Cerebral white matter structure is disrupted in Gulf War Veterans with chronic musculoskeletal pain

Abstract

Chronic musculoskeletal pain (CMP) affects ∼25% of the 700,000 Veterans deployed during the Persian Gulf War (1990-1991). The cause of their pain is unknown, and there are no efficacious treatments. A small body of literature suggests that brain abnormalities exist in Gulf War Veterans (GVs), yet relationships between brain abnormalities and disease symptoms remain largely unexplored. Our purpose was to compare white matter (WM) integrity between GVCMP and matched, healthy Veteran controls (GVCO) and investigate relationships between cerebral WM integrity and symptoms. Thirty GVCMP and 31 controls completed magnetic resonance imaging with diffusion tensor imaging. Tract-based spatial statistics estimated WM fractional anisotropy, mean diffusivity, radial diffusivity, and axial diffusivity over the whole brain (P < 0.05) and were corrected using threshold-free cluster enhancement. GVCMP had greater pain symptoms and mood disturbance and lower quality of life and physical function compared with GVCO (P < 0.05). GVCMP had lower WM integrity across several brain regions implicated in chronic pain (P < 0.05) including the middle and inferior frontal gyrus, corpus callosum, corona radiata, precentral gyrus, external capsule, and posterior thalamic radiation. For GVCMP, WM integrity was associated with pain and mood symptoms in widespread brain areas that were found to be different between groups (P < 0.05). Results indicate widespread WM microstructure disruption across brain regions implicated in pain processing and modulation in chronic pain. The observed relationships between WM microstructure and symptoms encourage the testing of treatments designed to improve the brain health of affected Veterans.

Diffusion tensor tractography of brainstem fibers and its application in pain

“…Much of the DTI and FA studies have been focusing on examining differences in white matter microstructure in chronic pain vs. non-pain controls, and correlating FA with pain levels (see a recent review paper [71]). Based on TBSS, pain-related FA reductions have been detected in multiple white matter tracts along diffuse 'white matter skeletons', including the internal and external/extreme capsules, corpus callosum, cingulum, thalamic radiation, and brainstem white matter, primary somatosensory and motor cortices, orbitofrontal cortex [72,73], rostral anterior cingulate, and dorsal lateral prefrontal cortex [74]. TBSS and most voxel-based analytic approaches, however, are known to be highly sensitive to registration errors and may produce false positive findings [75].…”

Oligodendrocyte involvement in Gulf War Illness

“…Based on our findings we predict that GW veterans would have decreased white matter integrity varying by brain region. These predictions are supported by the brain imaging studies of GW veterans (Bierer et al, ; Rayhan et al, ; Van Riper et al, ). The published neuroimaging data reflect both increased and decreased myelin integrity depending on the myelin track analyzed and methodological differences in measurement.…”

“…Importantly, an equal number of studies have identified decreased myelin integrity depending on the brain region. It has been shown in veterans with GWI and chronic pain that there is a lower white matter integrity across multiple brain regions including the frontal gyrus, corpus callosum, and precentral gyrus (Van Riper et al, ). GW veterans with PTSD also display significantly reduced mean diffusivity in the right, but not left cingulum (Bierer et al, ).…”

“…Recent studies provide support for this previously unexplored hypothesis of involvement of myelinating glia in the pathophysiology of GWI. Brain imaging studies have reported white matter abnormalities in GW veterans (Chao, Zhang, & Buckley, 2015;Heaton et al, 2007) and such disruption has been associated with the key diagnostic symptoms of GWI: musculoskeletal pain (Rayhan et al, 2013;Van Riper et al, 2017), impaired attention (Janulewicz et al, 2017), disturbances of mood (Van Riper et al, 2017), and chronic fatigue (Rayhan et al, 2013). However, white matter is a complex tissue comprised of axons, astrocytes, oligodendrocytes, vascular cells, and microglia.…”

Diffusion Tensor Tractography of Brainstem Fibers and Its Application in Pain

“…Much of the DTI and FA studies have been focusing on examining differences in white matter microstructure in chronic pain vs. non-pain controls, and correlating FA with pain levels (see a recent review paper [40]). Based on TBSS, pain-related FA reductions have been detected in multiple white matter tracts along diffuse ‘white matter skeletons’, including the internal and external/extreme capsules, corpus callosum, cingulum, thalamic radiation, and brainstem white matter, primary somatosensory and motor cortices, orbitofrontal cortex [41,42], rostral anterior cingulate, and dorsal lateral prefrontal cortex [43]. TBSS and most voxel-based analytic approaches, however, are known to be highly sensitive to registration errors and may produce false positive findings [44].…”