A Central Nervous System Hypothesis of Chronic Fatigue Syndrome

“… neurophysiological and neuroimaging studies in combination with subjective or a newly developed objective evaluation method of chronic fatigue have begun to clarify the  mechanisms underlying chronic cognitive fatigue …”

Deciding that ‘chronic  fatigue’ had become not just an illness problem but a productivity concern for their economy, the Japanese initiated a program a couple of decades ago to understand and treat it. They note that a third of the Japanese population complains of  “chronic fatigue” and that “chronic  fatigue” contributes to cardiovascular conditions,  epilepsy, and early death.  Their program has encompassed all levels of fatigue from chronic fatigue to chronic fatigue syndrome. We’ve missed out on a lot of their work focused on fatigue because it doesn’t show up in searches for Chronic Fatigue Syndrome (ME/CFS).


Japan hosts one of the largest efforts to understand chronic fatigue and Chronic Fatigue Syndrome

Relative to the most of the rest of the world, the Japanese program is a large one – probably larger than the NIH/CDC efforts in the U.S.  Led by Drs. Watanabe and Tanaka, it was the Japanese that found the first direct evidence of neuroinflammation in the brains of Chronic Fatigue Syndrome patients.

The Japanese doctors believe they understand enough of the origins of chronic physical and cognitive fatigue in ME/CFS to develop a hypothesis about how they develop and why they persist.  Displaying an initiative rarely seen in western ME/CFS researchers, they’ve put their ideas on the line and actually published them.

Masaaki Tanaka, Akira Ishii, Yasuyoshi Watanabe, Regulatory mechanism of performance in chronic cognitive fatigue.  Medical Hypotheses 82 (2014) 567–571.

Tanaka M, Ishii A, Watanabe Y (2013) Neural Mechanism of Facilitation System during Physical Fatigue. PLoS ONE 8(11): e80731. doi:10.1371/

Let’s see what they have to say.

The Origins of Physical Fatigue in Chronic Fatigue Syndrome (ME/CFS)

Muscle Fatigue

When we exercise, our muscle activity is impaired by declining ATP and glycogen levels, problems with calcium transport, and oxidative stress. (The author do not believe that lactate buildup is particularly important.) Muscle fatigue due to metabolic problems, however, is not the kind of fatigue they’re interested in.  Nor do they appear to believe it plays much of a role in Chronic Fatigue Syndrome.  They’re focused on another place – the brain – and they’ve done enough original research to propose not just a new hypothesis of fatigue but to assert the presence of neural circuits specifically designed to reduce or accentuate fatigue.

Central Fatigue

muscle fiber

The motor cortex should engage more muscle fibers when we start becoming fatigued.

When we engage in any physical task, the primary motor cortex in our brain activates the motor neurons in our spinal cord which then sends a signal to the neuromuscular junction of the muscle telling the muscle to move.  As a muscle fiber becomes fatigued more muscle fibers are recruited.  So long as new, fresh muscle fibers remain to be recruited, the exercise can continue.  If no muscle fibers are left to be recruited or if the brain has a problem recruiting new muscle fibers, fatigue sets in.

When fatigue becomes apparent during exercise we can do one of two things: we can stop the exercise or we can increase our effort.  In a process they call “facilitation”, increasing our effort causes the primary motor cortex in the brain to increase its output to the muscles.

We all did this without thinking thousands of times prior to the onset of ME/CFS; we started to get tired, we increased our effort, and the fatigue disappeared for a time.  That bull-through-the-fatigue approach obviously doesn’t work well after Chronic Fatigue Syndrome has set in.

Facilitating Muscle Activity and Energy

In 2012 these researchers proposed the existence of a central nervous system circuit that allows humans to “increase their motor output”.  It includes the limbic system, basal ganglia, thalamus, orbitofrontal cortex, prefrontal cortex, anterior cingulate cortex, premotor area, supplementary motor area, and primary motor cortex.

The first six of these regions (limbic system, basal ganglia, thalamus, orbitofrontal cortex, prefrontal cortex, anterior cingulate cortex) have consistently popped up in ME/CFS studies. The last three regions involving the motor section of the brain have shown up in ME/CFS literature, but not a lot, and it’s been years since they’ve been studied. Since the motor section of the brain basically drives physical activity, it’s puzzling it hasn’t been given more emphasis in the most fatiguing disorder of them all.  The Lights noted that the most common cause of muscle failure is a decrease in the command signal from the motor cortex to the muscles. 


An earlier study suggesting impaired motor drive in ME/CFS was not followed up on

A 2003 study suggested that reduced muscle recruitment due to reduced motor cortex output might be the cause of the fatigue in ME/CFS. That study suggested that “… changing motor deficits in CFS have a neurophysiological basis [which] … supports the notion of a deficit in motor preparatory areas of the brain”.  That study titled, “Deficit in motor performance correlates with changed corticospinal excitability in patients with chronic fatigue syndrome“, to my knowledge was never followed up on.

In a process they call “central fatigue”, Watanabe and Tanaka believe the brains of people  with ME/CFS are simply not recruiting enough muscle fibers.

They also believe that reduced dopaminergic inputs into the system are thwarting motor cortex activity in ME/CFS. That’s an interesting conclusion given recent work by Andrew Miller of Emory University suggesting that reduced dopaminergic drive plays a key role in the basal ganglia dysfunction and fatigue seen in ME/CFS. (A blog on Miller’s work is upcoming.)

