Connectivity differences between Gulf War Illness (GWI) phenotypes during a test of attention

One quarter of veterans returning from the 1990–1991 Persian Gulf War have developed Gulf War Illness (GWI) with chronic pain, fatigue, cognitive and gastrointestinal dysfunction. Exertion leads to characteristic, delayed onset exacerbations that are not relieved by sleep. We have modeled exertional exhaustion by comparing magnetic resonance images from before and after submaximal exercise. One third of the 27 GWI participants had brain stem atrophy and developed postural tachycardia after exercise (START: Stress Test Activated Reversible Tachycardia). The remainder activated basal ganglia and anterior insulae during a cognitive task (STOPP: Stress Test Originated Phantom Perception). Here, the role of attention in cognitive dysfunction was assessed by seed region correlations during a simple 0-back stimulus matching task (“see a letter, push a button”) performed before exercise. Analysis was analogous to resting state, but different from psychophysiological interactions (PPI). The patterns of correlations between nodes in task and default networks were significantly different for START (n = 9), STOPP (n = 18) and control (n = 8) subjects. Edges shared by the 3 groups may represent co-activation caused by the 0-back task. Controls had a task network of right dorsolateral and left ventrolateral prefrontal cortex, dorsal anterior cingulate cortex, posterior insulae and frontal eye fields (dorsal attention network). START had a large task module centered on the dorsal anterior cingulate cortex with direct links to basal ganglia, anterior insulae, and right dorsolateral prefrontal cortex nodes, and through dorsal attention network (intraparietal sulci and frontal eye fields) nodes to a default module. STOPP had 2 task submodules of basal ganglia–anterior insulae, and dorsolateral prefrontal executive control regions. Dorsal attention and posterior insulae nodes were embedded in the default module and were distant from the task networks. These three unique connectivity patterns during an attention task support the concept of Gulf War Disease with recognizable, objective patterns of cognitive dysfunction

Increased brain white matter axial diffusivity associated with fatigue, pain and hyperalgesia in Gulf War illness

Background Gulf War exposures in 1990 and 1991 have caused 25% to 30% of deployed personnel to develop a syndrome of chronic fatigue, pain, hyperalgesia, cognitive and affective dysfunction. Methods Gulf War veterans (n = 31) and sedentary veteran and civilian controls (n = 20) completed fMRI scans for diffusion tensor imaging. A combination of dolorimetry, subjective reports of pain and fatigue were correlated to white matter diffusivity properties to identify tracts associated with symptom constructs. Results Gulf War Illness subjects had significantly correlated fatigue, pain, hyperalgesia, and increased axial diffusivity in the right inferior fronto-occipital fasciculus. ROC generated thresholds and subsequent binary regression analysis predicted CMI classification based upon axial diffusivity in the right inferior fronto-occipital fasciculus. These correlates were absent for controls in dichotomous regression analysis. Conclusion The right inferior fronto-occipital fasciculus may be a potential biomarker for Gulf War Illness. This tract links cortical regions involved in fatigue, pain, emotional and reward processing, and the right ventral attention network in cognition. The axonal neuropathological mechanism(s) explaining increased axial diffusivity may account for the most prominent symptoms of Gulf War Illness

Increased brain white matter axial diffusivity associated with fatigue, pain and hyperalgesia in Gulf War illness. PLoS One

Abstract Background: Gulf War exposures in 1990 and 1991 have caused 25% to 30% of deployed personnel to develop a syndrome of chronic fatigue, pain, hyperalgesia, cognitive and affective dysfunction

Connectivity differences between Gulf War Illness (GWI) phenotypes during a test of attention

