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

[WillowJ]

I don't have any problem with this...this fits me to a T and I'm very happy to have found a biological marker that may help with my 'system arousal', irritability, cognitive problems, etc. By the way guys - my understanding - if my memory is right and it could be wrong - is that she ties NPY upregulation to an immune defect.... (Either that or she ties them the other way around).

And there are others in your subgroup.

But there are others in my subgroup, too, who just don't find any correlation between stress and our disease (other than that having a chronic disease causes a certain amount of stress--which doesn't make this a stress-related disease; and this disease in particular makes certain kinds of stress harder to deal with, especially if there's any adrenalin involved--which still doesn't make this a stress-related disease).

And studying the stress connection in your subgroup at this point in time will reinforce negative stereotypes and stymatizing myths, even if that wasn't intended, even if linked to a real biomarker. The psychobabble crowd will either ignore the biomarker or make an ad hoc fallacy incorporating it into their model (like they have done with cytokines).

And it still doesn't explain why their background reads like most of it was written by William Reeves, James Jones, or Samuel Harvey.

edit: background sounding like it was written by Reeves, etc. was probably an overreaction on my part, due to higher expectations given Klimas and Fletcher's names on the study and given that I don't normally read psychology studies other than those related to CFS, and particularly given the politicized environment surrounding ME/CFS at the current time (and that a huge part of that politicization is the fraudulent idea that stress and maladaptive coping, such as focusing on symptoms [or even on "normal bodily processes" erroneously believed to be symptoms] and believing one has a serious debilitating physiological disease which should be treated with rest/pacing, cause the disease instead of an organic disease process).

The paper did leave a lot to be desired as far as explaining what the disease was (which, in my opinion, should be done at every opportunity--although possibly they had a better chance of being published without), and as far as being careful to define what they meant by terms which have standard uses in CFS (standard uses which were established by the Wessely crowd) but which this study was using differently.

The focus on excacerbation via stress was understandable given that they were specifically talking about those patients who have a worse response to stress (patients who do exist), but this was still a little confusing to me given the points that 1) they were also talking about a group who doesn't respond to CBT (if you can't remediate it through psychotherapy, it's doubtful that psychosis played any significant role, even in an exacerbatory role) and 2) they were talking about a biomarker they tied to a viral infection (also doubtful that stress plays a role, even in an exacerbatory function).

 

[lansbergen]

Also read the last 3 sentences before "Competing interests" on page 15 of the pdf. Unfortunately, i can't copy from that document, for whatever reason.

The renewed interest in viral infections in CFS suggests further studies. It is possible
that NPY is induced by such infections. As reliable assays become available it will be important to determine the relationship of plasma NPY to potential pathogens.

 

[IamME]

The paper claims the neuropeptide reflects symptom severity yet the only symptoms they could find mysteriously enough were psychological ones, no muscle weakness/fatiguability, pain, sensory abnormalities, cardiovascular, gastroenteric etc. And using Reeves' definition? Not happy at all about this. this is the sort of thing that just reifies "symptoms = mood and psych stuff". How about actually trying to objectively measure disability as good papers have done in the past.

 

[WillowJ]

not Reeves definition; that was my bad. they were citing that other paper about resolving ambiguities (with Jason and Klimas in addition to Reeves), and used Fukuda as modified by the international group cited previously in this thread

 

[Angela Kennedy]

And there are others in your subgroup.

But there are others in my subgroup, too, who just don't find any correlation between stress and our disease (other than that having a chronic disease causes a certain amount of stress--which doesn't make this a stress-related disease; and this disease in particular makes certain kinds of stress harder to deal with, especially if there's any adrenalin involved--which still doesn't make this a stress-related disease).

And studying the stress connection in your subgroup at this point in time will reinforce negative stereotypes and stymatizing myths, even if that wasn't intended, even if linked to a real biomarker. The psychobabble crowd will either ignore the biomarker or make an ad hoc fallacy incorporating it into their model (like they have done with cytokines).

And it still doesn't explain why their background reads like most of it was written by William Reeves, James Jones, or Samuel Harvey.

