Measuring Fatigue Finally?

Has a test that objectively measures fatigue been found?

Has a test that objectively measures fatigue been found?

How to objectively measure fatigue has dogged chronic fatigue syndrome field for decades. Until researchers can tell how fatigued a person really is people with ME/CFS and FM will always have to deal with the “I’m tired, too” response from both their friends and from  the medical  community.

An objective measure of fatigue, on the other hand, would differentiate the normal fatigue that healthy people experience from the numbing exhaustion that people with ME/CFS and FM often experience. It would allow the measurement of a fatigue that is more than fatigue; it would enable researchers to measure a pathological state of exhaustion.

These Japanese researchers have been examining fatigue closely for decades now, and they think they may have not only found a way to measure fatigue but to assess post-exertional relapse as well.  That sounds like a recipe made for ME/CFS.

They did this by a)  knocking people on their butt a bit and b) then carefully measuring how their autonomic nervous system (ANS) responded.

Autonomic Nervous System Breakdown = Fatigue?

Prior studies have found that giving healthy people short-term fatigue-inducing mental exercises results in decreased parasympathetic nervous system (PNS) activation and increased sympathetic nervous system (SNS) activation.  A longer eight-hour test designed to simulate an eight-hour working day indicated that fatigue was also associated with SNS hyperactivity and a corresponding reduction in PNS activity.

This is the same pattern of autonomic nervous system functioning found in ME/CFS and fibromyalgia. The difference, of course, is that you don’t need to whack ME/CFS patients with a fatiguing inducing mental test to institute this type ANS ‘breakdown’;  studies indicate it’s present all the time  – even when they’re asleep.

The Study

Fatigue correlates with the decrease in parasympathetic sinus modulation induced by a cognitive challenge. Kei Mizuno, Kanako Tajima, Yasuyoshi Watanabe, and Hirohiko Kuratsune. Behavioral and Brain Functions 2014, 10:25  http://www.behavioralandbrainfunctions.com/content/10/1/25

In this study, they used a difficult cognitive test called the Kana pick-out test (KPT). It had the 28 healthy college-age female participants in the study read a story while asking them to simultaneously count the vowels in the story, and then answer questions about the story afterward.

Prior to and after the 4-minute KPT the subjects rested with eyes open for 3 minutes and then eyes closed for 3 minutes.  During the entire 16 minutes, the researchers recorded electrocardiography (ECG) for subsequent statistical analysis to assess ANS functioning.  Subjects self-reported their fatigue on a 0 to 100 scale at the beginning of each period.


The researchers found that the self-reported perception of fatigue was, as they had found earlier, positively correlated with decreased parasympathetic nervous system (‘rest and digest’) activity and increased sympathetic nervous system (‘fight or flight’) activity.

The authors targeted the brains autonomic network that controls the wide array of ANS functionsin the body.

The authors targeted the brain’s autonomic network that controls the wide array of ANS functions in the body.

They noted that the autonomic nervous system is controlled in the brain by a central network composed of the prefrontal cortex,  anterior cingulate, insula, amygdala, hypothalamus, and periaqueductal gray matter.

Note that the 2011 Barnden ME/CFS study we just covered found reduced grey or white matter in three of these areas;  the prefrontal cortex, hypothalamus, and periaqueductal regions, and reductions in these areas were associated with autonomic nervous system problems in ME/CFS.

Prefrontal Cortex Targeted

These Japanese researchers focused on the prefrontal cortex in the front part of the brain. The prefrontal cortex is in charge of knocking down sympathetic nervous system-charged ‘threat circuits’;  i.e. it’s the part of the brain that turns the threat response off.

A Region of Concern in Chronic Fatigue Syndrome

Studies suggest that the prefrontal cortex has indeed taken a hit in ME/CFS.  Along with other parts of the autonomic network in the brain, the Barnden study found reduced white matter levels in the prefrontal cortex were present in people with ME/CFS.  Since white matter is the communication conduit through which the signals in the brain pass, reduced white matter in the prefrontal cortex could reduce its ability to turn off the ‘threat circuits’ in the brain.

frontal lobe

The prefrontal cortex has shown up in several ME/CFS studies and in other fatiguing disorders.

The same Japanese group found that reduced grey matter in the prefrontal cortex was highly associated with fatigue in ME/CFS.  A 2002 study by this group finding reduced acetylcarnitine uptake in the prefrontal lobe  (and other regions of the brain) in ME/CFS  suggest the prefrontal cortex was not up to snuff. Ten years ago this group suggested “the prefrontal cortex might be an important element of the neural system that regulates sensations of fatigue.”

