Brain abnormalities in ME/CFS

Examples of T1 weighted, T2 weighted and PD weighted MRI scans
Examples of T1 weighted, T2 weighted and PD weighted MRI scans

Prof Jose Montoya’s group at Stanford University School of Medicine has just published a scientific report (see abstract below) containing some striking results. The researchers’ aim was to see whether ME/CFS patients had “differences in gross brain structure, microscopic structure, or brain perfusion that may explain their symptoms”, so they compared brain MRI images from 15 ME/CFS patients, chosen from a group which had been followed over many years, with images obtained from 14 age- and sex-matched healthy volunteers with no history of relevant symptoms.

They found abnormalities in a brain tract called the arcuate fasciculus, as well as reductions in the volume of white matter in the brain in patients compared with healthy controls. In the accompanying press-release, lead author Dr Michael Zeineh, assistant professor of radiology, explained that “Using a trio of sophisticated imaging methodologies, we found that CFS patients’ brains diverge from those of healthy subjects in at least three distinct ways.”

Overall, the three key findings were, first, that white-matter content (which tends to carry information between different parts of the brain) was reduced, by about 7%, in the brains of ME/CFS patients compared with healthy subjects. Second, using an advanced imaging technique, diffusion-tensor imaging, a consistent abnormality in the right arcuate fasciculus (which connects the frontal lobe and temporal lobe) was identified, and there was a thickening of the grey matter at the two areas of the brain connected by the right arcuate fasciculus. Lastly, the researchers reported a significant correlation between the severity of the patient’s condition (assessed by psychometric and other testing) and the degree of abnormality in the right arcuate fasciculus.

The San Francisco Chronicle has published an interesting context article on the results, and it quotes Dr. Michael Zeineh, the lead author, as saying, “White matter is thought to be highly susceptible to inflammation, and researchers have previously noted other areas of inflammation in patients with chronic disease, so this result wasn’t surprising….Unexpected, however, was the discovery of abnormalities in the arcuate fasciculus…” As the article points out, the Stanford study adds to the growing body of evidence that people with ME/CFS have real physical defects, especially in the central nervous system, and may point to an underlying mechanism in the disease process.

The last word goes to Prof Montoya who is planning a substantially larger study to explore the findings: “In addition to potentially providing the CFS-specific diagnostic biomarker we’ve been desperately seeking for decades, these findings hold the promise of identifying the area or areas of the brain where the disease has hijacked the central nervous system”. He makes the point, however, that these results, though quite robust, need to be confirmed. “This study was a start. It shows us where to look.”


To identify whether patients with chronic fatigue syndrome (CFS) have differences in gross brain structure, microscopic structure, or brain perfusion that may explain their symptoms.

Materials and Methods
Fifteen patients with CFS were identified by means of retrospective review with an institutional review board–approved waiver of consent and waiver of authorization. Fourteen age- and sex-matched control subjects provided informed consent in accordance with the institutional review board and HIPAA. All subjects underwent 3.0-T volumetric T1-weighted magnetic resonance (MR) imaging, with two diffusion-tensor imaging (DTI) acquisitions and arterial spin labeling (ASL). Open source software was used to segment supratentorial gray and white matter and cerebrospinal fluid to compare gray and white matter volumes and cortical thickness. DTI data were processed with automated fiber quantification, which was used to compare piecewise fractional anisotropy (FA) along 20 tracks. For the volumetric analysis, a regression was performed to account for differences in age, handedness, and total intracranial volume, and for the DTI, FA was compared piecewise along tracks by using an unpaired t test. The open source software segmentation was used to compare cerebral blood flow as measured with ASL.

In the CFS population, FA was increased in the right arcuate fasciculus (P = .0015), and in right-handers, FA was also increased in the right inferior longitudinal fasciculus (ILF) (P = .0008). In patients with CFS, right anterior arcuate FA increased with disease severity (r = 0.649, P = .026). Bilateral white matter volumes were reduced in CFS (mean ± standard deviation, 467 581 mm3 ± 47 610 for patients vs 504 864 mm3 ± 68 126 for control subjects, P = .0026), and cortical thickness increased in both right arcuate end points, the middle temporal (T = 4.25) and precentral (T = 6.47) gyri, and one right ILF end point, the occipital lobe (T = 5.36). ASL showed no significant differences.

Bilateral white matter atrophy is present in CFS. No differences in perfusion were noted. Right hemispheric increased FA may reflect degeneration of crossing fibers or strengthening of short-range fibers. Right anterior arcuate FA may serve as a biomarker for CFS.

Right Arcuate Fasciculus Abnormality in Chronic Fatigue Syndrome. Zeineh MM, et al. Radiology. 2014 Oct 29:141079.

Further reading
Study finds brain abnormalities in chronic fatigue patients. Stanford Medicine News Center Press Release.
Some headway on chronic fatigue syndrome: Brain abnormalities pinpointed. SCOPE
Findings of brain anomalies may shed light on chronic fatigue. The San Francisco Chronicle
Is this proof chronic fatigue DOES exist? Scientists find three differences in the brain that suggest condition may not just be ‘in the mind’. Daily Mail, UK
Brain changes identified in chronic fatigue syndrome. Clinical Neurology News

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