The following is a summary of : "Gray Matter Volume Reduction in the Chronic Fatigue Syndrome," by de Lange F.P. et al.,  NeuroImage July 26 (3) (2005): 777-781.

The team conducted this important research at the Centre for Neuroimaging at Radboud University in Nijmegen in the Netherlands. They used " unbiased morphometric technique to test whether CFS patients display structural cerebral abnormalities (in the brain)."

Structural cerebral morphology (physical character) and volume were mapped in two separate groups of Chronic Fatigue Syndrome (CFS) patients (in total 28 patients) and healthy controls (also totaling 28 patients). This mapping was conducted using high-resolution structural magnetic resonance images "...using voxel-based morphometry (VBM). Additionally, we recorded physical activity levels to explore the relation between severity of CFS symptoms and cerebral anamolies." [Massachusetts CFIDS/ME & FM Association emphasis].

An important aspect of the research was the use "...of a fully automated, observer independent procedure [VBM, which]...provides an unbiased and validated...technique for measuring cerebral volume and tissue concentration..."

The team also used actigraphic assessment to measure the physical activity levels of patients as well as that of a portion of the healthy controls.


The study was restricted to women for several reasonsincluding the fact that more women than men suffer from CFS and also because of the differences in brain size and morphology between the sexes.

The first cohort consisted of 13 CFS patients (mean age: 28.9 years) and 15 healthy controls (mean age: 25.7 years). The two groups were matched for age, sex, and education. The second cohort consisted of "...15 older CFS patients (mean age 43.9 years)..." and an appropriately matched group of healthy controls. Two weeks prior to the scanning, 26 of the CFS patients and 14 of the healthy controls were evaluated for their physical activity level. This was done using a motion-sensing device that fits on the ankle. The device provides an activity score for each 5 min. of movement (multi-directional). This device was worn continuously day and night for at least the 14-day period.

Only patients meeting the 1994 CDC diagnostic criteria were included in the studybut, significantly, any patient exhibiting depression was excluded. (Note: while many patients with ME/CFS actually show secondary depression, the exclusion increased the likelihood that more patients who really do have ME/CFS were included in the study.)

Two other measures of the patient group were included: self-reported disease severity (measured by the Checklist of Individual Strengtha questionnaire that measures fatigue), and self-reported disease duration.

Imaging protocol:

Images of the whole brain were analyzed "...for computational analysis of differences in global and local gray and/or white matter volume." Highly sophisticated techniques were used to provide valid comparisons by normalizing a variety of variables (including population-specific biases). Then, in a second stage, statistical methods were used to correct for non-uniformities in "...signal intensity and partitioned into gray and white matter, cerebrospinal fluid, and background."

In the statistical analysis, "Global differences in gray and white matter between groups were assessed..." taking into account age as a confounding covariant." Statistical methods were also used to assess, correct and correlate physical activity and gray matter volume, and regional differences (in the brain) in gray matter between groups taking into account age and other variables.


"Both cohorts of CFS patients showed significant reductions in gray matter volume...compared to healthy controls." Even when the two cohorts are put together the reduction of gray matter in patients remains "highly significant", amounting to a reduction of "approximately 8%".

The study, interestingly, did not find a difference in gray matter reduction by brain region the reduction in gray matter was only significant globally. There were also no local foci of reduced gray matter.

"White matter volume was not significantly different between groups."

Correlation with physical activity

There was a positive correlation between daily physical activity and gray matter within the CFS patients. At the same time, there was no such correlation in the control group. The age variable was found not to affect the physical activity level in the CFS group. This means that the positive correlation between gray matter and physical activity in the CFS population is not countered by the age variable. "There were no significant correlations between gray matter and...illness duration or CFS measured by the Checklist of individual Stength."


"Our findings appear to provide a reliable somatic marker for CFS." The authors suggest the finding may corroborate the primary involvement of the central nervous system in ME/CFS. However, the authors acknowledge that the meaning of the findings may not be "straightforward". The correlation between reduced global gray matter and reduced physical activity in CFS cohorts might be causative—that is the reduced gray matter might be influencing the ability to conduct physical activity.

Alternatively, the reduction of physical activity caused by ME/CFS might be itself having the effect of reducing gray matter in the brain.

There is some research that lends credence to the effect of reduced physical activity on the amount of gray matter in the brain. However, interestingly, in this study illness duration was not found to affect the gray matter decrease in the CFS subjects. This would, obviously, suggest that the reduction of gray matter in the CFS subjects was not due to reduced physical activity.

The study found "...substantial and consistent reductions in gray matter CFS patients... This GM reduction was associated to the decline in physical activity in the CFS patients..."