Thank you Willow. Key problems. I will say I believe 'sub-groups'/'subsets' are highly problematic notions at this time also (and may always be.) I think these notions, accepted uncritically, have caused terrible trouble for people with the neurological, cardiovascular and other physiological impairments that fall into the Canadian Criteria, and have confounded nearly all research on 'CFS'.

 

[Angela Kennedy]

The paper claims the neuropeptide reflects symptom severity yet the only symptoms they could find mysteriously enough were psychological ones, no muscle weakness/fatiguability, pain, sensory abnormalities, cardiovascular, gastroenteric etc. And using Reeves' definition? Not happy at all about this. this is the sort of thing that just reifies "symptoms = mood and psych stuff". How about actually trying to objectively measure disability as good papers have done in the past.

Yes- beautifully put IamME. "symptoms = mood and psych stuff'. Funny but completely apt. I wish Klimas and colleagues could understand this problem that they actually perpetuate. It shocks me they appear not to, frankly.

 

[eric_s]

I would also prefer a study that focuses less on stress and the sort of symtoms looked at here, but if what they've found is true then it's true and one step forward. If they have found a biomarker then that seems like quite a breakthrough and could lead to more knowledge if they follow that lead.

Some people have those symptoms and i think the idea that a pathogen could explain the abnormally high NPY and thus those symptoms is interesting. I don't consider ME/CFS stress-related, btw, and don't like that idea. I believe it's caused by a pathogen.

 

[oceanblue]

I think the Fukuda criteria modified by Reeves (2003) are fine; this work was done by an international study group including Lenny Jason and just tweaked the Fukuda definition. It was the later Reeves 2005 Empirical definition, produced in isolation by the CDC, that causes the problems since it allows patients to qualify for CFS even if their inactivity is the result of psychological factors.

However, the ability of NPY as a biomarker is not supported by the data. An ROC of around 0.65 for separating CFS patients from Healthy and Gulf War Illness patients is very poor, given that random chance would give an ROC of 0.5, and a perfect marker would give a score of 1.0. I think you need at least 0.85 to be useful in clinical practice.

 

[eric_s]

Thanks Oceanblue for that information. So in this case, i guess they think the more important finding is that NPY correlates with some symptoms and is a biomarker for those, not so much for the illness itself. Are the numbers better there?

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.

 

[aruschima]

It is unfortunate, actually very manipulative, that this study (paper) highlights the stress factor of elevated NPY . NPY has been found and associated in many disorder and diseases. It is certainly wrong (I think) that elevated levels should be construed as a bio marker for ME/CFS, since it is found elevated, or decreased, in many other diseases associated with the brain diseases, even cancers.
I wonder what Nancy Klimas role was in this study and I am also not happy with the interpretation of this study.
ADD ON, if elevation correlates with symptom severity, than yes, it could be helpful for disability claims, but it should not be construed as a marker in respect to stress or shady behavior studies in ME/CFS

http://www.google.co.in/search?hl=e...ancer&btnG=Search&aq=f&aqi=&aql=&oq=&gs_rfai=

http://atlasgeneticsoncology.org/Genes/NPYID44438ch7p15.html

Quote
NPY has been involved in the regulation of a wide range of physiological central effects like the control of appetite, body weight homeostasis, the modulation of reproductive processes, the regulation of growth hormone secretion. Moreover, it is involved in the anxyolytic effect and sedation, in the endogenous anticonvulsant activity, in the circadian rhythm regulation, in learning and memory, in analgesia and hyperalgesia.
Cancer
Besides these physiological events, in the context of the biology of cancer progression, recent evidence has extended the oncological relevance of NPY to endocrine-related cancers (see below).

Quote
Neuropeptide Y (NPY) is a 36-amino acid peptide neurotransmitter found in the brain and autonomic nervous system.

"NPY has been associated with a number of physiologic processes in the brain, including the regulation of energy balance, memory and learning, and epilepsy."[1] The main effect is increased food intake and decreased physical activity. NPY is secreted by the hypothalamus, and, in addition to increasing food intake, it increases the proportion of energy stored as fat and blocks nociceptive signals to the brain.[2] NPY also augments the vasoconstrictor effects of noradrenergic neurons.

