NPY, HPA axis disturbances are also found in infectious and auto-immune diseases, they are not restricted to so-called functional illnesses and mental disorders as some people may have you believe.

There are so many unresolved issues relating to CFS criteria, the concept of stress, and so-called psychoneuroimmunological mechanisms, it is an interesting but extremely slippery slope which must be approached with great care.

Thanks biophile,

Nice analysis of the problem. I think this is indeed a 'slippery slope' issue which should be approached with great care - but currently isn't. Sadly, every piece of flawed research just adds to the edifice of psychogenic explanation, with all it's confusion of concepts and character denigration of patients.
 

alice1

Senior Member
Messages
457
Location
Toronto
Klimas is one of several docs I see and I take everything all of them say with a grain of salt.But I would like to add that Dr Klimas is the only doctor with whom I've met over the past 24 years whose given me a straight answer to questions I ask even if she doesn't know the answer.I don't regard her as a hero nor does she ever give me the impression she sees herself as one.
It would of been great had she written the study herself as it may have included a better interpretaion..Who knows.
 

Cort

Phoenix Rising Founder
did hear back from Dr. Klimas who was kind and replied to my somewhat grumpy email, and she noted that she was not the lead author so had not written the manuscript, and that some of the others use "psychology speak" (although she doesn't feel they are coming at it from a psychogenic or Wessely school standpoint), but that no subgroup is being left behind,

They've looked at a variety of possible markers over the years. NPY is certainly a tenable one given the evidence of sympathetic nervous system dysregulation and its connection to other issues and to the CD26 immune marker and it some extent you have to follow the research where it leads; if its there - its there.

When I see NPY possibly linked to immune dysregulation, POTS and autoimmune disorders - I think even better.

I don't mind the stress connection as much - at least for me it fits at least to some degree and I recognize that it doesn't fit for other people and its a very problematic term (we seem to specialize in those) given our history. It distorts things and lessens the severity of the disorder in many peoples minds - it sucks!

I don't fit criteria for depression or anxiety (and like many I have seem psychs in my journey with CFS) but the irritability, difficult focusing, difficulty calming down is definitely a feature of this disorder for me. So when I see a biological marker that could help explain those problems I tend to think - good!

The NPY connection could help in an odd way because if you can carve out an NPY subset then you can then concentrate on people with different problems. ELevated NPY wasn't found in everybody and it appears to have lots of other ramifications as well - my guess is that these go hand in hand with this sympathetic nervous system arousal and as they continue to dig deeper into NPY and its connections in CFS things will blossom. I hope this is like a rough entry into a potentially valuabe area.

One problem is that it easier to give somebody a questionnaire than to dig into their biology and that too often happens.

I'm glad Dr. Klimas didn't write the paper; I think she would have approached it and written it differently. Ifelt the conclusions section was really not very well done - it seemed off to me....not well written, not very conclusive...:)
 

Cort

Phoenix Rising Founder
I would advise the community to stop looking for heroes. These people are mostly working to further careers and research interests. This means they get involved in woefully poor science authored by promoters of psychogenic explanations. I don't hink we can 'trust' Klimas to be painting a bigger picture by this project necessarily - if, by the sound of her email, she doesn't understand what might be wrong with this latest project she put her name to.

I wholeheartedly agree about not looking for hero's. Researchers have a duty to publish their results no matter what they are - which can be difficult when the results do not turn out how we want..and there goes our 'hero'.

I think Dr. Klimas can be trusted to paint a bigger picture of this disorder. She's collaborated with Dr. Fletcher for decades and both of them have been the key figures in documenting the immune problem in this disorder - natural killer cell function. We would not have natural killer dysfunction documented if not for them. I cant think of another paper she's co-authored that has raised any concern at all.
 

WillowJ

คภภเє ɠรค๓թєl
Messages
4,940
Location
WA, USA
I wholeheartedly agree about not looking for hero's. Researchers have a duty to publish their results no matter what they are - which can be difficult when the results do not turn out how we want..and there goes our 'hero'.

I think Dr. Klimas can be trusted to paint a bigger picture of this disorder. She's collaborated with Dr. Fletcher for decades and both of them have been the key figures in documenting the immune problem in this disorder - natural killer cell function. We would not have natural killer dysfunction documented if not for them. I cant think of another paper she's co-authored that has raised any concern at all.

I wholeheartedly and unreservedly second the motion of trust. Dr. Klimas has untiringly looked for answers and has been finding some very good ones. When she does write the manuscripts she explains our disease quite well. Dr. Fletcher also has been working on immunological answers.
 
Messages
61
When I see NPY possibly linked to immune dysregulation, POTS and autoimmune disorders - I think even better.

Me too. I was... and still am... looking at the science of this. Sometimes we have to wade through the muck to find a pearl or two.

Klimas.... I don't know enough about her personally to give her a thumbs up or down. I have some catching up to do.

Heroes... they are like the rest of of. They have feet of clay.

I did find this on NPY...

Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic [antianxiety] peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.

I added the [antianxiety]

http://www.nature.com/nature/journal/v452/n7190/abs/nature06858.html
 

lancelot

Senior Member
Messages
324
Location
southern california
Klimas.... I don't know enough about her personally to give her a thumbs up or down. I have some catching up to do.

Dr Klimas gets a thumbs up from her overall CFS work but a thumbs down in this particular study, but always remember she is here for US. She is a good person trying to do what is right. We can help her not to get involved in bad phsycobabbly studies by criticizing this study and emailing her our objections as WillowJ has done. Dr Klimas will not make that mistake again! patient pressure and lobbying works!
 
