Combat exposure is associated with cortical thickness in Veterans with a history of chronic pain
Introduction
Chronic Pain (CP) is defined as pain that persists for longer than three months (International Association for the Study of Pain, http://www.iasp-pain.org/) and appears to be highly prevalent in Veterans of the recent conflicts in Iraq and Afghanistan. For example, one study has revealed that CP affected upwards of 50% of 685 Veterans seeking care in a Veterans Health Administration facility (Kerns et al., 2003), whereas other reports have indicated prevalence rates of 40% (Cifu et al., 2013). The presence of CP in Veterans is especially important since it is one of the main causes of disability (McWilliams et al., 2003, Patzkowski et al., 2012).
Chronic pain in Veterans appears to occur in a particular context of co-morbidities that may impact its diagnosis, treatment and outcome. Specifically, CP in Veterans occurs more frequently in individuals who are suffering from deployment-related disorders, such as Post-traumatic Stress Disorder (PTSD), and post-concussive symptoms related to mild Traumatic Brain Injury (mTBI) (Lew et al., 2013, Lew et al., 2009, Ullrich et al., 2013) than it does in individuals without these conditions. The co-occurrence of PTSD and CP was already shown to be as high as 80% in a sample of Vietnam era Veterans (Beckham et al., 1997), speaking to a possible link between psychological and physical pain. Investigators have hypothesized that CP and PTSD are not simply independent yet co-occurring factors, but that they might interact to create a cycle of mutual maintenance (Sharp and Harvey, 2001), which requires specific therapeutic approaches in treatment (Otis et al., 2009) to break. Further, the co-morbid presence of anxiety disorders and CP has been shown to be associated with greater use of opioid-based medication (Schwartz et al., 2006), resulting in an increased risk for abuse, dependence and overdose (Bohnert et al., 2014, Dobscha et al., 2013, Seal et al., 2012). Additionally, co-occurring CP and sleep disorders was present in 55% of a large sample of OEF/OIF/OND veterans and, together, accounted for 16% of cases in the sample who suffered from substantial disability (Lippa et al., 2015). There is furthermore a significant financial and human cost associated with treating comorbid CP and other deployment-related disorders (Beehler et al., 2013). For example, one study indicated a four-fold increase in costs of treating Veterans with comorbid CP and psychiatric conditions (Taylor et al., 2012). There is therefore a critical need to better understand the contribution of CP to the psychological and physical burdens related to deployment experiences. However, such an investigation is constrained by the natural clustering of disorders observed in Veterans sample, which imposes the use of a multivariate approach to these complex conditions (Lippa et al., 2015).
In examining the effects of CP in Veterans, few studies have examined potential impacts of CP and its interaction with deployment-related conditions on the integrity of the brain. Nevertheless, advances in brain imaging methods have helped identify brain networks thought to support the sensation of pain, as well as areas susceptible to the effects of pain alone (Apkarian, 2011, Hayes and Northoff, 2012, Lumley et al., 2011). These networks have been operationalized across two dimensions representing the sensation of pain (somatosensory cortex) and the affective component of pain (cingulate cortex, prefrontal cortex and insula). Studies in civilian samples have shown that the diagnosis of CP itself was associated with decreased gray matter volume or thickness in the cingulate and insular areas (Apkarian et al., 2011, Baliki et al., 2011, Burgmer et al., 2009, Kuchinad et al., 2007, Rodriguez-Raecke et al., 2009, Schmidt-Wilcke et al., 2005, Valet et al., 2009), as well as in the dorso-lateral prefrontal cortex (Schmidt-Wilcke et al., 2006). Some studies (Apkarian et al., 2004, Valet et al., 2009) further found that the observed decrease in gray matter density in the clinical group was significantly associated with the duration of clinical pain, suggesting a model of gradual atrophy of gray matter due to the pain. Despite the elevated prevalence of CP and associated costs in Veterans, findings of decreased gray matter integrity have yet to be replicated in a sample of Veterans. Examining this specific population is important since the association between brain structures and CP in Veterans may differ from that observed in civilians due to the deployment-related comorbidities. If this is the case, such an exacerbation could significantly impact the integrity of the brain, the phenomenological experience of pain and the effectiveness of treatments designed for pain alone.
