Chronic fatigue syndrome may be explained by limbic kindling

​A team of researchers have recently published a new hypothesis that could explain what causes chronic fatigue syndrome (ME/CFS) and the symptoms and physiological dysfunction associated with it. The researchers believe 'kindling', or hypersensitivity of the brain, to be at the root of the illness.

Kindling is a process that develops when the brain is chronically exposed to low-level stimuli with the ultimate result being hypersensitivity and seizure-like activity when that stimulus is encountered again at lower levels, or even in its absence. Essentially the brain is left in a state of constant "high alert".

In their paper published in the journal Neuroscience and Medicine, the scientists from DePaul University in Chicago suggest that a chronic viral illness, which may originally have been asymptomatic, may illicit an immune response involving pro-inflammatory cytokines such as interleukin-1beta (IL-1β) which act as a chronic stimulus to the brain, altering its electrical activity, and ultimately causing kindling. They add that an acute trauma like a high impact head injury sustained in a car or sports accident, for example, could also trigger the kindling response. Both scenarios are consistent with reports from ME/CFS patients regarding the onset of their illness and evidence of chronic viral infections and cytokine abnormalities have consistently been found.

While the DePaul researchers do not mention other factors as triggers for kindling, and hence the initiation of ME/CFS, it seems likely that such stimuli as toxic chemical exposure and psychological trauma, either chronic or acute, may also be involved. Toxic chemicals themselves could stimulate brain activity and/or do so via an immunological mechanism or through production of reactive molecules e.g. reactive oxygen and nitrogen species. Psychological stress causes numerous changes in physiology and levels of neuro-endocrine-immune active chemicals that might stimulate brain activity and induce hypersensitivity and kindling.

It is important to remember that ME/CFS is not a mental illness or psychiatric diagnosis. Although psychological stress may play a role in its genesis, once kindling is triggered it becomes independent of external psychological factors and is a self-perpetuating biological dysfunction.

What makes this hypothesis so interesting is that it is able to explain the various abnormal immunological, endocrine and neurological findings that studies of ME/CFS patients have shown over the past few decades.

Since kindling is a hypersensitivity response and typically occurs in the limbic system (emotional/threat response centre) of the brain it would initially result in overactivity of brain circuits and the stress response system. However, over time the authors believe that sustained kindling would result in depletion of key hormones of the hypothalamic-pituitary-adrenal (HPA) axis and result in the low cortisol levels consistently seen in ME/CFS patients. Research is conflicting but such low cortisol levels may contribute to symptoms such as fatigue and cognitive difficulties.

The HPA axis problems seen in ME/CFS (proposed to be triggered by kindling) may contribute to oxidative stress, another key finding in patients. Oxidative stress occurs when reactive oxygen molecules overwhelm the body's antioxidant defences. When this occurs the reactive oxygen molecules cause havoc with effects including direct damage to tissues, altering of gene expression, and the triggering of a pro-inflammatory immune response. A chronically activated but dysfunctional immune system being another cornerstone of ME/CFS.

Finally, by its very nature kindling would induce overactivity of the sympathetic nervous system which could contribute to fatigue and sleep problems in ME/CFS. Studies have shown that sufferers are prone to missing out on deep restorative sleep (stages 3 and 4) and instead get stuck in the first two stages of light sleep, also experiencing higher than normal levels of alpha wave activity (brain waves usually seen when awake). Additionally, the researchers explain that kindling may lead to abberations in levels of important neurotransmitters including serotonin and dopamine which would affect factors such as energy levels, sleep, and cognitive function.

Not only does this kindling hypothesis potentially explain the pathophysiology and symptoms of ME/CFS but the authors also suggest reasons why although the vast majority of the population are exposed to chronic viral infections and other stimuli implicated in kindling, only a minority develop ME/CFS. They say evidence suggests that healthy individuals with lower cortisol levels, greater heart rate variability (a measure of autonomic nervous system activity), and a predisposition to greater production of inflammatory immune chemicals are most at risk for developing ME/CFS given the presence of chronic stimuli e.g. viral infection.

This paper only presents a hypothesis, yet it is a comprehensive and intriguing one. However, further research is needed to put it to the test. The authors acknowledge the complexity of ME/CFS and point to the need for the use of systems biology to unravel it, concluding "With studies involving larger samples, it would be possible to identify many subtypes of ME/CFS. In addition, as recommended by Landmark-Høyvik et al., we need studies based on systems biology that explains the illness, in combination with more details about the environmental contributors to the illness as well as validation of findings with functional studies."

As an aside, it is interesting to note that kindling has been proposed as a mechanism to explain multiple chemical sensitivity (MCS) for many years and that many ME/CFS patients also suffer from MCS. Kindling and MCS is well described in Chemical Exposures: Low Levels and High Stakes by Ashford and Miller.

Source: Jason LA Sorenson M Porter N Belkairous N (2011) An Etiological Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Neuroscience and Medicine 2(1):14-27