The brain imaging studies have brought some real excitement to the CFS research field. Among others they have suggested CFS patients have reduced blood flows to the brain, altered patterns of brain activation, reduced grey matter volume, altered serotonergic neurotransmission, reduced acetyl carnitine uptake and others.

Dr. Lange is a careful and conservative researcher and her talk brought us down to earth a bit. She noted that the brain is a difficult organ to study and elucidated a large number of possibly confounding variables (amount of resolution, different normalizing protocols, different types of brain slices, etc.) found in them. She noted that all the early brain imaging studies had poor methodology or sampling techniques. Her point was elucidated when a physician asked her about the remarkable similarity he had seen in the brain images of his CFS and MS patients. Dr. Lange replied that the CFS sample set must be very carefully assessed and gathered, that she sees no such similarities in her CFS patients, and that these kinds of findings are a big problem in CFS research.

This said, she gave us her view of what we can say with some assurance about the CNS research in CFS:

• The major cognitive problem seen is in ‘information processing’.
• The studies showing reduced cerebral blood flows are starting to show consistency.
• There appears to be a problem with serotonergic neurotransmission in the hippocampus and anterior cingulate regions of the brain.
• The brain volume reductions appear to be relatively minor.
• There appear to be spinal fluid abnormalities
• fMRI studies are showing altered patterns of brain activation in CFS.

Dr. Lange believes CFS studies need to be more rigorous. She believes CFS patients need to be carefully screened and to be accompanied by appropriate control groups and they should be stratified according to sex, type of onset, presence of mood disorder (and probably others). She also, much like Dr. Hanna of the NIH, wants more hypothesis driven studies and fewer fishing expeditions. She sounds like she is quite intrigued but not yet convinced about the central nervous system findings to date.

Just about everybody believes that neuro-immune interface is disturbed in CFS but this is the first study I know of that has tried to unite immune findings with brain scans. This international collaboration between researchers from Spain, Belgium and Australia used a SPET scan to look at patterns of brain activity. Not surprisingly they found that areas of the frontal lobe including the anterior cingulate had reduced activity levels.

They then checked to see if these abnormalities were correlated with abnormal immune readings and they found that they were; they found that CFS patients with more abnormal RNase L measures, in particular, but also elastase levels tended to display the most altered brain activity patterns. The brain abnormalities were not, however, correlated with symptom expression, i.e. they were not accentuated in the most severely ill patients. Unfortunately there was no control group.

A. Garcia Quintana, A. Garcia-Burillo, J. Alegre-Martin, I Mena, J. Garcia-Quintana. Brain SPET quantification in Chronic Fatigue Syndrome: comparison of basal and post-stress studies.

This group from Spain used a SPET scan to examine brain activity before and after an exercise session. This, again, is the first time, to my knowledge, that this has been done. It found that one area in particular, the Wernicke area, showed evidence of reduced activity after exercise. This area, which is found in the cerebral cortex, is thought to be ‘essential for understanding and formulating coherent speech'. (This certainly rings true for me.) Other areas in the temporal lobe were affected. Interestingly it was difficult to tell if the anterior cingulate region was affected because the activity in this region was too low to begin with.

The actigraphy (activity) study found that there were four different types of fatigue; long sleepers (hypersomnia-like), severe insomnia, short sleep (‘wired but tired’ – hyposomnia), and delayed sleepers. When this researcher looked at heart beat variability he found that parasympathetic nervous system activation was significantly decreased during sleep in CFS patients.

This study examined how often CFS shows up in the children of mothers with CFS. It found a rather shockingly high rate of either CFS (5.5%) or chronic fatigue (11.5%) in these children. Remarkably 24% of the mothers with CFS had at least one child with CFS or CF. Dr. Underhill noted that these numbers were low as some children will develop CFS as they age. Interestingly, most of the children with CFS were born before their mothers came down with it. This perhaps suggests an infectious component is present (?) That none of the adopted or step children became ill suggested that genetics plays an important role. Recovery rates seemed pretty high with half the children with CFS recovering over time.

Next up we have a study that appears to confirm Dr. Underhill’s findings.

Utah is our Sweden, in that the Mormons’ fascination with genealogy has left us with a data base that can be used to tease out the role heredity plays in disease. These researchers did statistical analyses on over 600 people with CFS to determine if they tended to be more related than would be expected. They found that they were. This suggests that some people have a genetic predisposition to getting CFS.

Then they looked at the CFS patients closest relatives to determine if they had higher rates than normal of pain and fatigue related diseases and again they did; these people had much higher than normal rates of migraine, irritable bowel syndrome, Raynaud’s disease, temporal mandibular disorder, osteoarthritis and myalgia. What about fibromyalgia? Rates of myalgia (muscle pain) were increased even in these patients’ distant relatives. This suggests that a genetic abnormality may underlie all these diseases and that they are at least distantly related to CFS.

They concluded that genetics plays a significant role in CFS.

Some researchers believe that CFS and fibromyalgia and other disorders such as TMD/TMJ, IBS and MCS are part of a broad spectrum of overlapping disorders that have a similar central nervous system abnormality that remains to be uncovered. We have seen, for instance, Dr. Kuratsune posit that dysfunctions in two closely related parts of the brain result in diseases either of pain or fatigue. People with problems in both experience both pain and fatigue.

This large study (217 CFS/184 FM) of well defined female patients examined the distribution of 90 single nucleotide polymorphisms (small gene mutations) to determine if the two groups had a similar genetic makeup or a different one.

It found that each group had a set of mutations that were unique to it, suggesting that these two diseases are quite different. Interestingly if they collapsed the CFS and FM patient data together, they couldn’t differentiate them from the controls. This suggests that not only did each disease present with unique gene mutations but that they didn’t even share many gene mutations. This indicates that, at least with regard to the mutations tested, these two groups are genetically quite different – a surprising finding.

Importantly this study highlighted many of the same genes as did the CDC studies on gene mutations; they included corticotropin releasing factor receptors, several serotonin transporters, glucocorticoid and dopamine receptors, trytophan metabolism and intriguingly a gene involved in inducible nitric oxide synthase, IL-6, and and to round it off, even a calcium channel transporter. This illustrates that the CDC and this group are very much on the right track here.

B. Evengard, H. Grans, M. Nilsson, K. Dalman-Wright. Reduced levels of oestrogen receptor (beta) mRNA in Swedish patients with Chronic Fatigue Syndrome.

CHASING DOWN THE FATIGUE GENES