Quote
The role of NPY in obesity

Dryden et al., conducted a study in 1995 using genetically obese rats to demonstrate the role of NPY in eating disorders such as obesity. The study revealed four underlying factors that contributed to obesity in rats: (1) an increase in glucocorticosteroid concentrations in plasma; (2) insensitivity or resistance to insulin; (3) mutation of leptin receptor; and (4) an increase in NPY mRNA and NPY release.[13] Furthermore, these factors also correlate with each other. The sustained high levels of glucocorticosteroids stimulate gluconeogenesis, which subsequently causes an increase of blood glucose that activates the release of insulin to regulate glucose levels by causing its reuptake and storage as glycogen in the various tissues in the body. In the case of obesity, which researchers speculate to have a strong genetic and a dietary basis, insulin resistance prevents high blood glucose regulation, resulting in morbid levels of glucose and diabetes mellitus.[14] Furthermore, high levels of glucocorticosteriods causes an increase of NPY by directly activating type II glucocorticosteriods receptors (which are activated only by relatively high levels of glucocorticosteriods) and, indirectly, by abolishing the negative feedback of CRF on NPY synthesis and release. Meanwhile, obesity-induced insulin resistance and the mutation of the leptin receptor (ObRb) results in the abolition of other negative feedback mechanisms to regulate NPYergic activity and ultimately food intake. Furthermore, obesity in rats was significantly reduced by adrenalectomy[15] or hypophysectomy.[16]

Quote
It is suggested that neuropeptide Y (NPY), an endogenous vasoconstrictor peptide, should be considered as one of the mediators involved in the cardiovascular response to sympathetic activation induced by myocardial ischaemia.

Neuropeptide Y (NPY) synthesis in lymphoblasts and increased plasma NPY in pediatric B-cell precursor leukemia

P Kogner, A Ericsson, G Barbany, H Persson, E Theodorsson and O Bjork

Department of Pediatrics, Karolinska Hospital, Stockholm, Sweden.

Neuropeptide Y (NPY), a regulatory peptide in both the central and peripheral nervous systems, has recently been found in neuroendocrine tumors as well as in the bone marrow of rat and certain autoimmune mice, but not in human bone marrow. To investigate a possible role for NPY in the human hematopoietic system, we have prospectively studied NPY-like immunoreactivity in plasma (P-NPY-LI) and NPY mRNA in bone marrow from children with acute leukemia. Northern blot showed high levels of NPY mRNA in bone marrow and peripheral lymphoblasts from children with B-cell precursor leukemia. In situ hybridization showed NPY mRNA in malignant B-cell precursor lymphoblasts. No NPY mRNA was detected in the bone marrow of children with T-cell leukemia. P-NPY-LI was higher (P less than .001) in 51 children with leukemia (200:50 to 385 pmol/L, median:interquartile range) compared to 51 age-matched healthy controls (37:20 to 52 pmol/L). P-NPY-LI was higher (P less than .001) in those with favorable clinical risk classification. Elevated P- NPY-LI, compared with the upper age-adjusted reference limit, was only found in children with B-cell precursor leukemia (31 of 40), whereas all children with B-cell, T-cell, or myeloid leukemia (n = 11) had normal P-NPY-LI (P less than .001). During the 2- to 46-month follow- up, children with elevated P-NPY-LI had better (P less than .001) outcome compared to those with normal P-NPY-LI (79.4% v 34.6% probability for event-free survival).

Quote
There is growing evidence that neuropeptides, including neuropeptide Y (NPY), act as neuronal messengers in the brain and have diverse neurobehavioral functions. Their therapeutic application for psychiatric disorders has been limited, however, by difficult and unreliable penetration of the blood-brain barrier (BBB). The BBB has prevented the use of many therapeutic agents for treating central nervous system (CNS) disorders. Several molecules have successfully been administered through intranasal delivery, however, thanks to the unique connection that the nerves involved in sensing odors and chemicals provide between the CNS and its environment.

