Rating The Months Research - The thesis of this newsletter is that the most important studies deal with the pathophysiology of CFS. Each month is graded according to the following criteria;

A – several difference making papers on CFS pathophysiology

B – a difference making paper on CFS pathophysiology plus several important ones

C - several important papers on CFS pathophysiology

Japan has become, after the US and the UK/Europe, a third center of CFS research. This is largely due to the ‘Tanaka/Kuratsune/Watanabe’ group which has in the last five years produced at least 9 studies on a variety of topics including serotonin, cholinergic pathways, brain acetylcarnitine uptake, EBV, Coxiellia, Borna virus and orthostatic intolerance (see The CFS Research Groups). >

This unique study focused on brain imaging. Most brain imaging studies examine brain activity at rest or during a task but this study added several twists. First it captured images of brain activity not just under the stress of doing a task but when the participants were mentally fatigued as well. The researchers did this by having the two groups do a very simple but mentally fatiguing task over and over again for a period of time; 30 minutes for the CFS subjects and an hour for the controls. After some testing the researchers decided that 30 minutes was sufficient to get CFS patients mentally fatigued.

The researchers provided a further twist by expanding the area of the brain they scanned. Usually brain imaging studies focus on the part of the brain engaged by the type of task the subject is engaged in; i.e. they monitor the activity of the motor cortex during tasks involving movement. In this study they did that (monitoring the visual center) but they also examined a part of the brain (auditory center) not involved in the task at hand. They did this by temporarily altering the sound of the MRI machine and measuring how well the auditory centers of the brain responded to that change. They appeared to do this for two reasons; (1) they wanted to determine what effect putting one part of the brain under the stress had on functioning in other parts of the brain, and, (2) although they did not state so, they presumably wanted to address issues of ‘information overload’ sometimes evoked by CFS patients.

Three sessions were run – a pre-fatiguing session, a fatiguing session, and a post-fatiguing session. Both groups had similar responses during the pre-fatiguing session. When both groups were fatigued, however, the groups diverged: while CFS patients were able to maintain the same degree of visual cortex activity as the healthy controls, the auditory centers of their brains were less responsive to changes in sound produced during the experiment. This suggested CFS patients have a reduced ability to pay attention to more than one stimulus at a time. Importantly the tests also were able to link fatigue with brain activity; the more fatigued the CFS patients were, the less well their brains were able to pay attention to the secondary stimulus (sound).

The authors were not clear why the activity levels of the auditory centers of the brain declined in CFS patients, but they noted that a similar phenomenon occurs during a process called ‘cortical spreading depression’ (CSD). CSD occurs when neuron and glial cell depolarization leads to reduced electrophysiological activity. This suggests that as the mental fatigue gets worse and worse and worse, more parts of the brain become, so to speak, ‘uncoupled’ from each other.

What an evocative term: cortical spreading depression; it turns out that this ‘depression’ does slowly spread across the brain; perhaps like the oft cited ‘fog’ CFS patients can feel at times settling in over their brains. CSD is believed to play a role in the pathogenesis of a wide variety of brain diseases including stroke, migraine, amnesia and cerebral ischemia. It can be induced in a number of ways, such as by elevated potassium or glutamate levels. CSD is characterized, interestingly enough, given the postulated neurological channelopathy in CFS, by altered intracellular and extracellular ion concentrations and swelling of the cells (see A Neurological Channelopathy in CFS?). Oddly enough CSD is first manifested by temporarily increased blood flows followed by prolonged periods of reduced blood flows.

The reduced cerebral blood flows are believed, not surprisingly, to be caused by constricted blood vessels in the brain. Just as in the periphery, the regulation of blood flow in the brain is a complex process involving many factors including CCGP, nitric oxide (NO), acetylcholine, vasoactive intestinal peptide (VIP), prostaglandin E2 (PGE2), substance P (SP) and others.

Abnormalities in several of these (NO, ACh) have been found in the vascular systems of CFS patients outside the brain. Except for substance P (which was normal) none have been assessed inside the brain. Pall has found evidence of increased NO levels in blood of CFS patients, while Stewart has found evidence of the opposite in a subset of POTS patients. Spence and Khan have found prolonged ACh activity in the blood vessels in the skin in CFS patients.

