In Wyller’s eyes chronic fatigue syndrome is not a ‘chronic fatigue’ disorder; it’s  an autonomic nervous system disorder. Wyller  has been studying ME/CFS for about five years; he knows the vast array of symptoms present in this disease and one gets the feeling he’s more than a little tweaked at the overwhelming focus on fatigue.

As well he should… this disorder is, after all, very, very good at  producing all sorts of symptoms;  why bury all  that richness under one symptom? Once fatigue was put in the name it was inevitable that that symptom took central stage but that doesn’t mean other symptoms won’t end up being more important.

Wyller’s results indicate you never know what’s going to pop out in a study..and how it might redefine  what you’re studying.

Instead of taking the mean, Wyller went to the edges, and found something that could help redefine this disorder

Instead of taking the mean, Wyller went to the edges, and found something that could help redefine this disorder

A New Focus: the More Severely Ill

In this study Wyller set out to figure out which symptoms contributed most to disability, what role the autonomic nervous system might play in producing those symptoms and  where the  standard definition for chronic fatigue syndrome fits into all that.

Wyller’s focus on more disabled patients  suggests  he believes you have to see it  at its worst (and weirdest)… in order to understand at its more moderate; the most severely ill patients provide the best roadmap to learning for this disorder.

The most common denominators of this disease  (fatigue, pain, poor sleep, etc.) are just too common to really tell you anything about cause. Since these symptoms can be caused by so many different things, taking this disorder to its limit and seeing what pops up there, and then reinterpreting it in the light of that, probably makes sense.

The Study

Wyller got clinical data, data on symptom severity, ability to meet the CDC criteria, disability and  autonomic measures taken during a tilt table test (20 degrees for 15 minutes) from adolescents  with severe fatigue (but not necessarily ME/CFS) and then did linear regression analyses to see what was associated with what.

The patients had to meet Wyller’s definition of chronic fatigue syndrome which is an interesting blend of the Oxford and Canadian Consensus definitions:  patients had to suffer from three or more consecutive months of unexplained disabling fatigue which was worsened by physical or mental exertion.

The patients were asked to provide clinical information  below and their BMI was measured and Wyller determined whether they  met the CDC criteria for CFS.

  • Age
  • Gender
  • Fatigue duration


They  rated their symptom levels  ()  which were put into the following categories

  •  fatigue (fatigue severity scale)
  •  cognitive alterations (memory, concentration)
  •  altered temperature control (feeling hot and cold)
  • Immune alterations (fever, lymph nodes)
  •  altered sleep (problems falling asleep)
  • Hypersensitivity (sound, light)
  •  pain (muscle, joints, head)
  •  altered peripheral circulation
  •  altered central circulation (palpitation, dizziness)
  •  gastrointestinal alterations (nausea)
  •  altered visual control
  •  altered muscle control (hand tremor)

Wyller then looked at which symptoms were most associated with  what he determined were the most disabled patients. (Bear in mind that these youngsters were healthy enough to get to Wyller and get tested etc; these are not the really, really disabled patients. They are, however, the most disabled of their set.)

Analysis of More Disabled Patients Prompts Reassessment

It turned out that disability was associated with cognitive symptoms, hypersensitivity symptoms, high fatigue score, and older age; i.e., the more disabled patients tended to have more cognitive symptoms, more hypersensitivity symptoms, be more fatigued and be older.

Even moderately well people with ME/CFS can have trouble in high stimuli environments

Even moderately well people with ME/CFS can have trouble in high stimuli environments

Fatigue was higher in the disabled patients but let’s throw that and older age out for now.  That leaves us with the more disabled patients displaying more cognitive and hypersensitivity symptoms and, of these, the hypersensitivity symptoms (to sound and light) stand out like a red flare because of how unusual they are.

Hypersensitivity to sound and light is something relatively distinct to ME/CFS and that’s what we were looking for; something that would allow us to distinguish this disorder from others.  If hypersensitivity and cognitive issues show up more in disabled patients then we have to consider if the same things causing these symptoms are also responsible for the fatigue, pain and other more common symptoms present.

The  symptoms that weren’t increased in the more disabled patients give us another reference point.  Gender differences  didn’t matter, nor did fatigue duration (these were young people) nor did sleep, pain, dizziness or immune symptoms. (Wyller only measured insomnia for sleep).  In short, many of the key symptoms in the International Definition such as muscle, joint and head pain and painful lymph nodes weren’t really  associated with disability; they were probably high (or low) in everybody.

Linking Central Symptoms with Physiological Problems; Getting at Cause?

The two key symptom sets that Wyller’s analysis uncovered were associated with ANS irregularities. Hypersensitivity was associated with increased heart rates during tilt table testing and decreased heart rate variability,  and cognitive issues were associated with increased heart rates during tilt and at baseline.

Wyller proposes chronic fatigue syndrome originates in the brainstem

Wyller proposes chronic fatigue syndrome originates in the brainstem

This suggested that sympathetic nervous system activation could be involved in producing both those problems.