Messages
61
Thanks Lancelot.

I think it might be wise to read the PDF of this paper. While it is not as strong as I would like for it to be, it does mention the possibility of NPY being elevated due to viral infection.
 

Marty

Senior Member
Messages
118
Quote from Lancelot: Dr Klimas gets a thumbs up from her overall CFS work but a thumbs down in this particular study.

I agree. Come on, Klimas can't put her name on a paper and then claim she's not responsible for it.
 

Dolphin

Senior Member
Messages
17,567
One problem is that it easier to give somebody a questionnaire than to dig into their biology and that too often happens.
I agree.
We need more biology, less questionnaires. For example, in this study it would have been interesting to know whether the results correlated with other biological measures or not.

Academic discussions are interesting. But it's biological/biomedical research that will give us the progress we want.
For that, researchers need money. Questionnaire research can be done cheaply.
 

Dolphin

Senior Member
Messages
17,567
Not really. First, they only had data on 42 CFS patients. Second, they looked mainly at psychological factors and not at the more physical measures such as the SF36 Role Physical and Physical Functioning sub-scales. The only SF36 measure to correlate with p<0.05 (the standard level of significance in studies) is the General Health sub-scale which other studies have shown correlates only weakly with CFS severity. OR put another way, they haven't measured CFS illness severity very well, and they've only used a small sample so it's all a bit of a waste of time and space. Guess I'm not feeling very charitable post-Christmas.
I'm not sure it is true that they only measured 3 of the 8 SF-36 subscales.
• The Medical Outcomes Survey Short Form-36 (SF-
36) assessed health-related quality of life including:
limitations in social activities, emotional problems
and general health [37].
I think "including" is the crucial word. If they were looking for just mental health measures, I would imagine they would have used both the "role emotional" and the "mental health" subscales.

But only three of the scales are listed in those scales that had "Pearson Correlations (with p < 0.1) ... with Plasma Neuropeptide Y".

Like oceanfree says, physical functioning and role physical are the more interesting ones in terms of physical functioning in CFS. So if they were measured but did not correlate much, then it would suggest NPY is not necessarily a good measure of SF-36 severity.

Somebody could write to the authors to double-check.

eric_s said:
Is it possible to say how likely it is (in a number) that the difference in NPY values between ME/CFS and healthies they have found is due to chance? What i also think would be interesting is if there was data about people suffering from depression, for example, if they also have elevated NPY.
Sorry, my stats isn't up to this but from what I know their findings on CFS vs healthy are not clinically useful. Just look at the data on page 27 to see the overlap between healthy and patients.
There is an average difference across the range of values that is not due to chance (see Table 1).

However, no particular value has a particularly good sensitivity and specificity (one is basically looking for the largest value above the diagnonal line).
 

Dolphin

Senior Member
Messages
17,567
(OT?) Criteria revision

Sam Carter said:
The definition they use isn't Reeves' Empirical Definition (2005) but one I haven't seen before:

Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution.

Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, Bleijenberg G, Evengard B, White PD, Nisenbaum R, Unger ER; International Chronic Fatigue Syndrome Study Group.

BMC Health Serv Res. 2003 Dec 31;3(1):25.

that's the one where they discuss exclusion criteria (and I think they decided to allow past history of psychiatric-classified disorders if they were considered resolved or controlled, but I don't recall for sure)

WillowJ later:
Permanent psychiatric exclusions include lifetime diagnoses of bipolar affective disorders, schizophrenia of any subtype, delusional disorders of any subtype, dementias of any subtype, organic brain disorders, and alcohol or substance abuse within 2 years before onset of the fatiguing illness. The 1994 case definition stated that any past or current diagnosis of major depressive disorder with psychotic or melancholic features, anorexia nervosa, or bulimia permanently excluded a subject from the classification of CFS. Because these illnesses may resolve with little or no likelihood of recurrence and only active disease or disease requiring prophylactic medication would contribute to confusion with evaluation of CFS symptoms, we now recommend that if these conditions have been resolved for more than 5 years before the onset of the current chronically fatiguing illness, they should not be considered exclusionary.

Contrast this with the sleight of hand in the Reeves et al, 2005 paper:
Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue syndrome--a clinically empirical approach to its definition and study.
BMC Med. 2005 Dec 15;3:19.
http://www.biomedcentral.com/1741-7015/3/19
Following recommendations of the International CFS Study Group*, only current MDDm was considered exclusionary for CFS.
* that's the Reeves et al, 2003 paper.

Why would he and the others not even follow their own paper?
I think it was to be able include more of these people who previously had MDDm i.e. not a good reason.
The specific reason I think was the following: when they took in the people who they had followed from 1997-2000 in 2003 (note: papers weren't published till 2005 on) for a barrage of testing, they found they had few CFS cases (10-16), out of the 227 people they invited in. They did all sorts of fancy tests on these people (the exercise cost $2m from what I hear) but it was going to be difficult to produce CFS papers especially as some patients were being excluded for one reason or another from some tests e.g. were on medications, problem with sample, they were male, etc. It would be a scandal if they didn't produce CFS after spending that amount of money from the CFS budget. The CDC CFS program had already gotten into trouble with Congress for not spending some of its allocation on CFS research.
Increase the number of people with CFS by broadening the definition and there is suddenly no problem about not having enough CFS cases.