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Does Chronic Fatigue Syndrome have a Neurological Origin?

By Leighton Barnden

Chronic Fatigue Syndrome may result from damage to a small but critical brain structure.

Chronic Fatigue Syndrome (CFS) is distinguished by a persistent malaise and lethargy that physical or mental exertion exacerbates for a period of several days. Sufferers can identify a clear-cut beginning to their condition. In many, it follows a viral infection such as glandular fever. Sufferers also experience cognitive difficulties and, sometimes, autonomic disturbances such as dizziness on standing, gastrointestinal upsets, cardiovascular irregularities and immune system dysfunction.

Despite this litany of symptoms, the exact diagnostic criteria for CFS are controversial and remain under review. This is all the more troubling because the root cause of CFS has not been identified.

In a new magnetic resonance imaging study of the brain involving 25 CFS and 25 control subjects (, sophisticated image processing and statistical analysis investigated local changes in grey matter and white matter volumes, and in myelin levels and blood volume. Myelin, in the form of a sheath around the axon of each nerve cell, controls nerve impulse conduction to elsewhere in the brain or the body. Myelin is what makes white matter white, while grey matter contains the working nerve cells. At sites throughout the brain, the study looked for changes in these MRI measures that correlated with CFS severity or duration.

White matter volume in the midbrain at the top of the brainstem decreased with longer CFS durations (blue in picture). The midbrain was also identified as a site of neuro-inflammation in CFS.

Neither of these observations, however, provides clues about underlying functional changes in the midbrain. A key insight was provided by the observation that myelin levels increased in the internal capsule (red in picture) when CFS symptoms were worse. The internal capsule is a white matter structure that carries nerve fibres from the midbrain to the cortex (the thinking part of the brain) after passing through a relay called the thalamus.

At first this seems counterintuitive. Why should increased myelinisation, and therefore improved nerve signal conduction, occur in more severe CFS?

This is not really such a paradox, as it is consistent with a compensatory response to weakened nerve impulses that arrive from the midbrain. That is, the midbrain shrinkage and inflammation are associated with impaired nerve impulse conduction, which stimulates upregulation of myelinisation in the unaffected internal capsule upstream from the midbrain.

The midbrain is a conduit for multiple two-way communications within the brain and to and from the body. In particular, it carries the input and output signals of the stress-handling hypothalamus, fibres that deliver hormones that influence cortical activity, and a complex of communicating fibres that constitute the reticular formation.

The reticular formation monitors body and brain activity to maintain appropriate cortical activation, and is involved in the inhibition of cortical activity that is necessary for sleep. Thus impaired nerve signal conduction in the midbrain can have far-reaching consequences and can potentially account for the major cognitive, autonomic (including immune) and sleep disturbance symptoms of CFS.

The bitter pill for sufferers is that their symptoms may derive from damage to the midbrain that is irreversible. Their symptoms may be lessened, however, if an effective control is developed for the associated inflammatory response.

The cause of such midbrain damage is unknown, although laboratory work suggests it may derive from a runaway process in which the immune cells of the brain (microglia), triggered by inflammatory signal molecules from infections in the body, amplify their own signal molecules to neurotoxic levels.

Dr Leighton Barnden is an imaging consultant at the National Centre for Neuroinflammation and Emerging Diseases at Griffith University.