One quarter of veterans returning from the 1990–1991 Persian Gulf War have developed Gulf War Illness (GWI) with chronic pain, fatigue, cognitive and gastrointestinal dysfunction. Exertion leads to characteristic, delayed onset exacerbations that are not relieved by sleep. We have modeled exertional exhaustion by comparing magnetic resonance images from before and after submaximal exercise. One third of the 27 GWI participants had brain stem atrophy and developed postural tachycardia after exercise (START: Stress Test Activated Reversible Tachycardia). The remainder activated basal ganglia and anterior insulae during a cognitive task (STOPP: Stress Test Originated Phantom Perception). Here, the role of attention in cognitive dysfunction was assessed by seed region correlations during a simple 0-back stimulus matching task (“see a letter, push a button”) performed before exercise. Analysis was analogous to resting state, but different from psychophysiological interactions (PPI). The patterns of correlations between nodes in task and default networks were significantly different for START (n = 9), STOPP (n = 18) and control (n = 8) subjects. Edges shared by the 3 groups may represent co-activation caused by the 0-back task. Controls had a task network of right dorsolateral and left ventrolateral prefrontal cortex, dorsal anterior cingulate cortex, posterior insulae and frontal eye fields (dorsal attention network). START had a large task module centered on the dorsal anterior cingulate cortex with direct links to basal ganglia, anterior insulae, and right dorsolateral prefrontal cortex nodes, and through dorsal attention network (intraparietal sulci and frontal eye fields) nodes to a default module. STOPP had 2 task submodules of basal ganglia–anterior insulae, and dorsolateral prefrontal executive control regions. Dorsal attention and posterior insulae nodes were embedded in the default module and were distant from the task networks. These three unique connectivity patterns during an attention task support the concept of Gulf War Disease with recognizable, objective patterns of cognitive dysfunction

Connectivity differences between Gulf War Illness (GWI) phenotypes during a test of attention.

One quarter of veterans returning from the 1990-1991 Persian Gulf War have developed Gulf War Illness (GWI) with chronic pain, fatigue, cognitive and gastrointestinal dysfunction. Exertion leads to characteristic, delayed onset exacerbations that are not relieved by sleep. We have modeled exertional exhaustion by comparing magnetic resonance images from before and after submaximal exercise. One third of the 27 GWI participants had brain stem atrophy and developed postural tachycardia after exercise (START: Stress Test Activated Reversible Tachycardia). The remainder activated basal ganglia and anterior insulae during a cognitive task (STOPP: Stress Test Originated Phantom Perception). Here, the role of attention in cognitive dysfunction was assessed by seed region correlations during a simple 0-back stimulus matching task ("see a letter, push a button") performed before exercise. Analysis was analogous to resting state, but different from psychophysiological interactions (PPI). The patterns of correlations between nodes in task and default networks were significantly different for START (n = 9), STOPP (n = 18) and control (n = 8) subjects. Edges shared by the 3 groups may represent co-activation caused by the 0-back task. Controls had a task network of right dorsolateral and left ventrolateral prefrontal cortex, dorsal anterior cingulate cortex, posterior insulae and frontal eye fields (dorsal attention network). START had a large task module centered on the dorsal anterior cingulate cortex with direct links to basal ganglia, anterior insulae, and right dorsolateral prefrontal cortex nodes, and through dorsal attention network (intraparietal sulci and frontal eye fields) nodes to a default module. STOPP had 2 task submodules of basal ganglia-anterior insulae, and dorsolateral prefrontal executive control regions. Dorsal attention and posterior insulae nodes were embedded in the default module and were distant from the task networks. These three unique connectivity patterns during an attention task support the concept of Gulf War Disease with recognizable, objective patterns of cognitive dysfunction

Exercise challenge alters Default Mode Network dynamics in Gulf War Illness

Abstract Background Gulf War Illness (GWI) affects 30% of veterans from the 1991 Gulf War and has no known cause. Everyday symptoms include pain, fatigue, migraines, and dyscognition. A striking syndromic feature is post-exertional malaise (PEM). This is recognized as an exacerbation of everyday symptoms following a physically stressful or cognitively demanding activity. The underlying mechanism of PEM is unknown. We previously reported a novel paradigm that possibly captured evidence of PEM by utilizing fMRI scans taken before and after sub-maximal exercises. We hypothesized that A) exercise would be a sufficient physically stressful activity to induce PEM and B) Comparison of brain activity before and after exercise would provide evidence of PEM’s effect on cognition. We reported two-exercise induced GWI phenotypes with distinct changes in brain activation patterns during the completion of a 2-back working memory task (also known as two-back > zero-back). Results Here we report unanticipated findings from the reverse contrast (zero-back > two-back), which allowed for the identification of task-related deactivation patterns. Following exercise, patients developed a significant increase in deactivation patterns within the Default Mode Network (DMN) that was not seen in controls. The DMN is comprised of regions that are consistently down regulated during external goal-directed activities and is often altered within many neurological disease states. Conclusions Exercise-induced alterations within the DMN provides novel evidence of GWI pathophysiology. More broadly, results suggest that task-related deactivation patterns may have biomarker potential in Gulf War Illness

Increased Brain White Matter Axial Diffusivity Associated with Fatigue, Pain and Hyperalgesia in Gulf War Illness

