Abstract
Kindling might represent a heuristic model for understanding the etiology of Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Kindling occurs when an organism is exposed repeatedly to an initially sub-threshold stimulus resulting in hypersensitivity and spontaneous seizure-like activity. Among patients with ME/CFS, chronically repeated low-intensity stimulation due to an infectious illness might cause kindling of the limbic-hypothalamic-pituitary axis. Kindling might also occur by high-intensity stimulation (e.g., brain trauma) of the limbic-hypothalamic-pituitary axis. Once this system is charged or kindled, it can sustain a high level of arousal with little or no external stimulus and eventually this could lead to hypocortisolism. Seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur among patients with ME/CFS. In addition, kindling may also be responsible for high levels of oxidative stress, which has been found in patients with ME/CFS.
Highlights
The kindling theory posits that repeated exposure to an initially sub-threshold stimulus can eventually exceed threshold limits, resulting in persistent hypersensitivity to the stimulus and spontaneous seizure-like activity
Seizure activity may spread to adjacent structures of the limbichypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur among patients with Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Low carnosine levels could contribute to increased oxidative stress. This genetic susceptibility may cause increased viral severity and duration, which in combination with a previous neurotropic viral infection such as Herpes viruses, Epstein-Barr Virus (EBV), XMRV, or HIV, could lead to the results found in kindling studies
Summary
The kindling theory posits that repeated exposure to an initially sub-threshold stimulus can eventually exceed threshold limits, resulting in persistent hypersensitivity to the stimulus and spontaneous seizure-like activity. As HDACs have been indicated to positively regulate pro-inflammatory gene expression [29], this could account for the increased expression of IL-8 that, in turn, suppresses the expression of cortisol [24] This dysregulation of gene expression could account for divergent immune cell class findings in those with fatigue, possibly through influence on coactivator proteins leading to differential cytokine/chemokine expression. Studies have found that patients with ME/CFS have abnormally high level of brain serotonin, and this may contribute to the persistent central fatigue [46]. Low carnosine levels could contribute to increased oxidative stress This genetic susceptibility may cause increased viral severity and duration, which in combination with a previous neurotropic viral infection such as Herpes viruses, EBV, XMRV, or HIV, could lead to the results found in kindling studies
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