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

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.

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.

Figure 1. Correlation between McGill total score, mean pain threshold and fatigue.

(A) The bar graphs show the magnitudes of the significant differences in ordinal fatigue (* P = 1×10⁻⁹), McGill total score (* P = 1×10⁻⁹), and pain threshold by dolorimetry (* P = 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; **P = 0.00005). The threshold for dolorimetry was 5.8 kg (specificity = 0.73; sensitivity = 0.84; AUC = 0.845; **P = 0.0007). McGill total score of 14 separated CMI from controls (specificity = 0.90; sensitivity = 0.91; AUC = 0.973; **P = 4.4×10⁻⁶). (*P<0.001, FDR corrected; **P<0.05; Asymptotic significance; error bars depict ±95% confidence intervals).

Figure 2. Increased axial diffusivity (AD) of right IFOF predicts CMI status.

(A) Representative transverse, sagittal, and coronal views of the right IFOF (red) demonstrate projections from the prefrontal to temporo-occipital lobe. (B) CMI subjects (red) have increased AD compared to controls (orange) (*P = 0.012) (C) AD values from the combined control (orange) and CMI (red) groups significantly correlated with fatigue (R = 0.398, *P = 0.012), dolorimetry (R = −0.407, *P = 0.012) and McGill total score (R = 0.448, *P = 0.008). (D) ROC analysis for right IFOF AD confirmed the potential to discriminate between CMI and control groups (threshold = 1.24, AUC = 0.760; P = 0.002, asymptotic significance). (*P<0.05, FDR corrected; error bar depicts ±95% confidence interval).

Figure 3. Increased mean (MD) and axial (AD) diffusivity in CMI compared to controls.

(A) Coronal view of the left corticospinal tract (CST) overlaid (green) onto the MNI template. (B) AD of the left CST correlated with ordinal fatigue across all subjects (R = 0.366, *P = 0.02). (C) The histogram depicts CMI subjects have significantly higher AD (*P = 0.047) than controls. (D) The ROC analysis confirmed the potential for AD of the left CST to distinguish CMI from controls (threshold = 1.29, AUC = 0.736; P = 0.006, asymptotic significance). (E) Sagittal view of the right superior longitudinal fasciculus (SLF) overlaid (red) for display purposes onto the mean tract skeleton (blue). (F) The histogram indicates CMI have increased right SLF MD compared to controls (*P = 0.048). (*P<0.05, FDR corrected; error bars depict ±95% confidence interval).

Figure 4. Increased axial diffusivity (AD) in left IFOF and bilateral UF predicts CMI subgroups.

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