Psychoneuroendocrinology (2015) 51, 567—576

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White matter abnormalities in Gulf War veterans with posttraumatic stress disorder: A pilot study Linda M. Bierer a,b,∗, Iliyan Ivanov a,b, David M. Carpenter c, Edmund W. Wong c, Julia A. Golier a,b, Cheuk Y. Tang c, Rachel Yehuda a,b a

Department of Psychiatry, Traumatic Stress Studies Division, Icahn School of Medicine at Mount Sinai, United States b Traumatic Stress Studies Division, James J. Peters VA Medical Center, United States c Department of Radiology, Icahn School of Medicine at Mount Sinai, United States Received 7 April 2014; received in revised form 1 October 2014; accepted 10 November 2014

KEYWORDS PTSD; DTI; Diffusion tensor imaging; White matter; Gulf War veterans; Connectivity; Cingulum bundle

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

∗ Corresponding author at: James J. Peters VAMC — (116/A; OOMH), 130 West Kingsbridge Road, Bronx, NY 10468-3904, United States. Tel.: +1 718 741 4000x5230; fax: +1 718 741 4703. E-mail address: [email protected] (L.M. Bierer). 0306-4530/© 2014 Published by Elsevier Ltd.


L.M. Bierer et al. 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. © 2014 Published by Elsevier Ltd.

1. 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, 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 metaanalysis (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, 2009) distinct from those associated with PTSD in veterans of other

White matter abnormalities in Gulf War veterans conflicts (Golier et al., 2006). Given the predominance of white matter abnormalities in the cingulum bundle in PTSD (Kim et al., 2005, 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.

569 difficulty, or loss of consciousness for .05; FWE corrected for multiple comparisons). The effect of multisymptom illness on the finding of reduced MD in veterans with PTSD was investigated. There was no effect of chronic multisymptom illness alone on right cingulum bundle MD (F(1,17) = .040, ns). However, a significant interaction was evident between PTSD and

White matter abnormalities in Gulf War veterans Table 1

Comparison of demographic and clinical characteristics for participants with and without PTSD.

Demographics — descriptive Age (years) Race White Black Latino Asian Other/Unknown Hispanic decent Education (years) Body Mass Index (BMI) Current tobacco user Current psychotropic medication Combat exposure severity (CES)b Head injury without LOCc Chronic multisymptom illness Age at combat exposure Years since trauma/symptom duration Clinical characteristics PTSD severity (CAPS total) Mississippi Scale Depression severity (BDI)d Spielberger Trait Anxiety Scale (STAI)e Childhood adversity (CTQ)f Current major depression Past alcohol abuse Past drug abuse MRI volume determinations Whole brain white matter volume (cc) Whole brain volume (cc) Neuroendocrine measures Urinary cortisol (␮g/24 h) 8am plasma cortisol (␮g/ml) a b c d e f


PTSD (−) (n = 8) Mean ± SD or n (%)

PTSD (+) (n = 12) Mean ± SD or n (%)

Group comparisons

45.3 ± 12.7

41.5 ± 11.2

F (1,19) = .48, ns 2 = 5.73, 1, ns

3 (37.5%) 3 (37.5%) 2 (25.0%) 0 1 (12.5%) 2 (22.2%) 13.9 ± 2.2 26.1 ± 3.4 2 (25.0%) 0 10.0 ± 9.7 3 (37.5%) 3 (37.5%) 30.5 ± 10.9 14.8 ± 5.0

1 (8.3%) 3 (25.0%) 5 (41.7%) 1 (8.3%) 2 (16.5%) 7 (58.3%) 13.1 ± 1.9 28.2 ± 3.3 6 (50.0%) 2 (16.7%) 15.2 ± 10.9 2 (16.7%) 9 (75%) 28.4 ± 12.0 13.1 ± 13.1

2 = 2.23, 1, ns F(1,19) = .73, ns F(1,19) = 1.82, ns 2 = 1.29, 1, ns 2 = 1.05, 1, ns F(1,19) = .73, ns 2 = .254, 1, ns 2 = 2.84, 1 (p = .092) F(1,19) = .16, ns F(1,19) = .12, ns

