White matter abnormalities in Gulf War veterans with posttraumatic stress disorder: A pilot study
Introduction
Neuroimaging studies in posttraumatic stress disorder (PTSD) have implicated brain regions and pathways involved in emotion regulation, response inhibition, and higher level cognitive processing (Francati et al., 2007, Simmons and Matthews, 2012). Functional neuroimaging studies have detected altered responsivity of the anterior cingulate, medial frontal cortices, hippocampus and amygdala in PTSD in response to provocation (e.g., Bryant et al., 2005, Shin et al., 2005, Williams et al., 2006, Brunetti et al., 2010). Amygdala hyper-responsivity has been noted repeatedly (reviewed in Shin et al., 2006) and associated with PTSD severity in several studies (Rauch et al., 1996, Shin et al., 2004, Armony et al., 2005, Protopopescu et al., 2005). On the contrary, PTSD has been associated with volume and functional deficits of the medial prefrontal cortex (Bremner et al., 1999, Carrion et al., 2001, De Bellis et al., 2002, Fennema-Notestine et al., 2002), and specifically of the anterior cingulate cortex, for which volume reductions (Rauch et al., 2003), and hypo-responsivity to fear- and trauma-related stimuli have been demonstrated (Yamasue et al., 2003, Woodward et al., 2006, Hopper et al., 2007) and also correlated with PTSD severity (Shin et al., 2004, Shin et al., 2005, Britton et al., 2005, Williams et al., 2006). The emerging picture is that of purported deficits in the pre-frontal cortex coupled with hyper-activation of limbic structures, specifically the amygdala (Liberzon and Sripada, 2008). Such alterations appear to be related to the clinical features of PTSD (re-experiencing, emotional and autonomic arousal) and may also affect the integrity of the white matter tracts connecting these brain regions (Sripada et al., 2012).
Diffusion tensor MRI (DTI) provides a radiographic method of examining the integrity of such white matter tracts. The technique examines white matter by using the random motion of water molecules as endogenous microstructural probes (Basser et al., 1994, Basser and Mattiello, 1994). The two most common DTI metrics used to quantify microstructural changes are mean diffusivity (MD) and fractional anisotropy (FA) (Pierpaoli and Basser, 1996). MD measures the displacement of water molecules and the presence of obstacles to diffusion, providing an inverse index of tissue microstructure. FA is an index of tissue architecture, measuring the coherence of fiber orientation, myelination, and axonal density, and increases with fiber density and decreasing membrane permeability (Le Bihan et al., 2001). These two measures are generally inversely associated, and alterations in MD and FA reflect perturbations in white matter integrity that have been demonstrated in a variety of psychiatric disorders (White et al., 2008).
A number DTI studies have been performed in PTSD using various image analytic techniques in dissimilar samples, and have yielded inconsistent results. Voxel-wise (Kim et al., 2005) and region of interest (ROI) analyses (Kim et al., 2006) have shown decreased right anterior cingulate FA in adults with PTSD. Similarly, decrements in white matter integrity (FA) of the posterior cingulum were shown for a sample of highly traumatized woman with PTSD in comparison to similarly exposed women without PTSD (Fani et al., 2012). On the contrary, increased FA in the right anterior cingulate was documented among survivors of the sarin attack of the Tokyo subway system with PTSD (Abe et al., 2006). A recent meta-analysis (Daniels et al., 2013) reported results from seven whole-brain DTI studies documenting considerable heterogeneity of FA findings with various brain regions shown to exhibit increased and decreased white matter integrity, with little overlap among brain regions showing these abnormalities. The cingulum bundle was among the most frequently identified regions showing alterations in association with PTSD.
Relatively less is known about white matter integrity in individuals with combat related PTSD. One report showed bilaterally diminished FA in the white matter tracts of frontal and limbic brain regions, including areas near the anterior cingulate cortex (as well as in the posterior internal capsule) compared to age-matched OIF/OEF veterans without PTSD (Schuff et al., 2011). A more recent report documented diminished white matter integrity in the right anterior corona radiata that was associated with PTSD among combat veterans with alcohol use disorder (Sanjuan et al., 2013). In a cohort of Gulf War veterans, an increase in white matter axial diffusivity in the right inferior fronto-occipital fasciculus was noted among those with chronic multisymptom illness that was not associated with PTSD (Rayhan et al., 2013).
