Researchers have found distinct brain molecular patterns in two disorders long thought to be psychological in origin: chronic fatigue syndrome (CFS) and Gulf War illness (GWI).

These disorders shared symptoms such as fatigue, pain, cognitive dysfunction, and sleep problems that are also common symptoms of other brain disorders.

But the most unique symptom shared by CFS and GWI is exhaustion after exertion or exercise. A patient’s physical and cognitive symptoms are made worse by efforts, suggesting that exertion alters central nervous system functions.

A new study of the cerebrospinal fluid of these patients before and after exercise showed distinct changes in the production patterns of the brain miRNA molecules. In both humans and animals, micro-RNAs regulate gene expression by turning protein production on or off.

This study, published in Scientific Reports, lays the groundwork to understand, diagnose, and treat CFS and GWI more effectively. Further studies may lead to the development of objective diagnostic biomarkers.

Background

Chronic fatigue syndrome (CFS) affects between 836,000 and 2.5 million Americans, according to a US National Academy of Medicine report. The disorder was thought to be psychosomatic until a 2015 review of 9,000 articles over 64 years of research pointed to unspecified biological causes. Still, no definitive diagnosis or treatment is available today.

Gulf War veterans were exposed to combinations of nerve agents, pesticides and other toxic chemicals. Twenty-six years after the first Gulf war, 25-32% of the 697,000 veterans of that conflict continue to experience post-exertion exhaustion and other related symptoms (see figure).

The study

Researchers assayed the spinal fluid of CFS, GWI and control subjects who were divided into non-exercise and exercise groups. Cerebrospinal fluid miRNA production patterns of the three non-exercise groups were the same.

In contrast, miRNA levels in spinal fluid were significantly different after exercise. The CFS, control and two subtypes of GWI patients each showed distinct patterns of change unique to that group.

CFS patients who exercised had reduced levels of 12 different mRNAs, compared to those who did not exercise. The miRNA changes in GWI patients after exercise were also different from their control groups.

In addition, the two subtypes of GWI showed significantly different pattern changes unique to each. Finding two distinct pathophysiological miRNA brain patterns in patients reporting Gulf War illness support neuropathology in the two different manifestations

One subgroup also developed jumps in heart rate of over 30 beats when standing up. This symptom lasted for two to three days after exercise. Magnetic resonance imaging (mri) showed that they have smaller brainstem regions that control heart rate, and did not activate their brains when doing a cognitive task.

The other subgroup did not have any heart rate or brainstem changes, but recruited additional brain regions when completing a memory test.

Findings

Exercise caused distinct pattern of miRNA changes in chronic fatigue syndrome and in the two subtypes of Gulf-war illness, indicating significant pathophysiological differences between these disorders.

There were no differences found in the miRNA levels between the three non-exercise groups. Baseline levels (what may be considered normal range) of cerebrospinal fluid miRNAs may not be useful for diagnosing CFS or GWI.

These findings are consistent with the known finding in CFS and GWI, that functions may appear when rested, but will deteriorate after physiological stress.

Spinal fluid miRNA levels in CFS and GWI were different from the ones that are altered in depression, fibromyalgia, and Alzheimer’s disease, suggesting that these are all distinct diseases, senior investigator of this research, James N. Baraniuk of Georgetown University School of Medicine in Washington, DC, concluded.

This study is also the first description of the effects of exercise on cerebrospinal fluid miRNA expression in healthy subjects. Exercise diminished miR-328 and miR-608 in all participants, suggesting a general effect on the brain.