Several studies have found evidence of reduced blood flows to or in the brains of CFS patients. Just this month Dr. Natelson published a study indicating reduced cortical blood flows in CFS patients. Baraniuk recently found evidence of a condition, amyloidosis (protein aggregation), in the brain which is often characterized by low blood flows.

Oxidative stress is raised in both CSD and CFS. The increased production of proinflammatory cytokines and superoxide and NO results in this increased oxidative stress during CSD. The production of metallomatrixproteinases (MMP’s) also increase permeability of the BBB. The origin of the increased oxidative stress in CFS is still not clear but Vernon’s study of patients whose CFS was triggered by infectious mononucleosis found evidence of increased MMP activity. Increased BBB permeability could allow fatigue-causing cytokines access to the brain. Tumor necrosing factor producing monocytes that were able to penetrate the BBB were recently implicated in the severe fatigue found in cholestatic liver patients (See Phoenix Rising VI.)

Alternatively, the reduced activation of the auditory centers in this study could be due to an inability to activate the neurons in the auditory cortex. There is evidence of impaired motor cortex activity in CFS. Some evidence suggests, however, that motor cortex problems in CFS are not due to motor cortex inactivation but to an impairment in the deeper (subcortical) areas of the brain. Either way, increased mental fatigue in CFS appears to reduce the activity of major parts of the brain outside of the specific area fatigued. Tanaka believes this phenomenon probably occurs brain-wide but this awaits the confirmation of more extensive studies.

There were two provisos to this study. First, the sample set may not have been representative of all CFS patients; it consisted entirely of males. Second, the sample set, as is often found in brain imaging studies, was very small, consisting of 6 CFS and 7 healthy controls. Hopefully this intriguing study will be quickly expanded and replicated.

The research into FMS is undergoing a quite fertile period. The March and April issues of Phoenix Rising take advantage of several recent papers to look at different theories regarding the origin of pain in this disease. The pain FMS patients suffer from could derive from two places in the body; the central nervous system/brain or in the muscles/tendons themselves. In part one we focus on evidence suggesting that the pain in FMS is due to an oversensitized central nervous system.

Background: There are different types of pain disorders; some people have what is called ‘hyperalgesia’ which is an increased sensitivity to painful stimuli, and some people have ‘allodynia’ which is a painful response to non-painful stimuli such as touch. FM is unusual in that FM patients often have both; not only are their responses to pain increased but normal stimuli often cause them pain as well.  The fact that they suffer from both types of pain gives us some clues as to where it comes from.  People with allodynia, for instance, usually exhibit either increased sensitization of their peripheral pain receptors (nociceptors) located outside of the brain, or increased excitability of neural circuits regulating pain in the brain (central sensitization). The search for the source of the pain in FM encompasses both peripheral and the central nervous system.

Tracking the Route of the Pain Signal: The signal for muscle pain travels via two types of nerve fibers to the dorsal horn of the spinal cord where it prompts the release  of pro-pain substances such as substance P and calcitonin gene-related peptide (CGRP). Substance P is a sensitizer; when it is it released into the neurons of the spinal cord it makes central pain receptors called NMDA receptors hypersensitive. When substance P is released into the tissues surrounding a wound it makes them more sensitive to stimuli.

NMDA receptor activation and the concomitant release of pro-pain substances such as substance P (SP), nerve growth factor (NGF), brain derived nerve factor (BDNF), and nitric oxide are believed to drive the process of nervous system excitation or 'central sensitization'. A recent text stated that the ‘recruitment of the NMDA receptor appears to be the pivotal event in increasing the sensitivity of the nociceptive (pain) spinal circuits to (painful stimuli)" (Staud 2004).

In order for a cell to respond to a substance it must have a receptor for that substance to bind to. Increased receptor activation occurs either when receptors are abnormally sensitive to stimuli or when high numbers of a receptor are present. High levels of the NMDA receptor on a cell , for instance, would indicate that that cell is hypersensitive; i.e. only small levels of its activator, a neurotransmitter called glutamate, are necessary to prod it into action.