The Zinn study reported at the Stanford Symposium found increased delta brain waves primarily in the frontal and limbic areas of the brain. They suggested a prefrontal-limbic connection between the prefrontal cortex and these important ANS-regulating areas of the brain was important. This was intriguing given the Barnden study finding that the prefrontal cortex might not be communicating well with the rest of the brain.  

A small study found that reduced prefrontal cortex oxygenation during exercise implicated exercise in the prefrontal cortex findings in ME/CFS.  The prefrontal cortex is also in charge of executive functioning which cognitive studies indicate is impaired in Chronic Fatigue Syndrome.  Executive functioning is commonly measured with the KPT mentioned earlier.

Other studies indirectly link prefrontal cortex dysfunction with increased fatigue. Increased prefrontal cortex lactate levels that were found in people with Gulf War Syndrome who did worse on a cognitive test after exercise, again linked energy production in the prefrontal cortex with exercise issues.

Alpha interferon (IFN-a) administration in hepatitis C patients creates similar levels of fatigue and the same kind of basal ganglia dysfunction that’s present in ME/CFS. The fact IFN-a administration also reduces glucose metabolism in the prefrontal cortex suggests that damage to this part of the brain (and energy production again) could play a key role in fatigue production.

If these researchers are right, the inability to effectively rest and recover from  ‘stress’ in ME/CFS may reflect an inability of the prefrontal cortex (and perhaps other parts of the autonomic network in the brain) to knock down sympathetic nervous system-derived ‘threats’ and reinstate the rest and digest (PNS) system.  Fatigue appears to be correlated to the extent to which the parasympathetic nervous system fails to assert itself during rest.

The prefrontal cortex is clearly a part of the brain to keep an eye on in ME/CFS.

Another Way to Explain Why You Need Peace and Quiet

This study also revealed one reason people with ME/CFS often go to a dark place and close their eyes when they’re fatigued. It turns out that sympathetic nervous system activity is higher when our eyes are open.

Sleeping dog

Why do people with ME/CFS and FM seek quiet places? Perhaps to calm down their sympathetic nervous systems…

The ECG revealed no differences in sympathetic nervous system functioning in the healthy controls whether their eyes were open or closed before the cognitive test. After the cognitive test, however, when their eyes were open, their SNS activity was increased, their PNS  activity was decreased, and as expected – their fatigue was increased. When their eyes were closed, however, their SNS activity decreased, their PNS activity increased, and their fatigue was reduced.

It appeared that the strain of the cognitive test had momentarily wiped out the ability of even these healthy brains to rein in their SNS when their eyes were open.

This, of course, makes perfect sense to ME/CFS patients who recognize that lying down in a dark place with their eyes closed is helpful.  This study suggests they’re engaging in an instinctual attempt to calm down their SNS (fight or flight system), bump up their PNS (rest and digest system) and reset their autonomic nervous system.  (Unfortunately studies indicate that the sympathetic nervous systems in ME/CFS tends to remain engaged even during sleep.)

Has an Objective Measure of Fatigue Been Found?

“The extent to which parasympathetic nerve activity is inhibited in the recovery phase of the resting state in the eyes-closed condition may depend on the extent of fatigue.” The authors

The link between autonomic nervous system (ANS) dysfunction and fatigue is growing.  Studies both in healthy people and in severely fatiguing disorders such as Chronic Fatigue Syndrome,  multiple sclerosis, and primary biliary cirrhosis indicate fatigue is associated with alterations in ANS functioning — specifically, increased sympathetic nervous system and reduced parasympathetic nervous system activity.


An objective test of fatigue would validate an often-dismissed component of
“Chronic Fatigue Syndrome”

This Japanese research group proposed that their test protocol described above might be able to quickly and easily assess the degree of exertion-induced fatigue present.

The degree to which the parasympathetic nervous system fails to return to its normal resting state after a short cognitive test would determine the level of fatigue present.

Being able to objectively validate the fact that the fatigue in ME/CFS or FM is not similar to the fatigue healthy people occasionally experience would be a major step forward. A pathological state of fatigue associated with a pathophysiological finding – a damaged parasympathetic nervous system – would validate the seriousness of ME/CFS and open new fields of research.

This is the same team, by the way, that startled the ME/CFS community this year with its finding of widespread neuroinflammation in the brain.


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