7.4 ± 9.0 75.4 ± 8.4 5.8 ± 6.1 14.6 ± 7.6 8.2 ± 2.3 0 3 (37.6%) 1 (12.5%)

67.8 ± 24.3 113.2 ± 27.7 23.5 ± 10.4 32.7 ± 9.3 8.4 ± 1.7 5 (41.7%) 5 (41.7%) 2 (16.7%)

F(1,19) = 44.57, p < .0005 F(1,19) = 13.76, p = .002 F(1,19) = 18.96, p < .0005 F(1,19) = 20.82, p < .0005 F(1,19) = .03, ns 2 = 6.19, 1, p = .013 2 = .035, 1, ns 2 = .067, 1, ns

436,350 ± 37,112 1,430,314 ± 145,218

457,288 ± 63,093 1,453,633 ± 126,654

F(1,18) = .709, ns F(1,18) = .154, ns

(n = 6) 51.0 ± 33.7 12.87 ± 5.52

(n = 9) 38.6 ± 8.6 19.68 ± 6.18

F (df) p or 2 (df) pa

F(1,12) = .89, ns F(1,14) = 4.74, p = .049

Likelihood ratio for all comparisons. Combat Exposure Scale (Lund et al., 1984). Loss of consciousness. Beck Depression Inventory (Beck et al., 1961). State-Trait Anxiety Inventory (Spielberger et al., 1983). Childhood Trauma Questionnaire (Bernstein et al., 1994).

chronic multisymptom illness on right cingulum bundle MD (F(1,15) = 4.17, p = .025) such that the lowest MD was apparent for participants with PTSD in the absence of Gulf War illness (Fig. 2). Thus, among veterans with PTSD, there was a significant post hoc difference for the presence or absence of chronic multisymptom illness (p = .026); and for veterans without Gulf War illness, right cingulum MD differed significantly between veterans with and without PTSD (p = .004). CAPS total scores were similar for veterans with PTSD who did (67.0 ± 24.4) and did not report co-morbid chronic multisymptom illness (70.3 ± 29.4).

PTSD symptom measures showed significant correlations with MD and FA in the right cingulum. The current CAPS total and Mississippi Scale scores were negatively correlated with right cingulum MD and positively with right cingulum FA (see Table 2 and Fig. 3). Among the subscale scores, the most substantial association, and the only correlation that survives Bonferroni correction for the three subscales, was for intrusive symptoms with right cingulum bundle MD (Table 2). Similar associations were evident within the PTSD group alone, but significance values are diminished due to the reduced sample size.


L.M. Bierer et al.

Figure 2 Interactions of PTSD and chronic multisymptom illness on right cingulum bundle mean diffusivity. Comparison is covaried for whole brain volume. *p < .05, **p < .005. The figure indicates that in the absence of chronic multisymptom illness, MD is significantly lower for participants with than without PTSD.

Table 2

Relationship of clinician- and self-rated PTSD severity to anterior cingulum bundle MD and FA.

Symptom rating measures

Anterior cingulum bundle MD FA (n = 20) (n = 20)

CAPS total score (current) Intrusive subscale score Avoidance subscale score Hyperarousal subscale score Mississippi Scale score 8am plasma cortisol (␮g/ml)

−.586 −.659 −.518 −.522 −.486 −.536

a b c d

(.008)a (.002)b (.023) (.022) (.035) (.048)c

.514 .509 .537 .424 .534 .736

(.025) (.026) (.018) ((.070)) (.018) (.003)

MD (n = 12) PTSD onlyd

FA (n = 12) PTSD only

−.604 −.711 −.407 −.519 −.387 −.150

.441 .380 .491 .327 .439 .665

(.049) (.014) ns ns ns ns

ns ns ns ns ns ((.078))

All correlations are partial r (p), controlling for total brain volume (df = 17). Survives Bonferroni correction for 3 subscale scores. df = 12. Within group correlations provided to illustrate that findings for MD are not driven by group differences.