NMDA receptors form ion channels at the excitatory synapses of these nerves. Ordinarily these ion channels are a) closed and b) blocked by extracellular magnesium ions. Two things needed to happen for these ion channels to open, first, the magnesium ions blocking the channel need to be flushed out by a process called membrane depolarization; secondly glutamate need to be present to trigger the NMDA receptor to open the ion channel. Negatively charged cells attract magnesium ions which then close the NMDA ion channels. If the cell loses its negative charge, the magnesium ions will drift away. The opening of the ion channnels allow sodium, potassium and most importantly calcium ions into the cell. Once inside the nerve cell the calcium ions activate signaling pathways that call for the production of glutamate, substance P and other pro-pain factors. The neurons then send a message to the part of the brain called the thalamus which processes it and amplifies the pain response. Prolonged periods of NMDA ion channel activation and the high intracellular Ca²⁺ levels that accompany it can, by triggering the apoptotic process (cell suicide), result in nerve cell death.

Glutamate is the chief excitatory neurotransmitter in the brain. Ischemia (low blood flows) and low glucose concentrations can stimulate glutamate production. Ischemia is found in several neurodegenerative diseases does. Increased glutamate levels are associated with increased oxidative stress.

The controversy in the central sensitization theory in FMS comes from inability of brain imaging studies, in contrast to other pain diseases, to identify a lesion or wound in the CNS. The one other pain disease in which a CNS lesion is not found, trigeminal neuralgia, involves, interestingly, circulatory problems. In trigeminal neuralgia, increased pressure from a blood vessel applied to a cranial nerve supplying the face causes spasms of severe facial pain. We will examine the possibility that circulatory problems in the brain or elsewhere play a role in FM later.

FMS patients have long reported that the pain they experience is not located in one place but often occurs body-wide. (Staud indicates it is more intense and widespread in the upper half of the body.) This is the first study to verify this anomaly; it found that the pain thresholds in both exercising and non-exercising muscles were increased after exercise in FMS patients. The pain intensity in the FMS patients did not appear to be particularly high – what was notable is that it increased at all.

Since trauma in the muscles results in local not systemic increases in pro-pain substances it is difficult to imagine how a peripheral process (one located in the muscles) could be at work here. This reaction, therefore, is another indication that a central pain mechanism is at work in CFS. It illustrates that a stimulus centered on one part of the body can, possibly by inducing a hyperexcitable response in the brain, can cause an aberrant response to normal stimuli across the body.

Just what is causing this hyperexcitability is unclear but there is evidence of increased levels of pro-pain substances in the brains of FMS patients.

Increased levels of at least three pro-pain compounds associated with NMDA activation (substance P, nerve growth factor (NGF), brain derived growth factor (BDNF)) have been found in FMS. Substance P, the most well-studied pro-pain substance in FMS, is a neurotransmitter and neuromodulator that, besides pain, has been associated with anxiety, stress, neurotoxicity and nausea. Substance P is also involved in the transmission of pain impulses from peripheral receptors to the central nervous system. Releases of substance P cause the area surrounding a wound to become more sensitive to pain. Several studies have found increased levels of substance P in the cerebral spinal fluid of FMS patients.

NGF and BDNF are two neurotrophins that are increased in the cerebral spinal fluid (CSF) of chronic headache patients. Neurotrophins enhance the survival of neurons by blocking the apoptotic process (suicide). They also regulate neuronal plasticity. Alterations in the neural network (neural plasticity) could result in a chronically increased pain state. In vivo studies have indicated that nerve growth factor (NGF) increases the level of the pro-inflammatory neuropeptides CGRP and substance P as well as the growth factor BDNF. One study has found increased levels of nerve growth factor in the CSF of FMS patients.

Like substance P, BDNF appears to be both a neuromodulator and neurotransmitter. BDNF appears to enhance NMDA activity in two ways; first it enhances the production of glutamate and secondly it is able to increase NMDA receptor activity. BDNF is particularly interesting in its ability to induce a long term increase of sensitization in some parts of the brain. Unfortunately, no studies have addressed levels of this important compound in the cerebral spinal fluid of FMS patients. BDNF levels have been assessed in the peripheral blood, however – See the next issue of Phoenix Rising.

In addition to having high levels of ‘pro-pain’ factors, FMS patients could also have low levels of ‘anti-pain’ factors. These are compounds that inhibit the pain response in the spinal cord. One anti-pain factor called ‘glial cell line derived neurotrophic factor (GDNF), which works specifically on the sensory neurons, was recently studied in relation to FMS.

