Prefrontal Structure Varies as a Function of Pain Symptoms in Chronic Fatigue Syndrome

Biol Psychiatry. 2017 Feb 15;81(4):358-365. doi: 10.1016/j.biopsych.2016.07.016. Epub 2016 Aug 31.


Background: Chronic fatigue syndrome (CFS) is characterized by severe fatigue persisting for ≥6 months and leading to considerable impairment in daily functioning. Neuroimaging studies of patients with CFS have revealed alterations in prefrontal brain morphology. However, it remains to be determined whether these alterations are specific for fatigue or whether they relate to other common CFS symptoms (e.g., chronic pain, lower psychomotor speed, and reduced physical activity).

Methods: We used magnetic resonance imaging to quantify gray matter volume (GMV) and the N-acetylaspartate and N-acetylaspartylglutamate/creatine ratio (NAA/Cr) in a group of 89 women with CFS. Building on previous reports, we tested whether GMV and NAA/Cr in the dorsolateral prefrontal cortex are associated with fatigue severity, pain, psychomotor speed, and physical activity, while controlling for depressive symptoms. We also considered GMV and NAA/Cr differences between patients with CFS and 26 sex-, age-, and education-matched healthy controls.

Results: The presence of pain symptoms was the main predictor of both GMV and NAA/Cr in the left dorsolateral prefrontal cortex of patients with CFS. More pain was associated with reduced GMVs and NAA/Cr, over and above the effects of fatigue, depressive symptoms, physical activity, and psychomotor speed. In contrast to previous reports and despite a large representative sample, global GMV did not differ between the CFS and healthy control groups.

Conclusions: CFS, as diagnosed by Centers for Disease Control and Prevention criteria, is not a clinical entity reliably associated with reduced GMV. Individual variation in the presence of pain, rather than fatigue, is associated with neuronal alterations in the dorsolateral prefrontal cortex of patients with CFS.

Keywords: Chronic fatigue syndrome; Dorsolateral prefrontal cortex; Gray matter volume; Magnetic resonance spectroscopy; N-acetylaspartate; Voxel-based morphometry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aspartic Acid / analogs & derivatives
  • Aspartic Acid / metabolism
  • Creatine / metabolism
  • Fatigue Syndrome, Chronic / complications
  • Fatigue Syndrome, Chronic / diagnostic imaging
  • Fatigue Syndrome, Chronic / metabolism
  • Fatigue Syndrome, Chronic / pathology*
  • Female
  • Glutamates / metabolism
  • Gray Matter / diagnostic imaging
  • Gray Matter / metabolism
  • Gray Matter / pathology
  • Humans
  • Magnetic Resonance Imaging
  • Magnetic Resonance Spectroscopy
  • Middle Aged
  • Pain / complications
  • Pain / diagnostic imaging
  • Pain / metabolism
  • Pain / pathology*
  • Prefrontal Cortex / diagnostic imaging
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / pathology*
  • Severity of Illness Index
  • Young Adult


  • Glutamates
  • Aspartic Acid
  • N-acetylaspartate
  • N-acetylglutamic acid
  • Creatine