Quote
NPY, the most abundant peptide in the mammalian brain, is co-localized with norepinephrine in sympathetic nerve fibers and has been of longstanding interest to our research group (Morgan et al., 2002; Morgan et al., 2003; Morgan et al., 2001; Morgan et al., 2000; Rasmusson et al., 2000; Rasmusson et al., 1998) because of its potential role in modulating mood and anxiety. NPY has been implicated as factor in the adaptive stress response (Thorsell et al., 1999), and has been shown to impact the consolidation of fear-related memories after shock (Flood et al., 1989). Clinically, lower plasma NPY levels have been correlated with greater psychological distress, increased symptoms of dissociation, and poorer performance among active duty military personnel. Acute stress in humans has been found to elicit NPY release, in a manner parallel to the changes in cortisol and norepinephrine that are usually seen, with a blunting of the plasma NPY response in response to yohimbine (Morgan et al., 2002). Baseline NPY levels in combat veterans with PTSD are reduced compared to healthy non-traumatized individuals (Rasmusson et al., 2000). Another study found that repeated exposure to traumatic stress, rather than the presence of PTSD or PTSD-type symptoms, is associated with a reduction in baseline plasma NPY (Morgan et al., 2003). A recent report found deceased CSF concentrations of NPY in patients with treatment resistant unipolar major depression (Heilig et al 2004). In summary, there has been suggestion from studies in patients with anxiety and mood disorders as well as healthy volunteers of an abnormal regulation of this peptide.

In this study, we will evaluate intranasal administration of NPY in healthy male volunteers ages 25-45 using a specialized delivery device. Pending the initial feasibility and tolerability in healthy volunteers, future protocols will examine the effect of intranasal NPY administration in patients with disorders such as PTSD, major depression, panic disorder, and social anxiety disorder.

 

[Angela Kennedy]

Well, bearing in mind Oceanblue and Arsuchima's comments, this study does become even more preposterous in appearance, because of its focus on 'perceived stress' and negative thoughts etc.

At its best it's confounding ubiquitous psychosocial variables that are found in response to major illness or even other conditions, and allowing causation direction fallacies as found in psychogenic explanations to abound, AND ignores the physiological abnormalities associated with 'Canadian' defined ME/CFS.

And no matter how we here can pick up the flaws and problems - Klimas et al are not likely to take them on board, and Heim, Reeves, Wessely, Jones et al will make their own predictable flawed interpretations, and the 'CFS = mood and psych stuff' myth is further reified.

 

[oceanblue]

So in this case, i guess they think the more important finding is that NPY correlates with some symptoms and is a biomarker for those, not so much for the illness itself. Are the numbers better there?

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.

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.

 

[alex3619]

Hi everyone, if the data holds NPY is a correlating biomarker for CFS severity, not a diagnostic marker. Bye, Alex

 

[WillowJ]

Thank you Willow. Key problems. I will say I believe 'sub-groups'/'subsets' are highly problematic notions at this time also (and may always be.) I think these notions, accepted uncritically, have caused terrible trouble for people with the neurological, cardiovascular and other physiological impairments that fall into the Canadian Criteria, and have confounded nearly all research on 'CFS'.

I'm not saying stress correlation is an invalid subgroup. It seems to be valid. I'm saying this is the wrong point in time to be looking at that, and/or the wrong way to write a background section without fully explaining that the stress is a symptom resulting from the disease.

 

[Cort]

My stress hormone is acting up, because of this paper.

Anyway, the conclusion is important I think. It says the stress mediator neuropeptide Y (NPY) could also be induced by viral infections and that more research is needed. Maybe this is why Klimas got involved?

It might not all be in our heads

Exactly......

 

[Cort]

It is unfortunate, actually very manipulative, that this study (paper) highlights the stress factor of elevated NPY . NPY has been found and associated in many disorder and diseases. It is certainly wrong (I think) that elevated levels should be construed as a bio marker for ME/CFS, since it is found elevated, or decreased, in many other diseases associated with the brain diseases, even cancers.
I wonder what Nancy Klimas role was in this study and I am also not happy with the interpretation of this study.
ADD ON, if elevation correlates with symptom severity, than yes, it could be helpful for disability claims, but it should not be construed as a marker in respect to stress or shady behavior studies in ME/CFS

http://www.google.co.in/search?hl=e...ancer&btnG=Search&aq=f&aqi=&aql=&oq=&gs_rfai=

http://atlasgeneticsoncology.org/Genes/NPYID44438ch7p15.html

It may be because she measured those variables. I have had similar complaints with hypercortisolism; its also found in FM and PTSD - which is always mentioned but it is also found in rheumatoid arthritis, I believe, which is never mentioned......