Wyller’s earlier studies suggest to him that ME/CFS is a disorder of ‘sustained arousal’ and this study suggested it originates in a part of the brain stem called the locus coeruleus (LD). Because the  LC produces the excitatory catecholamine norepinephrine (noradrenaline) and  regulates sympathetic nervous system activity, it could be responsible for the increased heart rate at rest, low heart rate variability and the exaggerated heart rate responses.

That’s not all…Brain stem hyperactivity can overwhelm the prefrontal cortex impairing our ability to perform executive functioning processes (working memory, attention, problem solving, planning, etc.) which are impaired in ME/CFS. The brain stems ability to amplify sensory signals coming from the body means its hyperactivity could also cause the hypersensitivity issues. Every issue Wyller’s study has raised; cognitive problems, hypersensitivity issues and autonomic problem could all originate in the brain stem.

Exciting Stuff! (Too Exciting…)

The idea of central nervous system over-activation has gotten around. The central sensitization theory that covers FM, ME/CFS, IBS, etc. relies on it; Ashok Gupta proposed the fear center of the brain, the amygdala, plays a key role in this disorder, Jason Leonard proposes a process called ‘kindling’ has set ME/CFS patients brains aflame (so to speak), and Marco on Health Rising recently published a neuroinflammatory model of ME/CFS that pegs glutamate, the main excitatory neurotransmitter as potentially a key factor in ME/CFS.

Now Wyller has proposed that another important excitatory compound,  norepinephrine (noradrenaline),  plays a key role.  Norepinephrine directly increases heart rate, heart contractions, etc.,  regulates amygdala functioning and is released in the body in same postganglionic neurons the Lights think may be pounding ME/CFS patients brains with stimuli. Norepinephrine also appears to regulate the release of a key pain factor in fibromyalgia (substance P) from these postganglionic neurons.

Possible Hypersensitivity-Cognition Connection

Hypersensitivity and cognitive problems could go hand in hand. Sensory processing or ‘gating’ problems could  flood the brain with  so much information that it becomes difficult to concentrate on outside stimuli.  The ‘low working memories’ in chronic fatigue syndrome could reflect how difficult it is divert ones attention from  the constant flow of body stimuli flooding the brain. Could a constant din of sensory data be blunting ME/CFS patients ability to  focus on something else?   (One part of Gupta’s Amygdala Retraining model is to turn the focus away from body stimuli…)

Marco’s recent blog suggesting ME/CFS could be a  ‘sensory gating’ disorder attempts to redefine this disorder in a similar fashion.

Hypersensitivity could contribute to the some of the cognitive problems found in chronic fatigue syndrome (ME/CFS_

Hypersensitivity could contribute to the some of the cognitive problems found in chronic fatigue syndrome (ME/CFS_

Studies have shown  the  brains of ME/CFS patients have difficulty in turning their attention away from innocuous stimuli such as background noises and light (sound and light :)) to the task at hand. This difficulty could suggest a kind of ‘fight/flight’ situation in which the brain feels the need to monitor everything.  Studies  also suggest that cognitive problems even show up in such basic things as movement and coordination. Could the loss of physical grace that so many people with chronic fatigue syndrome experience be partially due to cognitive problems (linked to sensory issues?)

What about the more normal symptoms found in chronic fatigue syndrome such as pain and sleep problems?  What about post-exertional malaise? Do hypersensitivity and cognitive issues provide a clue to how those symptomsare caused?

Pain is essentially defined as a hypersensitivity issue in fibromyalgia and sensory overload could surely complicate getting relaxing sleep. Dr. Klimas finding that autonomic nervous system irregularities (fight or flight response) early in the exercise period trigger an immune cascade that causes post-exertional malaise fits well with Wyller’s model of brain stem issues ramping up the sympathetic nervous system which in turn triggers an immune response putting post-exertional malaise and possibly hypersensitivity issues into play.

Defining Moments

The fact that the CDC definition was not associated with any autonomic measures or disability suggests the definition is missing some key elements. If Wyller’s study is correct, if you were to take a lot of people with ‘chronic fatigue’ and then picked out the most disabled ones – they would not be the ones that met the CDC definition for CFS.  Certainly some disabled people would meet the criteria but others would not. Nor does the definition pluck out people with autonomic nervous system issues; a worrying situation given how important that research field is becoming.

Wyller’s analysis, interestingly, enough suggested to him that this really is all one disorder. In fact, he appears to believe that chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome are all the same type of disorder.


This study comes with a number of proviso’s and Wyller called the study ‘exploratory’.  These types of studies uncover associations but never prove causality. The small size of the study limited  the number of symptoms Wyller could measure and it’s overall power. Wyller used  his own unvalidated measure of disability and the studies focus on adolescents means it may not apply to adults.   On the plus side the very strong  ‘significance’ values (p<.000x)  suggested Wyller may very well be  onto something.

  • Next Up: we take a deeper look at what Wyller believes is the seat of it all –  the Brain Stem and Chronic Fatigue Syndrome

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