Post hoc associations with cortisol measures showed significant partial correlations between 8am plasma cortisol and MD (r = −.536, df = 12, p = .048) and FA (r = .734, df = 12, p = .003) in the right cingulum bundle, accounting for total brain volume (Fig. 4). Duration since combat exposure or

focal trauma was inversely associated with right cingulum FA (r = −.536, df = 17, p = .018) but not with MD (r = .171, df = 17, ns). No significant associations were observed for cortisol and left cingulum DTI measures. Of note, a significant correlation was evident for cortisol and current CAPS

Figure 3 Partial correlations of mean diffusivity and fractional anisotropy in right cingulum bundle with CAPS total scores. The data was adjusted for total brain volume using linear regression and adding unstandardized residuals to the initial raw levels. The figures indicate significant associations of both MD and FA in the right cingulum with PTSD severity (CAPS with MD r = −.586, p = .008; with FA r = .514, p = .025).

White matter abnormalities in Gulf War veterans


Figure 4 Partial correlations of mean diffusivity and fractional anisotropy in right cingulum bundle with 8am plasma cortisol. The data was adjusted for total brain volume using linear regression and adding unstandardized residuals to the initial raw levels. The figures indicate significant association of both MD and FA in the right cingulum with stress elevations in 8am plasma cortisol (cortisol with MD (r = −.536, p = .048); with FA (r = .734, p = .003)).

total score (r = .517, n = 15, p = .049). As shown in Table 1, plasma cortisol was significantly higher among participants with versus without PTSD.

4. 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 illness significantly attenuated the increase in cingulum microstructure associated with PTSD, while having minimal effect on MD in the absence of PTSD. PTSD severity and 8am plasma cortisol were inversely associated with right cingulum MD and positively associated with right cingulum FA; plasma cortisol was significantly associated with PTSD severity. As the anterior cingulum bundle reciprocally connects the amygdala with the anterior cingulate cortex, the observation of increased microstructural integrity is consistent with plastic adaptation in PTSD to increased neuronal activity within these regions. Given the significant associations of both right hemisphere MD and FA with PTSD symptom severity ratings, this adaptation is a likely result of neuronal recruitment as a consequence of repeated stimulation in the context of symptom expression, in particular of intrusive and triggered re-experiencing of traumatic memories and associations. Indeed, in an experimental behavioral paradigm to test inhibitory neural networks, individuals with PTSD showed deficient right dorsal anterior cingulate activation that was predominant in controls (Falconer et al., 2008), providing support not only for the laterality of the present findings (but see Kim et al., 2005, 2006), but also for a model of PTSD as a disorder characterized by deficient inhibitory control. The exploratory data of this report are consistent with an interpretation that altered connectivity in the cingulum reflects a functional interaction between limbic and cortical regions in which exaggerated amygdala

activity is insufficiently suppressed by cingulate activation. Such enhanced connectivity might represent a mechanism for the development of PTSD symptoms that tend to persist long after the focal trauma (van Wingen et al., 2012). The finding of significantly increased 8am plasma cortisol in the context of non-significantly reduced ambient cortisol (reflected by 24-h urinary cortisol excretion) suggests an increased response to the stress of venipuncture for the Gulf War participants with PTSD. The associations noted between PTSD severity and the elevations in plasma cortisol, and between both of these measures and both DTI indices in the right cingulum bundle suggests that increased glucocorticoid responsivity is an integral feature of the neuropsychiatric presentation of PTSD in this cohort. Indeed, enhanced pituitary ACTH response to CRF challenge was found for Gulf War veterans with PTSD that was not observed for PTSD in Vietnam or OIF/OEF veterans, suggesting increased sensitivity of pituitary corticotrophs or basal CRF hyposecretion (Golier et al., 2012). Diminished diffusivity and increased anisotropy are consistent with increased myelination that is known to occur in association with neuronal activity (Markham and Greenough, 2004; Wang and Young, 2014). In humans, extensive piano practice results in regionally specific augmentation of white matter microstructure (Bengtsson et al., 2005). Mechanisms by which neuronal activity regulates myelination include the production of cell adhesion molecules in response to electrical activity (Itoh et al., 1995, 1997), direct stimulation of oligodendrocyte proliferation by axonally released ATP (Ishibashi et al., 2006), and terminal release of adenosine — which induces myelin production (Stevens and Fields, 2000; Stevens et al., 2002). Moreover, the expression of glucocorticoid receptors in oligodendrocytes and their progenitor cells mediate oligodendrocyte differentiation and myelination in adult CNS (Matsusue et al., 2014) and are therefore a target for the action of glucocorticoids. Thus, amygdala activation in association with spontaneous or triggered intrusion of traumatic memories, coupled with cingulate modulation of amygdala discharge, may initiate a signaling cascade that results in the augmentation of cingulum bundle myelination, as reflected by diminished diffusivity. It is additionally possible that transient stress induced glucocorticoid elevations, promoted in association with this signaling cascade,

