The RFA grant is a quasi-legal document that lays out in some detail what types of research the NIH is interested in. In effect it is a promise from the Department of Health and Human Services (DHHS) that states what it will use the people’s money for. In order to understand exactly what the NIH is looking for, this overview will highlight and attempt to explicate different sections of the text. (Click here to read the full text of the RFA).
A Grant For CFS? - We might as well start at the title. Note that the grant is not for "Neuroimmune Mechanisms IN Chronic Fatigue Syndrome". It is for "Neuroimmune Mechanisms AND Chronic Fatigue Syndrome". Why not use the more inclusive ‘IN"? Does this suggest that the grant may fund proposals that explicate neuroimmune mechanisms but not necessarily in CFS? Or is this just a bit of paranoia?
"The goal of this request for applications (RFA).is to solicit applications .on the neuroimmune mechanisms involved in the pathogenesis and pathophysiology of Chronic Fatigue Syndrome (CFS) and spectrum disorders."
Perhaps some paranoia is justified. This 'CFS grant' can also be used to fund research into ‘spectrum disorders’, which include Fibromyalgia Syndrome (FMS), temporal mandibular joint disorder, post-traumatic stress disorder, irritable bowel syndrome and chemical sensitivities. Given the history of this grant this is not be surprising at all. A review of the 2003 Neuroimmune Conference the RFA was based on (‘Neuroimmune Mechanisms and CFS’) finds as many overviews of Fibromyalgia (FMS) in the research section as on CFS. The NIH has, furthermore, recently attributed grants to CFS that have little or nothing to do with the disease. CFS is not even mentioned in the abstracts of a significant number of the studies that the NIH categorizes as ‘CFS research’ (click here).
Yet notice that the RFA does not call for research into the neuroimmune mechanisms in CFS or spectrum disorders, it calls for research into the neuroimmune mechanisms involved in CFS and spectrum disorders. This presents an entirely different scenario: that of the RFA supporting studies examining neuroimmune mechanisms in general but not involving either CFS or spectrum disorder patients. As noted above, this has, in fact, been common practice at the NIH for a number of years now. The NIH has repeatedly used funds for CFS research for studies that examine processes that could conceivably underlie some of the problems of CFS but do not actually involve CFS patients. It’s basically a dodge to underwrite projects the NIH wants to see accomplished but doesn’t otherwise have the money to do so. Given the pitiful amount of funding available for CFS even in the best of times CFS advocates have been understandably riled when they see what little funding they have going to fund non-CFS studies. But would this happen in a grant that has been advertised specifically for CFS? Would they dare?
A Focus on ‘Stress’ - The emphasis throughout the RAF is on the effects of ‘stress’. This is made clear in the first paragraph when, after an elucidation of possible dysregulating elements in the central nervous system (CNS) and immune system, stress is the only item mentioned as a potential cause;
‘Stress affects the activities of many of these mediators. Physiologic functions altered by stress and the ability to respond to stress likely play a role in the clinical manifestations of CFS¼ Internal and external stressors lead to altered signaling in the central nervous and immune systems".
‘Stress’ is a pretty hot button term. The NIH clears up what it means by stress when it states that ‘stressors, including infection, enzyme, gene and cytokine abnormalities, hormonal fluctuations toxicant exposures that affect brain function,’ can trigger the ‘stress response’.
Nowhere is psychological stress mentioned. Indeed it is not stress the NIH is primarily interested in but the ‘stress response’. The stress response primarily involves two systems, the sympathetic nervous system (SNS) and the HPA axis, both of which work intimately with the immune system to modulate it (and vice versa).
These systems, which maintain the ‘homeostasis’of the body, are responsible for returning it to its normal operating state after an infection, exercise or other stressor has altered it. They play a major role even in such common activities as standing. They are at rest only when a healthy person is supine. By inhibiting the immune response the HPA axis prevents it from inflicting tissue damage or attacking the body. By inhibiting the pro-inflammatory response the SNS downgrades the activity of many immune mediators and cells that, left unchecked, can cause inflammation, high levels of oxidative stress, tissue injury, etc. The pro-inflammatory cytokines (IL-1B, IL-6, TNF-a) the immune system produces during infection are able to interact with the central nervous system (CNS) to produce what is called ‘sickness behavior’. Since many of the symptoms seen in CFS (fatigue, aching muscles, sore throat, altered sleep, etc.) can be evoked by these cytokines, a dysregulated neuroimmune interaction could be the source of them.
The NIH lays out six factors it is looking for in these applications; two of which are noteworthy.
Elucidate the development of influences that may enhance disease susceptibility...
Unfortunately the meaning of ‘influences’ is not made clear. Most studies in the past that have looked for risk factors in CFS have concentrated on psychological issues rather than biological ones.