Examining the impact of CP on gray matter integrity in Veterans specifically becomes increasingly relevant when we consider that the areas affected by CP in studies of civilians seem to overlap with areas affected by other deployment-related conditions like PTSD and mTBI. Studies from various groups have shown a decrease in the thickness and volume of gray matter in the insular and cingulate cortices of individuals suffering from PTSD (Bryant et al., 2008, Corbo et al., 2005, Corbo et al., 2014, Dickie et al., 2012, Eckart et al., 2011, Geuze et al., 2008, Herringa et al., 2012, Kasai et al., 2008, Kitayama et al., 2006, Lindemer et al., 2013, Woodward et al., 2006). Other studies have investigated the impact of TBI, which has also been shown to co-occur with CP, on gray matter integrity and have found some evidence of regional and global atrophy (Bergeson et al., 2004, Celik et al., 2005, Gale et al., 1995, Levine et al., 2008, Strangman et al., 2010, Yount et al., 2002). These findings mirror evidence from clinical studies showing possible interaction between psychological symptoms and pain sensations. This in turn raises an important question: if a history of CP is associated with a greater severity of PTSD and mTBI symptoms, and if these clinical conditions in isolation have been shown to affect overlapping cortical gray matter, is there a difference in the relationship between gray matter integrity and deployment-related conditions in Veterans with versus without a history of CP?
In the current study, we took advantage of a well-characterized sample of Veterans from Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND). We elected to approach CP in Veterans from an ecological perspective to study two primary questions.
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First, based on the studies showing gray matter thickness and volume decreases in individuals with CP, we investigated if Veterans with CP would also present similarly decreased gray matter integrity measured using cortical thickness, while controlling statistically for other symptoms (e.g. PTSD, Depression, mTBIs). Based on previous studies, we hypothesized that Veterans with CP would evidence decreased thickness in the ACC, insula and dorso-lateral prefrontal cortex.
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Second we investigated whether the presence of CP modifies the association between gray matter integrity and severity of trauma, as well as clinical symptoms of PTSD. Based on studies showing greater PTSD severity in Veterans with CP, we hypothesized that Veterans with CP would present stronger association between cortical thickness and PTSD severity/Combat Exposure than Veterans without CP.
Section snippets
Subjects
157 Veterans were recruited from the Translational Research Center for TBI and Stress Disorders (TRACTS), a VA Rehabilitation Research and Development, National Center for TBI Research (NRC) of the Veterans Affairs Boston Healthcare System (VABHS). Participants were from all branches of the military and from the greater New England area. The TRACTS cohort has been describe elsewhere (Lippa et al., 2015) and is considered representative of the current population of OEF/OIF/OND Veterans. In
Clinical variables
There were no significant differences between groups for PTSD symptoms severity, number of TBIs across the lifetime, combat exposure, age, education, IQ, depression, stress, anxiety, age of first trauma, deployment duration or time since duration (see Table 1).
Cortical thickness differences in CP
Looking at overall mean thickness, we did not find any significant differences between the CP and control groups. However, we found a significant effect of group on the association between thickness and combat exposure (see Fig. 1).
Discussion
The aims of the current study were to examine if a history of CP in deployed Veterans was associated with smaller cortical thickness derived from MPRAGE MRI scans, and if a history of CP impacted the association between thickness and deployment-related conditions. We hypothesized that Veterans with a positive history of CP would show reduced cortical thickness in the cingulate and insular areas as had been previously demonstrated in civilian populations (Apkarian et al., 2011). Our analyses did
Conclusions
Despite these limitations, we believe that the current findings support the need for greater research of the neurological aspect of chronic pain in the population of Veterans returning from recent conflicts. Our results indicate that CP may selectively affect some areas of the brain associated with cognitive processes important for psychological well being after deployment.
Acknowledgments
The authors would like to thank Wally Musto for his championship of our work among military personnel and his tireless recruitment efforts on our behalf, as well as Drs. Alexandra Kenna, Catherine Fortier, Ann Rasmusson, Brad Brummett, Sara Lippa and Colleen Jackson for the clinical assessments and diagnoses. The authors would also like to thank Dr. Jennifer Fonda for assistance in the processing of the clinical data.
This research was support by the Translational Research Center for TBI and
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