GDNF is intriguing in several ways; first it belongs to the transforming growth factor family, one of whose members (TGF-B) is often increased in CFS, and it interacts with the sodium channels in cells. There is some indirect evidence of altered sodium channel activity in CFS (See A Channelopathy in CFS?)

GDNF plays an important role in the regulation of pain in the body. Since GDNF appears able to modify the expression of two NGF regulated pro-pain factors; substance P and the capsaican receptor, low GDNF levels could be at the heart of the sensitization seen in FMS. GDNF also appears to modulate the release of another anti-pain factor called somatostatin. Somatostatin is a key regulatory and anti-inflammatory peptide produced throughout the central nervous system and in most of the peripheral organs.

This study, which appears to be the most complete survey yet of anti-nociceptive factors in FMS, found that levels of both GDNF and somatostatin were markedly reduced in both FMS and chronic migraine patients. That somatostatin and GDNF levels were correlated with each other suggests that GDNF, in particular, plays a key regulatory role in these diseases.

This study suggests drugs developed to increase GDNF and somatostatin could be effective in FMS.

A recent trial involving electroconvulsive therapy (ECT, i.e. electroshock) also suggests that the hyperexcitability seen is due to lack of anti-nociceptive activity. ECT was found to significantly improve the pain scores in FMS patients with severe pain. Their scores, promisingly, remained low three months after the treatment.

An examination of regional cerebral blood flows after ECT found that it significantly improved blood flows to the thalamus, a part of the brain involved, among other things, in the interpretation of sensory inputs. Chaudhuri and Behan suggested thalamic inhibition may also cause central fatigue in CFS. It is believed that ECT activated anti-pain nervous system pathways involving serotonin, norepinephrine or dopamine. Prior studies have found reduced serotonin levels in FMS. Once again we see evidence suggesting that circulatory problems may play a role in FMS pathophysiology.

There are a number of similarities between migraine and FMS; both disease appear to involve an exquisite sensitization to stimuli, both are pain syndromes, and depression and anxiety are common in both. Although migraine is chiefly thought of as headache, recent reports indicate that increased sensitization in the periphery is common as well – almost half of migraine sufferers suffer from allodynia (a painful response to normal stimuli) and about 40% display widespread tender points. A recent study found that about 15% of migraine sufferers fit the criteria for FMS.

This study found that almost half of FMS patients suffered from migraine and 80% suffered from severe headaches. Most intriguingly a finding that headache preceded FMS symptoms in almost half of the FMS patients suggests that sensitization began in the brain and later spread to periphery. Other studies have found an increased incidence of another pain disease possibly allied with FMS, irritable bowel syndrome (IBS), in migraine patients. We just saw that both migraine and FMS patients have low levels of the anti-pain factor BDNF in their spinal cords.

SPECIAL REPORT

The Review Panel plays an important role in the public funding of medical research. Indeed it is hard to overestimate how important these review panels are. The fact that every study the NIH funds must go through a review panel means these panels play an enormous role in determining the direction medical research takes in the U. S.

The Center for Scientific Review (CSR) which oversees the scientific review panels is cognizant of the important role these panels play and has laid down a series of guidelines and requirements that members of them must meet. A few are highlighted below.  

•  Candidates must be a principal investigator on a research project comparable to those being reviewed.when developing/updating a study section roster
• Expertise is the paramount consideration
• Each scientific area reviewed by the study section needs an appropriate expert representation.
• Study sections that review multidisciplinary or interdisciplinary applications have a greater need for scientists who have broader expertise.

Because this RFA calls for research exploring the relationship between two large fields, neurology and immunology, and a complex disease the need for reviewers with broad and extensive expertise is paramount

The Process - Each reviewer will typically review two or three proposals. Typically about half the proposals are rejected outright, the rest are scored and given written reviews on the proposal’s significance, approach, innovation, investigator’s experience and ‘environment’. and then sent onto another review by the various government agencies involved in this RFA.

At the moment here are two CFS Review Panels; a standing panel that reviews all other proposals for CFS research, and one created specifically to review the proposals in the Neuroimmune RFA, and. We first examine the history of the standard review panel in order understand the context in which the neuroimmune review panel was created.