In this exploratory study, DTI was used to investigate white matter integrity in a small cohort of Gulf War veterans with and without PTSD, accounting for the presence of chronic multisymptom disease (also described as Gulf War illness). This was of particular interest in that PTSD among Gulf War veterans is associated with a unique clinical and neuroendocrine profile (Golier et al., 2007, Golier et al., 2009) distinct from those associated with PTSD in veterans of other conflicts (Golier et al., 2006). Given the predominance of white matter abnormalities in the cingulum bundle in PTSD (Kim et al., 2005, Kim et al., 2006, Abe et al., 2006), we chose to focus our investigation on this region in MRIs from a sample of Gulf War veterans who had previously participated in a neuroimaging study for which MRIs and neuroendocrine measures had been obtained (Yehuda et al., 2010). We also examined the relationship between DTI indices and severity of current PTSD symptoms.
Based on conflicting reports with respect to laterality and direction of alterations in cingulum bundle DTI indices in PTSD, we did not have directional hypotheses for MD or FA differences between Gulf War veterans with and without PTSD. There have been equally conflicting findings pertaining to the relationship of DTI measures to clinical severity (Abe et al., 2006, Zhang et al., 2011). However given a model that posits prefrontal-limbic dysregulation in PTSD, we hypothesized that white matter integrity of the cingulum would be positively correlated with PTSD severity. Lastly, we hypothesized that these relationships would obtain for PTSD in a sample of Gulf War veterans after accounting for the presence of chronic multisymptom disease.
Section snippets
Subjects
The sample consisted of 20 Gulf War veterans (12 with PTSD and 8 without PTSD) previously described in Yehuda et al. (2010). All volunteers provided written informed consent before undergoing study procedures. Approval for the study was obtained from the Institutional Review Boards of Mount Sinai School of Medicine and the James J. Peters Veterans Affairs Medical Center.
Evaluation
Subjects underwent a comprehensive medical and psychological evaluation as part of their participation. The Clinician
Results
Subjects were 20 Gulf war veterans (aged 43.0 ± 11.6 years (M ± SD)) with no significant difference in age between subjects with and without PTSD (Table 1). None had experienced head injury with loss of consciousness or residual orientation or memory deficits, and none had been exposed to blast injury during deployment. As previously reported, no group differences were observed in demographic characteristics between the PTSD and no-PTSD groups, including race, education (in years), employment,
Discussion
In this exploratory study, DTI measures were used to describe white matter integrity in the cingulum bundle for Gulf War veterans with and without PTSD in order to better characterize fronto-limbic connectivity associated with PTSD in this cohort. Gulf War veterans with PTSD showed significantly lower mean diffusivity in the right cingulum bundle (with a trend for elevated FA in this tract). There was an interaction of PTSD with chronic multisymptom illness such that the presence of Gulf War
Role of the funding sources
This work was supported principally by a VA MERIT entitled “Glucocorticoid Responsivity in Gulf War Veterans.” In addition, partial support was obtained through a grant (5 MO1 RR00071) to the Mount Sinai General Clinical Research Center from the National Center for Research Resources, National Institutes of Health.
Conflict of interest
None declared.
Acknowledgements
The authors thank Heather Bader for her assistance with the figures. VA MERIT entitled ‘Glucocorticoid responsivity in Gulf War veterans,’ (Award # GWRA-008-04S).
References (72)
- et al.
Voxel-based diffusion tensor analysis reveals aberrant anterior cingulum integrity in posttraumatic stress disorder due to terrorism
Psychiatry Res.
(2006) - et al.
Estimation of the effective self-diffusion tensor from the NMR spin echo
J. Magn. Reson. B
(1994) - et al.
MR diffusion tensor spectroscopy and imaging
Biophys. J.
(1994) - et al.
Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery
Biol. Psychiatry
(2005) - et al.
Neural networks of information processing in posttraumatic stress disorder: a functional magnetic resonance imaging study
Biol. Psychiatry
(2005) - et al.
Elevated response of human amygdala to neutral stimuli in mild post-traumatic stress disorder: neural correlates of generalized emotional response
Neuroscience
(2010) - et al.
Attenuation of frontal asymmetry in pediatric posttraumatic stress disorder
Biol. Psychiatry
(2001) - et al.
Brain structures in pediatric maltreatment-related posttraumatic stress disorder: a sociodemographically matched study
Biol. Psychiatry
(2002) - et al.
Brain morphometry in female victims of intimate partner violence with and without posttraumatic stress disorder
Biol. Psychiatry
(2002) - et al.
Twenty-four hour plasma cortisol and adrenocorticotropic hormone in Gulf War veterans: relationships to posttraumatic stress disorder and health symptoms
Biol. Psychiatry
(2007)
Pituitary response to metyrapone in Gulf War veterans: relationship to deployment, PTSD and unexplained health symptoms
Psychoneuroendocrinology
Neuroendocrine response to CRF stimulation in veterans with and without PTSD in consideration of war zone era
Psychoneuroendocrinology
Between session reproducibility and between subject variability of diffusion MR and tractography measures
Neuroimage
Astrocytes promote myelination in response to electrical impulses
Neuron
Diffusion tensor imaging evidence of white matter disruption associated with loss versus alteration of consciousness in warfighters exposed to combat in Operations Enduring and Iraqi Freedom
Psychiatry Res.
