Reprinted with the kind permission of Simmaron Research 
By Cort Johnson
At times Dr. Wyller of Oslo University has seemed more like a Norwegian version of Simon Wessely than anything else. He’s shown that biological issues were present in ME/CFS, but always manages to come back to the psychological or behavioral elements he believes are perpetuating the disease. His new research, however, is taking him in another direction.
Wyller appears to believe that the fatigue in ME/CFS is the result of a false alarm in the same way that pain is in fibromyalgia.
Wyller’s research group has highlighted sympathetic nervous activation and inflammation in chronic fatigue syndrome (ME/CFS) adolescents. His “sustained arousal” hypothesis, however, is a mishmash of physiological (infections, genetics) and psychological components (psychosocial challenges, illness perceptions, poor control over symptoms, “inappropriate learning processes”, personality traits, etc.).
That hypothesis posits that a “false-fatigue alarm” state exists in ME/CFS which is largely held in place by classical and/or operant conditioning. That conditioning can be ameliorated by behavioral techniques which tamp down the “alarm” and the sympathetic nervous system activation.
Wyller’s belief that ME/CFS is an infection/stress triggered disease of sympathetic nervous system (SNS) activation, however, took a hit when clonidine – an SNS inhibitor – actually made ME/CFS adolescents worse. Since SNS activation is arguably present and would certainly contribute to the inflammation in ME/CFS, that result probably shocked just about everyone. It suggested, though, that just as in some cases of POTS, the sympathetic nervous system activation found might be a compensatory, not pathological, response to the illness.
‘Sustained Arousal’ Hypothesis Not Sustained: Wyller’s Clonidine Trial for Chronic Fatigue Syndrome Fails
Wyller admits that that CBT’s “effect size” is “modest” and that there is little evidence that it helps sicker patients, but asserts that the evidence-base is “so-solid” that it should be attempted in every patient.
“We believe the evidence base for cognitive behavioural therapy is so solid that all patients with chronic fatigue syndrome/myalgic encephalomyelitis should be offered this treatment.” Wyller et. al.
Wyller 2017: the Evolution of an ME/CFS Researcher?
Wyller may be a CBT/GET apologist, but he’s mostly done physiological research, and whatever his CBT/GET beliefs, it’s difficult to pigeonhole him. His failed Clonidine trial constituted a biological approach to ME/CFS plus his 2016 followup study suggested that a genetic polymorphism in the COMT gene may be responsible for reduced physical activity and impaired sleep and quality of life in some ME/CFS patients.
It’s Wyller’s latest study, however, that takes him into entirely new ground. To his credit, he’s allowing the data to lead him where it will.
Wyller is clearly heavily invested in CBT/GET, while his Norwegian counterparts, Drs. Fluge and Mella, eschew CBT/GET and focus on Rituximab and immune modulation. Wyller mentioned Rituximab in his 2015 overview, but not surprisingly gave it short shrift because of the lack, what else, of follow up studies. But here’s Wyller in 2017 with a study that’s pointing an arrow right at the B-cells in ME/CFS and perhaps even Rituximab.
Whole blood gene expression in adolescent chronic fatigue syndrome: an exploratory cross-sectional study suggesting altered B cell differentiation and survival. Chinh Bkrong Nguyen,1,2 Lene Alsøe,3 Jessica M. Lindvall,4 Dag Sulheim,5 Even Fagermoen,6 Anette Winger,7 Mari Kaarbø,8 Hilde Nilsen,3 and Vegard Bruun Wyller. J Transl Med. 2017; 15: 102. Published online 2017 May 11. doi: 10.1186/s12967-017-1201-0 
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Using his own definition of ME/CFS, Wyller and his research team took a deep look at gene expression using a technology called high throughput sequencing (HTS) which has not been used before in ME/CFS. You never know what exploratory studies like this will turn up.* (See editor's note below)
The 176 genes whose expression was highlighted in the ME/CFS group most prominently featured a down-regulation of genes involved in B-cell differentiation. The activity of five genes involved in B-cell development, proliferation, migration and survival were significantly reduced in Wyller’s ME/CFS adolescents.
This finding, Wyller reported, jived with findings from the Australians of decreased levels of some B-cells and increased levels of others. (Decreases in the gene expression of genes regulating B-cell proliferation could result in either reductions or increases in different types of B-cells).
At the same time the B-cells in his ME/CFS adolescents were taking a hit, the expression of their innate immune system genes were being upregulated. Interestingly, given the idea that a pathogen is whacking the B-cells in ME/CFS, the expression of several genes associated with pathogen defense were increased in ME/CFS. (Wyller, in fact, reported this was the first time that increased expression of genes associated with innate antiviral responses has been seen in ME/CFS.)
Then, remarkably, Wyller – who recently criticized antivirals as he argued that CBT/GET should be the treatment of choice in ME/CFS – asserted that this finding could reflect problems his ME/CFS adolescents were having with clearing latent herpesviruses.
They “might suggest less efficient viral clearance or reactivation of latent viruses such as members of the herpes virus family, in the CFS group” Study Authors.
Then Wyller suggested that “inefficient viral clearance or reactivation” or chronic viral infection-triggered immune dysfunction warrants further study in ME/CFS.
Then he referred to a remarkable 2014 German study which suggested that a deficient B- and T-cell memory response to EBV may be making it difficult for ME/CFS patients to control EBV infections. That’s really no surprise to the ME/CFS community; it’s long been clear that infectious mononucleosis is a common trigger for people with ME/CFS and FM – but it’s for a CBT proponent to make the connection.
Finally, Wyller’s study suggested that neither inactivity nor mood disorders had any effect on the biological findings presented. (One of his earlier studies discounted the idea that deconditioning was a relevant factor. )
Wyller’s findings are good news, not just because he’s been so committed to his idea that “classical or operant conditioning” perpetuates ME/CFS, or that he’s been such a robust CBT/GET advocate, but because he has shown the ability to get funding.
His next step is to determine how effectively the B cells in ME/CFS are responding to EBV antigens (VCA, EBNA-1) before and after the introduction of stress hormones. If he finds that B-cells are not doing their job with respect to EBV, then both Wyller and the ME/CFS research field are going to have a take a closer look at the role EBV plays in ME/CFS. What a switch that would be!
Wyller isn’t the only one diving back into the herpesviruses. Two Solve ME/CFS Initiative studies are examining metabolic issues in B-cells and cells infected with HHV-6. Plus studies into B-cell issues in ME/CFS are continuing.
One wonders what further positive results would do to Wyller’s view of the appropriate treatments for ME/CFS. Given the tendency of herpes viruses to reactivate during stressful situations, stress reduction techniques (CBT, meditation, MSBR) might, in fact, be useful, but more importantly, so might antivirals, and immune modulating drugs like Rituximab or cyclophosphamide.
It’s possible that at some point that researchers on both sides of the ME/CFS divide will someday meet in the middle.
*Editor's Note: High Throughput Sequencing has been used in two prior studies: M. Frémont et al . (2013), Brenu et al . (2014).