I would hope that she would reference those other connections in the conclusions of the paper...I don't know if she did...However people researching NPY should be familiar with them.

 

[Angela Kennedy]

I'm not saying stress correlation is an invalid subgroup. It seems to be valid. I'm saying this is the wrong point in time to be looking at that, and/or the wrong way to write a background section without fully explaining that the stress is a symptom resulting from the disease.

But trying to find a 'stress-correlated subgroup' for G.93 Myalgic encephalomyelitis/Canadian defined ME/CFS is like looking for a 'stress-correlated subgroup' for AIDS, or MND. It only gets entertained because of the incorrect conflation of ME with 'chronic fatigue', and the special pleading given about people diagnosed with 'CFS' but with signs and symptoms of 'ME' or other neurological/cardiovascular conditions.

That's before we even consider the problems in claims around 'stress' and somatic illness per se (which has been critiqued by others, by the way).

 

[Angela Kennedy]

It may be because she measured those variables. I have had similar complaints with hypercortisolism; its also found in FM and PTSD - which is always mentioned but it is also found in rheumatoid arthritis, I believe, which is never mentioned......

I would hope that she would reference those other connections in the conclusions of the paper...I don't know if she did...However people researching NPY should be familiar with them.

But 'people' researching ME/CFS, especially given the amount of logical errors made in ME/CFS research, are likely to fixate on the myth of 'stress' and other psychosocial variables as causative .

Yes- I'm accusing the scientists of getting it very, very wrong. That's why people are in the mess they are in: various scientists have been getting it very, very wrong. (What was that about a recent press release getting it very, very wrong? From scientists?)

 

[Cort]

And there are others in your subgroup.

But there are others in my subgroup, too, who just don't find any correlation between stress and our disease (other than that having a chronic disease causes a certain amount of stress--which doesn't make this a stress-related disease; and this disease in particular makes certain kinds of stress harder to deal with, especially if there's any adrenalin involved--which still doesn't make this a stress-related disease).

And studying the stress connection in your subgroup at this point in time will reinforce negative stereotypes and stymatizing myths, even if that wasn't intended, even if linked to a real biomarker. The psychobabble crowd will either ignore the biomarker or make an ad hoc fallacy incorporating it into their model (like they have done with cytokines).

And it still doesn't explain why their background reads like most of it was written by William Reeves, James Jones, or Samuel Harvey.

I understand and I fully agree that I am part of one subgroup that does not apply to others.....I think she is elucidating a subset - the subset who's ANS is aroused and just will not turn off..On the other hand that is what she has found....Stress is tough subject...for sure...full of pitfalls

Here's from a paper I did.

NPY is stored in the nerve terminals of the sympathetic nervous system (SNS) and is released in conjunction with SNS nerve agents called catecholamines (norepinephrine, epinephrine). Recent evidence suggests that the activity of the SNS – which is part of the stress response - is increased in ME/CFS. Given that it stands to reason that NPY levels would be increased in ME/CFS as well - and they are – quite significantly so (p<.001).

The thing about NPY is that it regulates immune and other systems. I'm still trying to find out how...I know I wrote something on it...

 

[Cort]

But 'people' researching ME/CFS, especially given the amount of logical errors made in ME/CFS research, are likely to fixate on the myth of 'stress' and other psychosocial variables as causative .

Yes- I'm accusing the scientists of getting it very, very wrong. That's why people are in the mess they are in: various scientists have been getting it very, very wrong. (What was that about a recent press release getting it very, very wrong? From scientists?)

I agree after reading the abstract again that it is a difficult pill to swallow....My hope is that she ties this to physiological measures; ie these factors are contributing or causing these problems. Of course it does reinforce stereotypes - you just can't get away from that....its rough, that's for sure.