Exercise challenge in Gulf War Illness reveals two subgroups with altered brain structure and function

Abstract

Nearly 30% of the approximately 700,000 military personnel who served in Operation Desert Storm (1990-1991) have developed Gulf War Illness, a condition that presents with symptoms such as cognitive impairment, autonomic dysfunction, debilitating fatigue and chronic widespread pain that implicate the central nervous system. A hallmark complaint of subjects with Gulf War Illness is post-exertional malaise; defined as an exacerbation of symptoms following physical and/or mental effort. To study the causal relationship between exercise, the brain, and changes in symptoms, 28 Gulf War veterans and 10 controls completed an fMRI scan before and after two exercise stress tests to investigate serial changes in pain, autonomic function, and working memory. Exercise induced two clinical Gulf War Illness subgroups. One subgroup presented with orthostatic tachycardia (n = 10). This phenotype correlated with brainstem atrophy, baseline working memory compensation in the cerebellar vermis, and subsequent loss of compensation after exercise. The other subgroup developed exercise induced hyperalgesia (n = 18) that was associated with cortical atrophy and baseline working memory compensation in the basal ganglia. Alterations in cognition, brain structure, and symptoms were absent in controls. Our novel findings may provide an understanding of the relationship between the brain and post-exertional malaise in Gulf War Illness.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Exercise elicits orthostatic tachycardia and diastolic hypertension.

(A) Prior to first exercise, all participants had equivalent ΔHR. Three hours after the first stress test, 10 GWI subjects met the criteria for orthostatic tachycardia (START phenotype; P = 0.037, Fisher's test). START (n = 10; magenta triangles) subjects compared to controls (n = 10; cyan circles) and STOPP (n = 18; yellow squares) continued to have higher ΔHR recordings at 8, 16, 24 and 29 hours after first exercise. (B) START had significant increase ΔDBP at 8 and 16 hours after the first stress test. (C) Exercise did not cause ΔSBP in any of the subgroups. Δ = postural change. SBP = systolic blood pressure DBP = diastolic blood pressure HR = heart rate. Black and red arrows are start of first and second stress test respectively.*P<0.001; Error bars are means ±95% C.I.

Figure 2. Pre-exercise compensatory activation during cognitive task.

(A) Controls significantly activated regions normally associated with working memory in the frontal and parietal lobes and basal ganglia. (B) STOPP subjects activated normal working memory regions in addition to significant areas in bilateral anterior insula and right caudate body. (C) START subjects activated cortical regions associated with working memory and extensive activation of bilateral posterior-lateral cerebellum and right vermis. Whole-brain maps are displayed at P<0.001 and were cluster corrected for multiple comparisons at P<0.05 using AlphaSim.

Figure 3. Acute exercise prompts changes in neural networks observed during cognitive task.

Exercise reduced cerebral and cerebellar activity for all groups. (A) Controls activated areas in agreement with normal working memory function in the frontal and parietal lobes. (B) STOPP subjects activated normal working memory regions as well as compensatory right cerebellar recruitment. (C) The largest decrement in activity was in the START group that had no net change in regional blood flow to the cerebrum or cerebellum. Whole-brain maps are displayed at P<0.001 and were cluster corrected for multiple comparisons at P<0.05 using AlphaSim.

Figure 4. Relationship of white matter FA with working memory scores.

(A) Sagittal view of the right superior longitudinal fasciculus (SLF) ROI’s (red) overlaid onto the mean FA tract skeleton for GWI subjects (n = 28), with scatterplot showing a relationship between right SLF and mean 2-back score (P = 0.010) (B) Sagittal view of left SLF ROI (red) overlaid onto the mean FA tract skeleton for GWI subjects (n = 28), with scatterplot showing a relationship between left SLF and mean 2-back score (P = 0.011).

Figure 5. Phenotype designation reveals differences in gray matter and white matter density.

(A) START subjects (in contrast to controls) had less gray matter volume in the left lingual gyrus extending into the left cuneus (P<0.025) and (B) right pons and right medulla (P<0.02) (C) STOPP subjects (in contrast to controls) demonstrated a trend of less gray matter in the right superior parietal lobule extending into the right precuneus (P<0.07). (D) START subjects had reduced white matter volume (in contrast to STOPP) in the left pons (P<0.004) and (E) left cerebellar tonsil and left pyramis (P<0.012) (F) Analyses also demonstrated START subjects (in contrast to STOPP) had decreased gray matter in the right culmen extending into the right fastigial and left dentate nucleus of the cerebellum (P<0.035). All P values are corrected for age, gender and multiple comparisons using non-stationary cluster correction.