Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study

Objective

It is not established whether myalgic encephalomyelitis/chronic fatigue syndrome (CFS) is associated with structural brain changes. The aim of this study was to investigate this by conducting the largest voxel-based morphometry study to date in CFS.

Methods

High-resolution structural 3 T cerebral MRI scanning was carried out in 26 patients with CFS and 26 age- and gender-matched healthy volunteers. Voxel-wise generalised linear modelling was applied to the processed MR data using permutation-based non-parametric testing, forming clusters at t>2.3 and testing clusters for significance at p<0.05, corrected for multiple comparisons across space.

Results

Significant voxels (p<0.05, corrected for multiple comparisons) depicting reduced grey matter volume in the CFS group were noted in the occipital lobes (right and left occipital poles; left lateral occipital cortex, superior division; and left supracalcrine cortex), the right angular gyrus and the posterior division of the left parahippocampal gyrus. Significant voxels (p<0.05, corrected for multiple comparisons) depicting reduced white matter volume in the CFS group were also noted in the left occipital lobe.

Conclusion

These data support the hypothesis that significant neuroanatomical changes occur in CFS, and are consistent with the complaint of impaired memory that is common in this illness; they also suggest that subtle abnormalities in visual processing, and discrepancies between intended actions and consequent movements, may occur in CFS.Myalgic encephalomyelitis, or chronic fatigue syndrome (CFS), as defined by the revised diagnostic criteria of the Centers for Disease Control and Prevention, is mainly characterised by persistent or relapsing fatigue lasting for at least 6 consecutive months [1]. As the aetiology of the disorder is currently unknown, it is important to establish whether it is associated with cerebral abnormalities; however, MRI has provided conflicting results when used to search for brain abnormalities in sufferers [2].A recent, large British MRI study by Perrin et al [2] of 18 CFS patients and 9 healthy volunteers, in which the images were examined for abnormalities in brain atrophy, deep white matter hyperintensities, and cerebral blood and cerebrospinal fluid flow, reported no significant differences in brain structure between the 2 groups at either baseline or 1-year follow-up, with the authors concluding that “These results throw open the debate into whether MRI scanning can reveal diagnostic signs of CFS and clinically questions the diagnoses of CFS made on the basis of previous research conclusions.”A small number of previous cerebral MRI studies have been conducted in CFS. A 1993 study involving the comparison by two radiologists of the scans of CFS patients and of controls whom had undergone imaging because of histories of head trauma or headache reported that the former had significantly more abnormal scans than controls (27% vs 2%) [3]; abnormalities included foci of increased white matter T₂ signal in 17% of the CFS patients and ventricular or sulcal enlargement in 10%. On the other hand, a 1997 study of white matter abnormalities found no significant difference between CFS patients and controls [4]. A 1999 study involving the comparison of MR scans by two to three radiologists found, overall, no significant differences between CFS patients and healthy controls, although those CFS patients without a psychiatric diagnosis since illness onset had more brain abnormalities on T₂ weighted images (mostly small, punctate, subcortical white matter hyperintensities, predominantly in the frontal lobes) than patients with such a diagnosis [5].Brain MRI analysis using voxel-based morphometry offers advantages over the methodologies used in the above studies. It is an objective method that is not operator dependent and that does not require a priori information about the location of possible differences between groups. The technique involves spatially normalising all the MR images to the same stereotactic space (by registering each of the images to the same template image, by minimising the residual sum of squared differences between them), segmenting the grey matter from the normalised images, correcting for volume changes arising from spatial normalisation and, finally, carrying out a statistical analysis to localise differences between groups; the output from the method is a statistical parametric map that shows regions where grey matter concentration differs significantly between groups [6,7].Thus far, just one voxel-based morphometry study of CFS has been published. In this 2004 Japanese study of 16 CFS patients, reduced grey matter volume was reported in the bilateral prefrontal cortex [8]. This represents the first report of focal grey matter atrophy in the prefrontal cortex of CFS patients. There have been no attempts, until now, to replicate this finding.Here, we report the largest voxel-based morphometry study of the brain in CFS.