Finally the NIH tells researchers it wants them to use the 2003 NIH sponsored conference, ‘Neuroimmune Mechanisms and CFS’, as a guide for the types of research it is interested in funding. Indeed much of the rest of the document is right out of the Conference proceedings.
Antidepressants and CFS? - The RFA highlights the stress response and antidepressant use in CFS. This is both bewildering and alarming given the relatively minor role antidepressants play in CFS treatment. The roles serotonin and norepinephrine play in CFS are of great interest but the NIH places them within a context (their relationship to antidepressants) that is not particularly useful.
Sleep - A long paragraph is taken up with a discussion of sleep, a problem for some CFS patients, but again hardly a central issue. Like studies of cortisol most sleep studies indicate only minor identifiable problems in most CFS patients. The intersection between cytokine production and ‘sickness behavior’ (fatigue, fever, headaches, etc.) - an important topic for CFS patients is - unfortunately placed within a context (cytokines’ relationship to sleep) that diminishes its importance.
Agency Input - The six sponsoring institutions are given a chance at the end of the document to state their preferences for research. The National Institutes of Alcohol Abuse and Alcoholism, rather amazingly states they would like to see studies on ‘alcohol health effects that are co-morbid with chronic fatigue syndrome’. (Why is agency on alcoholism is doing sponsoring research on a disease that leaves its sufferers notably intolerant of alcohol???)
Competing Continuation Grants? - In the Awards section we learn that this RFA need not be devoted to new studies but could also be used to fund ‘competing continuation grants’. Since this would simply shift the funding responsibility for old studies to the RFA this would hardly count as new funding for CFS and would be extremely disappointing.
Missed Opportunities? – Science moves rapidly and research since the 2003 Conference has continued to illuminate both the neurological and immunological aspects of CFS, yet two years after the conference, the RFA was still almost entirely based on the 2003 conference. There is currently great interest in serotonin dysfunction in CFS but it is only briefly mentioned and within the context of antidepressant therapy. Similarly, oxidative stress plays a large role in both neurological and immunological disorders and CFS; yet no mention is made of it. Surprisingly no mention is made of the evolving evidence of CNS dysfunction using neuroimaging. Neuroimmune research into two fatiguing disorders, multiple sclerosis and cholestatic liver disease, indicates that cytokine/brain interactions can lead to excessive fatigue; yet fatigue, surprisingly enough, given the disorder under question, is rarely mentioned.
Summary - While one may question the emphases of this RAF, it is, at least, with the exception of the section on antidepressants and some allusions to ‘external stress’, refreshingly free of reference to psychological stress, mood disorder, etc. Its discussions of stress are placed solely within the context of the endocrinological, immunological and neurological responses to it.
The RFA, like the Conference that inspired it, suggests the NIH is most interested in the HPA axis/immune interface, sleep, anti-depressants in CFS, etc. The emphasis on cytokines was gratifying given the infectious trigger that often occurs in CFS and its symptom presentation. A stated emphasis put on finding a biomarker for CFS was also very welcome. Some other emphases were, at least as I, a laymen, judge them, questionable and do not display a creative approach to this disease. Disturbingly, the RFA has also left open the possibility that portions of it may be used to continue funding for projects already in progress or for projects not directly on CFS.
Will this grant ‘Make the Difference" in CFS? Even with the proviso’s noted, it has the potential to fund studies able to elucidate key aspects of CFS. Most CFS patients would probably state that they handle ‘stress’ of any kind, be it from exercise, infection, toxins, mental effort, emotions, etc. much less effectively than before. The ‘wired but tired’ feeling, the inability to sleep well, the inability to ‘settle down’, the difficulty with exercise, the increased mental efforts needed, are all states that suggest the internal homeostasis of CFS patients is indeed altered. The idea that central signaling mechanisms involving the nervous and immune systems are disturbed in CFS is an intriguing one that has only begun to be addressed. Hopefully this RFA grant will fund studies able to address this question in a creative and meaningful way. Much will, of course, depend on the quality of the applications the NIH receive and their disposition by the reviewing committee.
The Next Step - In the next step in this process the Reviewing Committee will review the 30 or so applications they have reportedly received, reject about half of them, score the rest and then send them onto another review by the various government agencies that make up the Chronic Fatigue Syndrome Working Group (CFSWG).
Since the fate of these grant applications rests in the hands of the Review Committee, the next paper will look at who the ORWH has decided is best suited to review proposals examining the neuroimmune mechanisms operating in CFS.
Neuro-Immune RFA Intro / The Neuro-Immune Conference / Reviewing the Reviewers / Conclusion: Assessing the Grants