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

Migraine headaches in Chronic Fatigue Syndrome (CFS): Comparison of two prospective cross-sectional studies

<p>Abstract</p> <p>Background</p> <p>Headaches are more frequent in Chronic Fatigue Syndrome (CFS) than healthy control (HC) subjects. The 2004 International Headache Society (IHS) criteria were used to define CFS headache phenotypes.</p> <p>Methods</p> <p>Subjects in Cohort 1 (HC = 368; CFS = 203) completed questionnaires about many diverse symptoms by giving nominal (yes/no) answers. Cohort 2 (HC = 21; CFS = 67) had more focused evaluations. They scored symptom severities on 0 to 4 anchored ordinal scales, and had structured headache evaluations. All subjects had history and physical examinations; assessments for exclusion criteria; questionnaires about CFS related symptoms (0 to 4 scale), Multidimensional Fatigue Inventory (MFI) and Medical Outcome Survey Short Form 36 (MOS SF-36).</p> <p>Results</p> <p>Demographics, trends for the number of diffuse "functional" symptoms present, and severity of CFS case designation criteria symptoms were equivalent between CFS subjects in Cohorts 1 and 2. HC had significantly fewer symptoms, lower MFI and higher SF-36 domain scores than CFS in both cohorts. Migraine headaches were found in 84%, and tension-type headaches in 81% of Cohort 2 CFS. This compared to 5% and 45%, respectively, in HC. The CFS group had migraine without aura (60%; MO; CFS+MO), with aura (24%; CFS+MA), tension headaches only (12%), or no headaches (4%). Co-morbid tension and migraine headaches were found in 67% of CFS. CFS+MA had higher severity scores than CFS+MO for the sum of scores for poor memory, dizziness, balance, and numbness ("Neuro-construct", p = 0.002) and perceived heart rhythm disturbances, palpitations and noncardiac chest pain ("Cardio-construct"; p = 0.045, t-tests after Bonferroni corrections). CFS+MO subjects had lower pressure-induced pain thresholds (2.36 kg [1.95-2.78; 95% C.I.] n = 40) and a higher prevalence of fibromyalgia (47%; 1990 criteria) compared to HC (5.23 kg [3.95-6.52] n = 20; and 0%, respectively). Sumatriptan was beneficial for 13 out of 14 newly diagnosed CFS migraine subjects.</p> <p>Conclusions</p> <p>CFS subjects had higher prevalences of MO and MA than HC, suggesting that mechanisms of migraine pathogenesis such as central sensitization may contribute to CFS pathophysiology.</p> <p>Clinical Trial Registration</p> <p>Georgetown University IRB # 2006-481</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00810329">NCT00810329</a></p

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

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

<p>(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) (*<i>P = </i>0.012) (C) AD values from the combined control (orange) and CMI (red) groups significantly correlated with fatigue (<i>R = </i>0.398, *<i>P = </i>0.012), dolorimetry (<i>R = −</i>0.407, *<i>P = </i>0.012) and McGill total score (<i>R = </i>0.448, *<i>P = </i>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; <i>P = </i>0.002, asymptotic significance). (*<i>P</i><0.05, FDR corrected; error bar depicts ±95% confidence interval).</p

Significant correlations between clinical and diffusivity parameters for controls and CMI.

<p>Significant correlations between dolorimetry pain threshold, ordinal fatigue and McGill pain score with white matter properties in axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD). (Pearson’s and Spearman’s one-tailed correlations corrected for multiple comparisons using FDR; *<i>P</i>≤0.02). IFOF = inferior fronto occipital fasciculus; UF = uncinate fasciculus; ILF = inferior longitudinal fasciculus; SLF = superior longitudinal fasciculus; CST = corticospinal tract.</p

MOS-SF-36 Quality of Life Domains for CMI and controls.

<p>CMI subjects have significantly impaired quality of life. (2-tailed unpaired student’s t-test corrected using FDR (<i>P</i><0.05): *<i>P</i><0.000001 vs. Controls (Mean [95% Confidence Intervals]).</p

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

<p>(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 (<i>R = </i>0.366, *<i>P = </i>0.02). (C) The histogram depicts CMI subjects have significantly higher AD (*<i>P = </i>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; <i>P = </i>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 (*<i>P = </i>0.048). (*<i>P</i><0.05, FDR corrected; error bars depict ±95% confidence interval).</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