Most studies in ME/CFS are cross-sectional in nature – researchers look at patients and controls at one point in time and make comparisons between the two groups. These investigations have their uses, but they don’t tell us about changes over time, which can be considerable if there is a continuing disease process. For instance, we know that ME/CFS patients who have been ill for longer periods have clinical and biochemical characteristics that differ from patients with a shorter illness duration (read more), and that age itself is a factor (read more), so investigations into the course of disease over years may be of great value.

One of the very few longitudinal studies in ME/CFS has just been published by researchers at Griffith University, Australia (read the report). The patients met both the Fukuda 1994 and Canadian criteria 2003, and had taken part in a study in 2011 which found a relative reduction in white matter in the midbrain of ME/CFS patients compared with healthy controls (see our overview). After approximately 6 years, 15 of the original ME/CFS patients and 10 healthy controls were still contactable and agreed to participate in a repeat evaluation, using the same MRI scanner, to measure any progressive changes in the brain.

Overall, there were no significant differences between the patients and the controls in the total volume of brain grey matter (which contains the bodies of nerve cells that serve to process information) or white matter (which contains mainly nerve fibres). In both groups, however, the total grey matter volume  had decreased and total white matter volume increased over the 6 years, presumably because of natural ageing.

It was when the researchers looked at two specific areas that they noticed pronounced changes over time. In ME/CFS patients, but not in the controls, there was a significant decrease in the volume of white matter (relative to the global volume) in the left inferior fronto-occipital fasciculus (IFOF) and/or the arcuate fasciculus. In addition, there were corresponding changes in grey and white matter volumes in neighbouring brain regions, and the brain volume changes were found to correlate with patients’ symptom scores.

Diagram showing principal systems of association fibres in the cerebrum. Gray's Anatomy, Plate 751

Diagram of principal systems of association fibres in the cerebrum. Gray’s Anatomy, Plate 751

The IFOF is a particular bundle of nerve fibres that passes backward from the frontal lobe, its fibres radiating in a fan-like pattern as it passes into the occipital and temporal lobes. It represents one of the many ‘long association fibres’ that unite different parts of the same hemisphere of the brain (see diagram). It’s thought that the IFOF connects attention, language processing and working memory networks, and its continuing shrinkage over time may be associated with the memory, concentration and attention problems and visual deficits known to occur in ME/CFS. Similarly, the arcuate fasciculus (part of the superior longitudinal fasciculus – see diagram) connects two areas that are important for language, and abnormalities in this structure were reported recently in ME/CFS patients by researchers at Stanford (read more).

The authors conclude from these longitudinal findings that ME/CFS is a chronic illness with abnormal connections among brain regions and reductions in white matter that continue as the illness progresses. This is in line with the findings of a recent literature review suggesting that structural changes in the brain and alterations in connectivity are a feature of the illness (read more).  What remains unknown is why the abnormalities in brain white matter are occurring. It may be, as the authors suggest, that a gradual and chronic reduction of blood flow (hypoperfusion) to the brain contributes to continuing shrinkage of white matter, with a corresponding increase in regional grey matter as the brain tries to compensate for the loss. However, white matter is thought to be highly susceptible to inflammation, and its loss could well be the result of chronic oxidative stress (read more) or an ongoing infectious process.

This report adds to the growing body of evidence that structural brain abnormalities, including problems of connectivity, feature prominently in ME/CFS. For this reason, ME Research UK actively welcomes applications from established researchers using state-of-the-art MRI technologies to carry out studies of brain structure and function, akin to the Australian study on youngsters which is underway.

fMRI example