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.

Left sensorimotor cortex (cluster level: p=0.004, FWE; kE=180) was one of two ROIs that did not have a voxel overlap with ROIs yielded by subsequent two-sample t-tests. The composition of this ROI per the AAL atlas was left paracentral lobule (32/180, 18%), postcentral gyrus (48/180, 27%), and precentral gyrus (83/180, 46%). The GWI group had significantly less activation in the left sensorimotor cortex than the HC or ME/CFS groups after exercise (Supplementary Figure 1). Specifically, activation levels were significantly higher for HC (p=0.00041, HSD) and ME/CFS (p=0.0041, HSD) relative to GWI. This difference reflects both a decrease in GWI (paired t-test: p=0.039) and an increase in ME/CFS (paired t-test: p=0.036) activation after exercise. Before exercise, there were no differences between groups.
Activation in the midbrain/isthmus (cluster level: p=0.040, FWE; kE=113) ROI greatly decreased after exercise in the GWI group (Supplementary Figure 3). This difference reflects a postexertional decrease in GWI (paired t-test: p=0.0012) activation alone, as exercise had little effect on HC and ME/CFS activation. Specifically, activation levels were significantly higher for HC (p=0.0024, HSD) and ME/CFS (p=0.00011, HSD) relative to GWI. There were no differences between HC, GWI, and ME/CFS before exercise. As stated in the main text, this ROI partially overlapped with the midbrain ROI yielded from the ME/CFS>GWI contrast.
Likewise, the right intraparietal sulcus (cluster level: p=0.051, FWE; kE=106) ROI shows differences in activation between the HC, GWI, and ME/CFS groups after exercise (Supplementary Figure 4). As this ROI results from a statistical trend, it is inappropriate to apply Tukey's HSD values to these ROI analyses. However, paired comparisons of BOLD activity elicited before and after exercise are still informative, showing that activation dropped after exercise in the GWI group (paired t-test: p=0.029) but increased in ME/CFS (paired t-test: p=0.013). As stated in the main text, this ROI completely overlapped with a right intraparietal sulcus ROI resulting from the ME/CFS>GWI contrast.
Lastly, the left Rolandic operculum (cluster level: p=0.066, FWE; kE=99) ROI shows differences in activation between the HC, GWI, and ME/CFS groups after exercise, despite having quite a different response profile from the ROIs above (Supplementary Figure 5). There were no differences between HC, GWI, and ME/CFS before exercise, as all three groups displayed a relatively high magnitude deactivation within this region. After exercise, both HC and GWI continued to display relative deactivation whereas the ME/CFS group failed to deactivate. Again, as this ROI results from a statistical trend, Tukey's HSD values are inappropriate to report. However, paired comparisons of BOLD activity before and after exercise reveal as significant increase in activity within the ME/CFS group alone (paired t-test: p=0.0040). Further, the pattern of activation within this region closely matches that of the 273-voxel Rolandic operculum ROI elicited by the ME/CFS>GWI contrast and is nearly identical to that of the 373-voxel Rolandic operculum ROI elicited by the ME/CFS>HC contrast. There is a high degree of overlap between these three Rolandic operculum ROIs, making similarities between their activation patterns unsurprising.
Supplementary Figure 2. Left cuneus/precuneus ROI identified by contrasting BOLD activity derived from the 2-Back>0-Back conditions in the HC, GWI, and ME/CFS groups via Oneway ANOVA after exercise (cluster level: p=0.046, FWE; kE=109). (A) Sagittal (top), coronal (middle), and transverse (bottom) slices of an MNI-standard brain, where crosshairs indicate the cluster's most active voxel (-12, -82, 44). (B) BOLD response for the 2-Back>0-Back condition (mean ± SEM) are shown for pre-exercise (top) and post-exercise (middle). DBOLD (bottom) is the post-minus pre-exercise BOLD response for the 2-Back>0-Back condition for the control (black bars), GWI (white bars), and ME/CFS (gray bars). Error bars represent 95% C.I. Figure 3. Midbrain ROI identified by contrasting BOLD activity derived from the 2-Back>0-Back conditions in the HC, GWI, and ME/CFS groups via One-way ANOVA after exercise (cluster level: p=0.040, FWE; kE=113). (A) Sagittal (top), coronal (middle), and transverse (bottom) slices of an MNI-standard brain, where crosshairs indicate the cluster's most active voxel (4, -28, -12). (B) BOLD response for the 2-Back>0-Back condition (mean ± SEM) are shown for pre-exercise (top) and post-exercise (middle). DBOLD (bottom) is the post-minus pre-exercise BOLD response for the 2-Back>0-Back condition for the control (black bars), GWI (white bars), and ME/CFS (gray bars). Error bars represent 95% C.I. Figure 4. Right intraparietal ROI identified by contrasting BOLD activity derived from the 2-Back>0-Back conditions in the HC, GWI, and ME/CFS groups via Oneway ANOVA after exercise (cluster level: p=0.051, FWE; kE=106). The ROI is green to signify that it is a trend and not statistically significant, like the ROIs in Supplementary  Figures 1-3. (A) Sagittal (top), coronal (middle), and transverse (bottom) slices of an MNIstandard brain, where crosshairs indicate the cluster's most active voxel (30, -56, 52). (B) BOLD response for the 2-Back>0-Back condition (mean ± SEM) are shown for pre-exercise (top) and post-exercise (middle). DBOLD (bottom) is the post-minus pre-exercise BOLD response for the 2-Back>0-Back condition for the control (black bars), GWI (white bars), and ME/CFS (gray bars). Error bars represent 95% C.I. Figure 5. Left Rolandic Operculum ROI identified by contrasting BOLD activity derived from the 2-Back>0-Back conditions in the HC, GWI, and ME/CFS groups via One-way ANOVA after exercise (cluster level: p=0.066, FWE; kE=99). The ROI is green to signify that it is a trend and not statistically significant, like the ROIs in Supplementary  Figures 1-3. (A) Sagittal (top), coronal (middle), and transverse (bottom) slices of an MNIstandard brain, where crosshairs indicate the cluster's most active voxel (4, -28, -12). (B) BOLD response for the 2-Back>0-Back condition (mean ± SEM) are shown for pre-exercise (top) and post-exercise (middle). DBOLD (bottom) is the post-minus pre-exercise BOLD response for the 2-Back>0-Back condition for the control (black bars), GWI (white bars), and ME/CFS (gray bars). Error bars represent 95% C.I.