<div><p>Background</p><p>Gulf War exposures in 1990 and 1991 have caused 25% to 30% of deployed personnel to develop a syndrome of chronic fatigue, pain, hyperalgesia, cognitive and affective dysfunction.</p> <p>Methods</p><p>Gulf War veterans (<i>n = </i>31) and sedentary veteran and civilian controls (<i>n = </i>20) completed fMRI scans for diffusion tensor imaging. A combination of dolorimetry, subjective reports of pain and fatigue were correlated to white matter diffusivity properties to identify tracts associated with symptom constructs.</p> <p>Results</p><p>Gulf War Illness subjects had significantly correlated fatigue, pain, hyperalgesia, and increased axial diffusivity in the right inferior fronto-occipital fasciculus. ROC generated thresholds and subsequent binary regression analysis predicted CMI classification based upon axial diffusivity in the right inferior fronto-occipital fasciculus. These correlates were absent for controls in dichotomous regression analysis.</p> <p>Conclusion</p><p>The right inferior fronto-occipital fasciculus may be a potential biomarker for Gulf War Illness. This tract links cortical regions involved in fatigue, pain, emotional and reward processing, and the right ventral attention network in cognition. The axonal neuropathological mechanism(s) explaining increased axial diffusivity may account for the most prominent symptoms of Gulf War Illness.</p> </div

Pain, fatigue and tenderness scores.

<p>Severity of fatigue using a 5 point ordinal scale verified by Chalder’s and MFI general fatigue scores. CMI subjects have significantly decreased systemic pain threshold and higher McGill total and subscale scores. (2-tailed unpaired student’s t-test corrected using FDR, <i>P</i><0.05; Mean [95% Confidence intervals]).</p

Increased axial diffusivity (AD) in left IFOF and bilateral UF predicts CMI subgroups.

<p>(A) Sagittal projection of the left IFOF (green) onto the MNI template. Individual left IFOF AD values correlated negatively with dolorimetry (<i>R = −</i>0.381, *<i>P = </i>0.015). Histogram show no significant difference but ROC analysis suggest discriminatory potential for AD of the left IFOF between CMI and control groups (threshold = 1.73;AUC = 0.690, **<i>P = </i>0.025). (B) The right UF (blue, transverse section) was correlated significantly with McGill total score (<i>R = </i>0.375, *<i>P = </i>0.018). Histogram shows no significant difference but ROC analysis suggested potential to distinguish CMI from controls groups (threshold = 1.22; AUC = 0.707, **<i>P = </i>0.016). (C) The left UF (blue, sagittal view) had AD values that significantly correlated with dolorimetry (<i>R = −</i>0.382, *<i>P = </i>0.015) and McGill total score (<i>R = −</i>0.440, *<i>P = </i>0.008). No significant difference in AD for the left UF but ROC analysis of the AD values confirmed its discriminatory potential (threshold = 1.23; AUC = 0.682, **<i>P = </i>0.034). (*<i>P</i><0.05, FDR corrected;**<i>P<</i>0.05, asymptotic significance; error bars depict ±95% confidence interval) IFOF = inferior fronto occipital fasciculus UF = uncinate fasciculus.</p

Correlation between McGill total score, mean pain threshold and fatigue.

<p>(A) The bar graphs show the magnitudes of the significant differences in ordinal fatigue <b>(*</b><i>P = </i>1×10⁻⁹), McGill total score <b>(*</b><i>P = </i>1×10⁻⁹), and pain threshold by dolorimetry <b>(*</b><i>P = </i>6×10⁻⁴) for control (orange) and CMI (red) groups. (B) Scattergrams from all subjects show the relationships between clinical measures. Dolorimetry pressures negatively correlated with McGill total score and fatigue ratings for control (orange) and GWI (red) subjects. McGill total pain and ordinal fatigue were positively correlated. (C) ROC analysis set the threshold for separation of controls from CMI subjects at 2.5 for ordinal fatigue (specificity = 0.818; sensitivity = 0.968; AUC = 0.915; **<i>P = </i>0.00005). The threshold for dolorimetry was 5.8 kg (specificity = 0.73; sensitivity = 0.84; AUC = 0.845; **<i>P = </i>0.0007). McGill total score of 14 separated CMI from controls (specificity = 0.90; sensitivity = 0.91; AUC = 0.973; **<i>P = </i>4.4×10⁻⁶). (*<i>P</i><0.001, FDR corrected; **<i>P<</i>0.05; Asymptotic significance; error bars depict ±95% confidence intervals).</p