Elsevier

Psychoneuroendocrinology

Volume 51, January 2015, Pages 567-576
Psychoneuroendocrinology

White matter abnormalities in Gulf War veterans with posttraumatic stress disorder: A pilot study

https://doi.org/10.1016/j.psyneuen.2014.11.007Get rights and content

Highlights

  • Gulf War veterans with and without PTSD were studied using diffusion tensor imaging.

  • Cingulum bundles, connecting amygdala and medial frontal cortices, were of interest.

  • Results showed lower mean diffusivity in the right cingulum bundle in PTSD.

  • This suggests enhanced connectivity between amygdala and anterior cingulate cortex.

  • Chronic multisymptom illness (CMI) alone did not affect DTI variables.

  • Lower right cingulum mean diffusivity was only significant in the absence of CMI.

  • Increased structural integrity in right cingulum was associated with PTSD severity.

  • Increased structural integrity was also associated with higher cortisol responsivity.

Summary

Background

Gulf War veterans were exposed to environmental toxins not present in other combat theaters resulting in a unique biological signature that only partially resembles that seen in other combat veterans with PTSD. Thus it is important to determine if brain abnormalities seen in non-Gulf War veterans with PTSD are also present in Gulf War veterans. In this pilot study, diffusion tensor imaging (DTI) tractography was used to assess the ultra-structural integrity of fronto-limbic white matter connections in Gulf War veterans with and without PTSD. The effects of chronic multisymptom illness on DTI measures was also evaluated.

Methods

Subjects were 20 previously studied Gulf War veterans on whom MRIs had been obtained. Mean diffusivity (MD) and fractional anisotropy (FA) were determined for left and right cingulum bundle by DTI tractography and compared in separate analyses for 12 veterans with, and 8 without PTSD. The effect of chronic multisymptom illness and it's interaction with PTSD, were similarly investigated using multivariate ACOVA. Partial correlations were used to test the associations of both DTI indices with PTSD severity and plasma cortisol, controlling for whole brain volume.

Results

Significantly lower MD was demonstrated in the right cingulum bundle among Gulf War veterans with PTSD. There were no significant differences in MD or FA in the left cingulum bundle. The presence of chronic multisymptom illness significantly attenuated the PTSD associated decrement in right cingulum MD. Clinician and self-rated PTSD symptom severity scores were significantly associated with reduced MD and increased FA in the right cingulum. Similar associations were observed for 8am plasma cortisol in a subset of participants.

Conclusions

The preliminary findings indicate increased structural integrity – supporting enhanced connectivity – between right amygdala and anterior cingulate cortex in PTSD. This effect was strongest among Gulf War veterans without chronic multisymptom illness. The association of both MD and FA in the right cingulum with PTSD severity, and with heightened glucocorticoid responsivity, suggests that these DTI findings are a reflection of current PTSD illness expression. Although based on a small sample, these microstructural observations are consistent with a functional model suggesting increased amygdala responsivity in association with anterior cingulate modulation in PTSD.

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).

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