Fig. 3

Hypothetical model of the development of chronic fatigue. When subjects are acutely fatigued through overwork and/or stress, they progressively increase their voluntary effort to maintain their performance to compensate for acute fatigue until the work requires a maximal effort. At that point, the facilitation system in the central nervous system is activated to overcome acute fatigue. The facilitation system consists of a re-entrant neural circuit that interconnects the limbic system, basal ganglia, thalamus, orbitofrontal cortex, prefrontal cortex, and anterior cingulate cortex, and a motivational input activates this system. In addition, as subjects become acutely fatigued, an alarm signal to take a rest (inhibitory system) is activated to avoid further fatigue. The inhibition system consists of a neural pathway that involves the insular and posterior cingulate cortices. After repetitive and prolonged overwork and/or stress that activates the facilitation system without sufficient recovery, the facilitation system dysfunctions, through neural damage to it caused by oxidative stress, inflammation, and energy deficiency. Subjects express impaired information processing in the central nervous system. In addition, repetitive and prolonged overwork and/or stress cause central sensitization and classical conditioning of the inhibition system. This conditioned inhibition system occurs in subjects with chronic fatigue, resulting in a long-lasting alarm signal to take a rest and a severe sustained fatigue sensation and functional disabilities