The CFS SEP’s mandate is to review applications that examine "the causes, manifestations and treatments of the Chronic Fatigue Syndrome, the Fibromyalgia Syndrome and other chronic polysystemic morbidity syndromes." It usually meets three times a year. As can be seen, despite its title, the CFS SEP, this review panel is not designed solely to review CFS grant proposals. Indeed, the qualifier at the end of the sentence (‘other’ polystemic morbidity syndromes) makes its purview quite open-ended. Still CFS makes up the title of the SEP, it always mentioned first, and it is the primary disease under consideration.

The difficulty with placing different diseases under the purview of one panel, of course, is assembling researchers with expertise in all these areas. These can be more easily achieved if these disorders are allied in significant ways and indeed many of them are; fibromyalgia, irritable bowel syndrome, temporal mandibular syndrome and pelvic pain syndrome are all ‘pain diseases’. Pain is the major presenting symptom and the research into them mostly explores ways to explain the heightened pain their patients suffer.

While CFS shares some minor symptoms with these other disease it is not a pain disease; it’s the major presenting symptom, the one that essentially defines the disorder, is fatigue not pain. Recent studies indicate that it’s not just fatigue but a particular kind of fatigue – post-exertional fatigue – that is the hallmark of CFS. This unusual symptom – not shared by the other diseases under consideration - strongly suggests the central pathophysiology in CFS is different. Pain is only one of eight symptoms the CDC uses to define CFS. Since only four of this symptoms need to be present CFS patients need not suffer from increased pain in order to meet the criteria for CFS.

Indeed pain is not a major issue for most CFS patients, and has not been even a minor research subject. A review of PubMed citations over the past five years indicated that few studies directly addressed the subject of pain in CFS and none have directly explored its pathophysiology. A 2004 study found that examined the influence of pain on CFS patients determined that it was a not a factor in the activity restriction seen in CFS (Nijs et. al. 2004). That a key finding in FMS research – increased levels of the pro-pain compound substance P – is not found in CFS, suggests that the central pathophysiology of the two diseases is different.

Dr. Hofford, the panel’s organizer, however, has stated that it’s to ‘everybody’s advantage to have them (the polysystemic morbidity syndromes)…. all considered together". This statement flies in the face of much of the current thinking on CFS. Instead of being subsumed into a larger disease category most thinking on CFS posits that CFS should be subtyped further (Jason et. al. 2005) and the inability or unwillingness to do so has contributed to some of the heterogeneous findings sometimes found in CFS research (Spence, 2005). The CDC – which recognizes this concern – recently participated in several studies designed to delineate the heterogeneity present in CFS. A recent study that subtyped CFS patients according to their minor symptoms found three coherent subsets; neurological, muscoskeletal and immunological (Janal et. al. 2006). What is needed in CFS is not lesser but greater differentiation.

The danger in lumping CFS in with a number of pain rather than fatiguing diseases is the creation of a review board that sees these diseases through a paradigm appropriate not for fatigue but pain. A shrewd organizer might be able to create a board diverse enough to accommodate the different research issues but a poor organizer will weight the board towards one of the different emphases present. As we shall see this is exactly what has happened. Researchers with expertise in pain and behavioral issues have dominated the SEP panels put together by Dr. Hofford and many of the areas of current research in CFS have not been represented.

A Continuing Source of Concern -The makeup of the Review Committee and its decisions have been an object of concern for CFS researchers and advocates for some time. Even as NIH funding has doubled in the past five years funding for CFS research has dropped. This in combination with low approval rates for CFS research proposals has lead CFS advocates to charge that the NIH in general, and the CFS SEP panels, in particular, exhibit bias.

`In particular, CFS advocates propose that the review panels created by Dr. Hofford lack the expertise to review the grants before them. The believe the presence of a review panel top loaded with researchers knowledgeable in pain and frequented by reviewers with no knowledge of the issues concerning CFS gives many CFS researchers little confidence that their grant proposals will be given a fair hearing. Some believe that has lead some CFS researchers to simply pull out of the process.

Craig Maupin’s review of the 2004 CFS SEP found few reviewers with research interests in CFS (6), a predominance of reviewers with a background in pain and containing reviewers with expertise in subjects like drug abuse, opiate management, retardation, spiritualism, psychosis and urological disorders (click here). Of the six with CFS research interests half focused on behavioral aspects of the disease.

