Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Gulf War Illness affects 25–30% of American veterans deployed to the 1990–91 Persian Gulf War and is characterized by cognitive post-exertional malaise following physical effort. Gulf War Illness remains controversial since cognitive post-exertional malaise is also present in the more common Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An objective dissociation between neural substrates for cognitive post-exertional malaise in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome would represent a biological basis for diagnostically distinguishing these two illnesses. Here, we used functional magnetic resonance imaging to measure neural activity in healthy controls and patients with Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome during an N-back working memory task both before and after exercise. Whole brain activation during working memory (2-Back > 0-Back) was equal between groups prior to exercise. Exercise had no effect on neural activity in healthy controls yet caused deactivation within dorsal midbrain and cerebellar vermis in Gulf War Illness relative to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients. Further, exercise caused increased activation among Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients within the dorsal midbrain, left operculo-insular cortex (Rolandic operculum) and right middle insula. These regions-of-interest underlie threat assessment, pain, interoception, negative emotion and vigilant attention. As they only emerge post-exercise, these regional differences likely represent neural substrates of cognitive post-exertional malaise useful for developing distinct diagnostic criteria for Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Exercise modifies glutamate and other metabolic biomarkers in cerebrospinal fluid from Gulf War Illness and Myalgic encephalomyelitis / Chronic Fatigue Syndrome

“…The STOPP – START dichotomy in GWI was associated with differences in postexercise cerebrospinal fluid glutamate ( Fig 1 ), miRNA [ 26 ] and differential activation of cerebellar and other brain regions by fMRI [ 31 – 33 ]. This dichotomy does not appear to be as influential in ME/CFS or control subsets.…”

“…The START phenomenon was also induced by exercise in ME/CFS and control groups [ 34 , 35 ]. However, START versus STOPP status was not associated with postexercise changes in fMRI in control or ME/CFS [ 31 – 33 ].…”

Differential Effects of Exercise on fMRI of the Midbrain Ascending Arousal Network Nuclei in Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) in a Model of Postexertional Malaise (PEM)

“…In a previous study, we examined blood oxygenation level dependent (BOLD) activation during a difficult, high cognitive load continuous 2-back working memory task and compared preexercise and postexercise scans. Control, ME/CFS and GWI were equivalent prior to exercise (baseline), but after exercise ME/CFS had a significant increase in blood oxygenation level dependent (BOLD) activation while GWI had a significant decrease in the dorsal midbrain, right middle insula and left Rolandic operculum [14]. The midbrain region of interest extended from the left to right periaqueductal gray (PAG) and to the adjacent right midbrain reticular formation (MRF), inferior colliculus and lateral lemniscus, and caudally to the right lateral isthmus (Figure S1).…”

“…In this report, we re-analyze the original BOLD data [14] using a seed region approach to gain a preliminary understanding of the nuclei that were activated within the midbrain region of interest. The seed regions were selected from the ascending arousal network that was defined from histological sections and diffusion studies of brainstem white matter tracts [14]. BOLD signals in each of the target nuclei were assessed on preexercise and postexercise days.…”

Are there subgroups of chronic fatigue syndrome? An exploratory cluster analysis of biological markers

“…Finally, as for sensory processing functions, three studies have reported strongly reduced pressure pain thresholds [ 53 – 55 ], suggestive of central sensitization to afferent sensory stimuli [ 56 ]. Accordingly, functional brain imaging studies have demonstrated differences across CFS patients and healthy controls [ 57 ].…”