The Cause of Cognitive Fatigue in Chronic Fatigue Syndrome

Two years later, Watanabe and Tanaka identified a cognitive facilitation circuit that allows one to push through mental fatigue.  It consists of a neural loop that interconnects the limbic system, basal ganglia, thalamus, orbitofrontal cortex, prefrontal cortex, and anterior cingulate cortex.

Motor imaging and cognitive task studies suggest this system is not working  well in Chronic Fatigue Syndrome.  This  is probably, they believe, due to metabolic, functional and (not or) structural damage to the basal  ganglia,  orbitofrontal cortex, prefrontal  cortex and anterior cingulate.

That’s not enough, however,  to account for the extreme fatigue found in ME/CFS or other disorders.

Enter the Fatigue Inhibition System

Studies indicated that giving a maximum effort plus electrical stimulation of the motor cortex was not enough to drive the spinal motor neurons to produce maximal muscle output. That suggested another neural circuit was involved.

bottled up

The fatigue inhibition system stops the motor cortex from activating more muscles

They called this circuit the “fatigue inhibition system”, but it’s really a “fatigue enhancement system”. This is a system that, perhaps somewhat like the pain inhibition system that has gone awry in Fibromyalgia, interacts with signals from the brain. When we’re fatigued, the fatigue inhibition system stops signals traveling from the motor cortex to increase muscle performance. This system essentially locks down further muscle recruitment and induces more fatigue.  They believe this ‘fatigue inhibition circuit’ (better understood as a fatigue inducing circuit) is turned on full-time in Chronic Fatigue Syndrome.

This circuit stretches from muscle nerves to the brain, and includes everything in between. It consists of the spinal cord, thalamus, secondary somatosensory cortex, insular cortex, posterior cingulate cortex, premotor area, supplementary motor area, and primary motor cortex.

Energy System Burnout


Push the energy facilitation system too hard and the authors suggest it will burn out leaving the fatigue enhancement system in charge

The authors believe that overuse of the facilitation system via continual attempts to overcome fatigue is counterproductive and ultimately impairs the system’s ability to produce energy.  Animal models indicate that continually pushing the energy facilitation system via overwork or prolonged  stress (or perhaps pushing the system during extreme fatigue after one has gotten ME/CFS?) causes this second ‘fatigue inhibition’ to lock everything down.

Their studies suggest this is the result of classical conditioning which means, if I understand it correctly, that after repeated attempts fail, the system simply shuts off that option.

Thus, there are two parts to centrally produced fatigue. There is the facilitation process that allows us to activate the motor cortex and recruit more muscles in the face of fatigue, and there is the inhibition system that stops the facilitation system in its tracks. The second of these is in control in ME/CFS.

Prefrontal Cortex Again

“This brain region also has a crucial role in determining physical performance.”

A recent blog suggested that damage to the prefrontal cortex in ME/CFS was associated with autonomic nervous system problems, and a review of the literature indicated that damage to that area of the brain has been implicated in other fatiguing disorders.

prefrontal cortex

The authors suggest damage to the prefrontal cortex may play a critical role in the fatigue found in ME/CFS

The Japanese researchers zeroed in on the dorsolateral prefrontal cortex (DLPFC), a part of the brain that regulates of a variety of functions often impaired in ME/CFS including sensory inputs (physical sensations, over-stimulation), emotions (high emotional lability), attention span (attention what?), working memory (“please repeat that”), planning (right!), self-control (highly needed) and decision-making (agonizing). It’s the seat of executive functioning, which studies suggests is not going so well in Chronic Fatigue Syndrome.

Cognitive processes are what the prefrontal cortex is known for, but that’s not why these researchers are zeroing in on it; it also plays an important role in motor control; i.e., movement. The DLPFC connects to several parts of the brain that regulate movement including the premotor cortex, supplementary motor area, cerebellum, and basal ganglia.

Because the dorsal lateral prefrontal cortex appears to decide which process – energy enhancement or the induction of fatigue – is going to prevail, the authors hypothesize that metabolic, functional, or structural damage to this part of the brain is key to the development of fatigue in Chronic Fatigue Syndrome.

In an Nutshell

Here in a nutshell is how it appears to work: Once you begin feeling mentally fatigued you, without knowing it, activate something called the facilitation system to enhance your mental performance. This system consists of a neural loop connecting the limbic system, basal ganglia, thalamus, and frontal cortex.  It’s thrown into action mainly through dopaminergic inputs into the striatal-thalamic-frontal loop, but studies suggest those are inhibited in ME/CFS.

Cranking up this facilitation system too often (something that will surely occur in ME/CFS) causes an inhibition system (consisting of the thalamus, somatosensory cortex, insular cortex, posterior cingulate cortex, and frontal cortex) to become activated to suppress performance — to induce rest and avoid more fatigue.

The more you try to punch through your fatigue, the more the inhibition system (via classical conditioning) induces fatigue. At this point you’re in a state of ongoing chronic fatigue.

Damage to the prefrontal cortex likely pushes the brain to increase activity in the fatigue-inducing circuit.

The Japanese do not appear to include peripheral sources of fatigue in their model.  However, evidence is accumulating both in ME/CFS and Fibromyalgia that problems below the head could play a role.  The Lights at the Univ. of Utah have stated they want to do for fatigue what’s been done for pain; namely they, like the Japanese, would like to elucidate unique fatigue producing pathways in the body.  Their studies suggest hypersensitive muscle receptors in ME/CFS  may be telling the brain that the muscles have been damaged and it’s time to shut them down.

It’s good to see ME/CFS research groups working on elucidating fatigue pathways to the brain.


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