A review the entire review panel for 2005 CFS s indicates more than half have a background in pain/fibromyalgia, and only two of the thirty-seven had published on CFS . Only nine of the 37 reviewers have expertise in fields relevant to CFS and almost half of these are focused on sleep abnormalities, few of which have been identified in CFS. It is remarkable given the rich field of CFS immunology that only three of 37 reviewers have immunological expertise. Even the experts in this important field have little expertise (e.g. brain mast cells, asthma) in the immunological issues relevant in CFS. Even more startling are the large number of reviewers (15) whose research interests had no discernable connection to CFS (dental pain, chiropractic, law and autism, exercise and smoking, hypertension/micturition, chronic pain, migraine, pain and alcoholism, etc.).

A December 2005 letter from the Chairman of the Board (Susan Jacobs) and President/CEO of the CFIDS Association of America (CAA) (Kim McCleary) to Vivian Pinn, the Asst. Director of the ORWH, indicated the CAA had objected to the makeup of the SEP Panel ‘on multiple occasions’. The CAA concluded that despite their attempts to be ‘collaborative’ and ‘reasonable’ their concerns had, once again, been ‘largely ignored’. They noted the dismay expressed by CFS researchers at the limited understanding of CFS that the reviewers comments on their applications reflected. The inability of some researchers with long track records of success in other fields to get their CFS studies approved suggested that the SEP panel is riddled with bias or incompetence or both

Dr Hofford implies the review panels makeup may not reflect many CFS research interests because they are dealing with cutting edge research. "If it is brand new to being applied to this particular syndrome, then we need to have people who have used it in related conditions". Dr. Hofford is correct that in rapidly evolving interdisciplinary fields such CFS the pace of knowledge may at times outpace the expertise of some researchers. Indeed a panel composed solely of CFS researchers would probably lack sufficient breadth to rapidly move the field forward. The NIH can hardly be accused of providing cutting edge research in CFS, however. In fact a lack of innovation is one of the key complaints that CFS advocates have towards the NIH.

One area the NIH has been ahead of the curve, so to speak, has been on circulatory issues and orthostatic intolerance. Yet only one out of some 30 odd reviewers in 2004 and 2005 had expertise in this field. One wonders how the few immune studies, one of which resulted in an important 2005 paper on NK cell function, managed to get funding given the low levels of immunological expertise found on the panels. Several of the innovative studies the NIH has funded in the last five years appear to have occurred despite the review panel expertise not because of it.

Dr. Hoffield asserts that if the CFS community does not like the kinds of studies being funded it is because the review panel is not getting the kinds of proposals the CFS community wants. He belies his former statement regarding ‘brand new’ approaches to CFS when he suggests that field of CFS research is actually in a kind of stasis. "My study section can only evaluate the applications being submitted. And, the applications being submitted are emphasizing palliative care more than they did in the past, and that is simply because that is what people are thinking about these days. They are sort of waiting for the next breakthrough in the technology to be able to study new things like biomarkers or diagnostic approaches".

It is hard to understand how this can be so given the rapid growth of the field over the past several years. Many of the studies now being released were probably funded not long before Dr. Hoffield made this statement. It seems more likely that either the NIH is not receiving proposals that could lead to breakthroughs because the researchers engaged in that kind of research do not feel it is viable source of funding for them , or the NIH often hasn’t recognized that kind of proposal when confronted with it.

Dr. Hofford assures us that "There are certainly always people in the room who have hands on experience with the disease [CFS]." That Dr. Hofford felt the need to make a statement like this regarding a review panel for CFS in itself speaks volumes. A few CFS experts in a sea of pain researchers, however, can hardly have a substantial effect. The scoring that is so important to a grants success is carried out by individual reviewers not the panel as a whole. Since grants with low scores are almost automatically rejected a CFS grant given low initial scores will not be aided by the presence of a few CFS researchers in a large panel.

Aside from its new funding the CAA was particularly interested in the Neuroimmune RFA because it allowed for the creation of a review panel outside the purview of the Center for Scientific Review. In this case the overseer of CFS research for the NIH - the Office of Research for Women’s Health (ORWH) - had the option of creating the new review panel. The depth of the CAA’s concern at this issue can be seen in the ‘enormous disappointment’ they expressed to Dr. Pinn when they learned that the CSR and Dr. Hofford had once again slotted to create the review panel for this.