574 may in part mediate the increased cingulum bundle myelination indicated by diminished diffusivity (see Chetty et al., 2014). The presence of chronic multisymptom illness significantly interfered with the expression of augmented cingulum microstructure among the veterans with PTSD in this study. In a prior investigation using DTI among Gulf War veterans and controls, prominent dimensions of chronic multisymptom illness were correlated with increased axial diffusivity in a fronto-occipital tract after whole brain analysis (Rayhan et al., 2013). In the present report, no such increase was observed in the cingulum bundle to associate with the presence of chronic multisymptom illness. However, the decrement in MD, indicating increased microstructure, that was observed in association with PTSD, was significantly less apparent among participants with additional evidence of chronic multisymptom illness. Thus, our preliminary results suggest that increased myelination is linked to the presence of clinically significant PTSD in the absence of chronic multisymptom illness. The mechanisms to explain this finding are presently unclear. However, to the extent that activity dependent myelination is a reflection of central adaptation, the findings of this report suggest that, in contrast to PTSD, Gulf War illness may be associated with diminished central plasticity. They further underscore the assertion that Gulf War illness and PTSD are distinct pathophysiologic processes. Finally, 5 participants (3 without PTSD and 2 with PTSD) had histories of head injury without loss of consciousness or residual symptoms that were not classified as minimal TBI at the time of evaluation. The frequency of head trauma history did not differ between PTSD and no-PTSD groups (see Table 1), and did not associate with anterior cingulum bundle MD or FA. Unlike the more recent conflicts in Iraq and Afghanistan, mTBI was not a signature injury in the Gulf War. Further, loss of consciousness appears to be a critical component of white matter disruption following blast exposure (Matthews et al., 2012), which was not reported by the participants in this study. These findings should be interpreted in light of several limitations. The sample size is small and therefore we consider our results preliminary. Optimal MRI and DTI techniques at the time of the study (with 4 mm slices and using only 12 gradient directions) had lower resolution than are currently available. Heiervang et al. (2006) have noted that 12 direction data are sufficient for reproducibly defining the core of large bundles but are less sensitive to smaller pathways. With this in mind, only the superior portion of the cingulum was analyzed as the inferior portion connecting amygdala to hippocampus was not reliably discernable for all subjects. The study does not have a longitudinal component, imaging only veterans with chronic PTSD, that precludes inferences relating white matter integrity alterations to the development or course illness. The subjects meeting criteria for chronic multisymptom illness in this report were further characterized according to currently accepted subsyndromal variants (Iannacchione et al., 2011), however the number of subjects was too small to permit further subgroup analysis. In summary, the preliminary findings of this report indicate increased white matter microstructure of the right cingulum bundle among Gulf War veterans with PTSD. This

L.M. Bierer et al. finding is consistent with increased amygdala — anterior cingulate connectivity and associated with severity of PTSD symptoms, in particular with intrusions. In this pilot study, the significant effect of PTSD on DTI indices among Gulf War veterans is not observed in the presence of co-morbid chronic multisymptom illness.

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

Gulf War veterans were exposed to environmental toxins not present in other combat theaters resulting in a unique biological signature that only parti...
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