Differential time courses and specificity of amygdala activity in posttraumatic stress disorder subjects and normal control subjects
Biol. Psychiatry
Reduced white matter integrity in the cingulum and anterior corona radiata in posttraumatic stress disorder in male combat veterans: A diffusion tensor imaging study
Psychiatry Res.
Patterns of altered cortical perfusion and diminished subcortical integrity in posttraumatic stress disorder: an MRI study
Neuroimage
Neural circuitry of PTSD with or without mild traumatic brain injury: a meta-analysis
Neuropharmacology
Threshold-free cluster enhancement: addressing problems of smoothing, threshold dependence and localization in cluster inference
Neuroimage
Tract-based spatial statistics: voxelwise analysis of multi-subject diffusion data
Neuroimage
Advances in functional and structural MR image analysis and implementation as FSL
Neuroimage
Adenosine: a neuron-glial transmitter promoting myelination in the CNS in response to action potentials
Neuron
Reproducibility of quantitative tractography methods applied to cerebral white matter
Neuroimage
White matter plasticity in adulthood
Neuroscience
Trauma modulates amygdala and medial prefrontal responses to consciously attended fear
Neuroimage
Decreased anterior cingulate volume in combat-related PTSD
Biol. Psychiatry
Hydrocortisone responsiveness in Gulf War veterans with PTSD: effects on ACTH, declarative memory hippocampal [(18)F]FDG uptake on PET
Psychiatry Res.
Different white matter abnormalities between the first-episode, treatment-naive patients with posttraumatic stress disorder and generalized anxiety disorder without comorbid conditions
J. Affect. Disord.
Amygdala response in patients with acute PTSD to masked and unmasked emotional facial expressions
Am. J. Psychiatry
An inventory for measuring depression
Arch. Gen. Psychiatry
Extensive piano practicing has regionally specific effects on white matter development
Nat. Neurosci.
Initial reliability and validity of a new retrospective measure of child abuse and neglect
Am. J. Psychiatry
The development of a Clinician-Administered PTSD Scale
J. Trauma Stress
Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder
Am. J. Psychiatry
Temporal characteristics of tract-specific anisotropy abnormalities in schizophrenia
Neuroreport
Cited by (41)
Persistence of post-traumatic stress disorder in Chinese Shidu parents is associated with combined gray and white matter abnormalities
2023, Psychiatry Research - NeuroimagingEffects of chronic social stress on oligodendrocyte proliferation-maturation and myelin status in prefrontal cortex and amygdala in adult mice
2022, Neurobiology of StressCitation Excerpt :Whilst the cellular pathophysiology of these stress-related disorders is poorly understood, several diffusion tensor imaging (DTI) and post-mortem histological studies have, in addition to neurons and other glial systems, identified alterations in the status of oligodendrocytes (OLs) and myelination within and between ACC-AMY. These include changes in white matter tracts, myelin status, OL lineage cell density, and expression of OL-related genes and proteins (Bierer et al., 2015; Birey et al., 2015; Guilloux et al., 2012; Hamidi et al., 2004; Harrison, 2002; Mosebach et al., 2013; Seney et al., 2018; Sibille et al., 2009; Tanti et al., 2019). The direction of reported changes is not always consistent across studies, and some also report no change in OL density and myelin content (Lutz et al., 2017; Rajkowska et al., 2015).
A review of pre-clinical models for Gulf War Illness
2021, Pharmacology and TherapeuticsGulf War veterans exhibit broadband sleep EEG power reductions in regions overlying the frontal lobe
2021, Life SciencesCitation Excerpt :Although subjective sleep complaints are a central feature of the GWI phenotype—and sleep disturbance has notable effects on the other hallmark symptoms of pain, fatigue, mood, and cognitive performance—remarkably little research has focused on characterizing sleeping brain function in this population. Though the basic sleep architecture of veterans with GWI has appeared normal in previous studies [1–3], the frontal lobe is thought to be vital to the restorative function of sleep [6,7], and a battery of literature demonstrates frontal lobe abnormalities in GWI—including deficits in function, performance, and perfusion, as well as pathologies of the gray matter (GM) and white matter (WM) [8–19]. In light of these relationships, it is conceivable that sleep pathology may play a significant role in the maintenance of the disorder.
Sex-related Differences in Stress Reactivity and Cingulum White Matter
2021, Neuroscience