We know Dr. Hofford’s past review panels have had a heavy emphasis on pain. But this is a new review panel with a more specific mandate. The RFA was largely focused on the stressors caused by immune activation, endocrine dysregulation and altered neurotransmitter levels (See Reading the Grant). Only indirect notice was given to FMS and/or pain (e.g. polysystemic disorders). The types of researchers Dr. Hofford has emphasized in the past are clearly not appropriate for this panel.

Conclusion: This review panel is better than the 2004 and 2005 panels. More CFS researchers are present and the expertise of the panel better reflects its mandate. Better is not necessarily good, however. While this review panel is better than the 2004/2005 panels, it could be argued, given those panels, that it could hardly have been worse. Much of this panel still fails the first criteria of the CSR that "Candidates must be a principal investigator on a research project comparable to those being reviewed"

Assuming 30 applications were received the low number of CFS researchers on the panel indicates that about 60% of the grants will be decided by reviewers with no history of CFS research. Given the voluminous literature produced on CFS over the course of almost 20 years (>3,000 papers) this is clearly an unacceptably low number of researchers with expertise in this field.

Despite repeated requests by the CAA and others that the CFS review panel contain substantial numbers of CFS researchers and that the panel display an expertise appropriate to its subject matter Dr.Hofford has once again assembled a review panel light on CFS researchers, heavy on pain researchers and with a significant number of panelists with little or no expertise in the subject matter before them. If the goal of this panel were to review grants for studies on Fibromyalgia/pain then Hershey. Goolkasion, Mauderli, Pezzone, Plesh, Zhang are appropriate choices. If instead it was set up, as its name implies, largely to study proposals on CFS, then these reviewers are clearly inappropriate.

Even if one stretches to include some panelists with peripheral connections to the research issues in CFS, it is impossible to make a convincing case for a substantial number of tne panelists. About twenty-five percent of the panel ISandy Berry, Lucille Eller, (Andrew, Hershey, Andre Mauderli, Dan Malone, Robert Roberts, Robert Tarran) have no expertise in the issues they are likely to face. Others are quite marginal (Paula Goolkasian, Michael Pezzine, Octavia Plesh, Mohan Sapori) others are satisfactory (Michael Irwin, James Jones, Randy Nelson, Peter Rowe, Ann Silverman, Renee Taylor) and some appear to be excellent choices (Mahendra Kumar, Gundrun Lange, Jon Russell, Shannon Kenney, Charles Raison, Peter Rowe, Jerry Taylor).

Dr. Hofford has again assembled a panel in which specialists in the disease under review are under represented and with a significant number of reviewers with no expertise in the issues under review. While this panel is better than those before, perhaps because of its more concentrated focus, it does not meet the standards of expertise laid out by the Center for Scientific Review.

Should Dr. Hofford continue assembling review panels for CFS? It is important that the researchers studying CFS have the confidence that the proposals they submit for review will get reviewed by panelists with expertise in their field. CFS is a multi-dimensionary research field in which studies on the brain, the cardiovascular system, metabolism, immunology, oxidation, etc are published every year. While virtually every paper on CFS begins with a short statement expressing the continuing mystery of its pathophysiology Dr. Hofford has apparently decided he knows better as he has consistently assembled teams that little reflect the rich milieu of CFS research. It is not, however, prudent to cut out large arenas of research out of the discussion in a disease of unproven pathophysiology. Entrusting review panels to an official who has repeatedly demonstrated he have no interest in much of CFS research is contrary to the strictures of the CSR that reviewers remain abreast of the fields they are overseeing.

Dr. Hoffield has argued that his review panels reflect the kinds of proposals the NIH is receiving. This seems hardly credible for reasons noted above but it is likely, given the bitterness Dr. Hoffield’s panels have engendered in CFS advocates and researchers that many CFS researchers do not believe their proposals will receive a qualified and unbiased appraisal by a review panel created by him. Panels such as these undermine the trust that CFS patients have in the public medical institutions of this country and, more importantly, impede the efforts of researchers attempting to understand a disease that not only substantially impedes the lives of hundreds of thousands of Americans but costs the U.S. economy billions a year in lost productivity.