White Matter

From: <a href="http://www.meresearch.org.uk/news/brain-white-matter/">White matter abnormalities | ME Research UK</a>

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 (<a href="http://www.meresearch.org.uk/news/robust-evidence/">read more</a>), and that age itself is a factor (<a href="http://www.meresearch.org.uk/news/mecfs-in-elderly-people/">read more</a>), 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 (<a href="http://onlinelibrary.wiley.com/doi/10.1002/jmri.25283/full">read the report</a>). 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 (<a href="http://www.meresearch.org.uk/news/insult-midbrain/">see our overview</a>). 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 of principal systems of association fibres in the cerebrum. Gray’s Anatomy, Plate 751

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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 <a href="http://www.meresearch.org.uk/news/memory-and-attention-problems/">memory, concentration and attention problems</a> and <a href="http://www.meresearch.org.uk/our-research/completed-studies/vision-related-symptoms/">visual deficits</a> 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 (<a href="http://www.meresearch.org.uk/news/brain-abnormalities-in-mecfs/">read more</a>).

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 (<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761639/">read more</a>). 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 (<a href="http://www.meresearch.org.uk/our-research/ongoing-studies/combat-oxidative-stress/">read more</a>) 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 <a href="http://www.meresearch.org.uk/our-research/call-for-applications-2016/">applications</a> from established researchers using state-of-the-art MRI technologies to carry out studies of brain structure and function, akin to the <a href="http://www.meresearch.org.uk/our-research/ongoing-studies/neurological-biomarkers/">Australian study on youngsters</a> which is underway.

From: <a href="https://link.springer.com/article/10.1007/s12035-017-0598-z">A Comparison of Neuroimaging Abnormalities in Multiple Sclerosis, Major Depression and Chronic Fatigue Syndrome (Myalgic Encephalomyelitis): is There a Common Cause? | SpringerLink</a>

Early research investigating potential neuroanatomical abnormalities using MRI focused on WM using observer-dependent analysis [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR14">14</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR179">179</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR180">180</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR181">181</a>]. Natelson and others reported subcortical WM hyperintensities in 52 subjects fulfilling the original CDC selection criteria [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR182">182</a>] compared with a control group who had undergone MRI investigation for head trauma [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR179">179</a>]. On the other hand, Greco and others reported widespread demyelination in many of their CFS participants but at a group level, WM hyperintensities were not significantly different from healthy controls [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR180">180</a>]. However, Lange and others also reported significantly increased WM hyperintensities in their CFS group who were free of comorbid anxiety or depression compared with healthy controls and CFS subjects with co-morbid psychopathology [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR183">183</a>]. Interestingly, when the data obtained from the two CFS groups were combined, the levels of WM hyperintensities were not significantly different from the control group [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR183">183</a>]. In another large study involving 48 CFS patients, Cook and others reported widespread WM abnormalities in their cohort whose extent correlated with symptom severity [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR14">14</a>]. It should also be noted that a more recent MRI study using observer-dependent methods failed to detect any WM abnormalities in their CFS cohort although these patients were not recruited according to international consensus guidelines [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR184">184</a>].

Recent studies based on T1- and T2-weighted MRI using VBM have universally reported significantly increased WM abnormalities in CFS subjects selected according to the “Fukuda” CDC criteria compared with healthy participants [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR185">185</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR186">186</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR187">187</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR188">188</a>]. Puri and others reported reduced WM voxel volumes in the left occipital lobe while Barnden and others reported reduced WM voxel volumes in the frontal cortex, caudate and hypothalamus [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR185">185</a>, <a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR186">186</a>]. Pertinently, Shan and others reported decreased WM volume in the left frontal occipital lobe and the fasciculus whose extent increased with self and clinically assessed symptom severity and also worsened over time [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR188">188</a>]. Finally, Barnden and others reported reduced WM volume in the prefrontal cortex, the ventrolateral thalamus and internal capsule even following correction for the potential effects of anxiety and depression [<a title="View reference" href="https://link.springer.com/article/10.1007/s12035-017-0598-z#CR187">187</a>].