Faculty Bibliography

OBJECTIVE: Combat stress exposed soldiers may respond to post-deployment stressful life events (SLE) with increases in symptoms of posttraumatic stress disorder (PTSD), consistent with a model of stress sensitization. Several lines of research point to sensitization as a model to describe the relations between exposure to traumatic events, subsequent SLE, and symptoms of PTSD. Based on previous findings we hypothesized that immune activation, measured as a high in vitro capacity of leukocytes to produce cytokines upon stimulation, underlies stress sensitization. METHODS: We assessed mitogen-induced cytokine production at 1 month, SLE at 1 year, and PTSD symptoms from 1 month up to 2 years post-deployment in soldiers returned from deployment to Afghanistan (N=693). Exploratory structural equation modeling as well as latent growth models were applied. RESULTS: The data demonstrated significant three-way interaction effects of combat stress exposure, cytokine production, and post-deployment SLE on linear change in PTSD symptoms over the first 2 years following return from deployment. In soldiers reporting high combat stress exposure, both high mitogen-stimulated T-cell cytokine production and high innate cytokine production were associated with increases in PTSD symptoms in response to post-deployment SLE. In low combat stress exposed soldiers as well as those with low cytokine production, post-deployment SLE were not associated with increases in PTSD symptoms. CONCLUSION: High stimulated T-cell and innate cytokine production may contribute to stress sensitization in recently deployed, high combat stress exposed soldiers. These findings suggest that detecting and eventually normalizing immune activation may potentially complement future strategies to prevent progression of PTSD symptoms following return from deployment.

Deployed soldiers are at risk of developing stress-related conditions, including posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and severe fatigue. We previously observed condition- and cell-specific differences in sensitivity of immune cells for regulation by glucocorticoids (GCs) pre-deployment between male soldiers with and without subsequent development of high levels of these stress-related symptoms. Here we investigated whether these pre-deployment dysregulations in GC-sensitivity of immune cells persisted after return from military deployment. In a prospective, longitudinal study including 721 male and female soldiers, the in vitro GC-sensitivity of monocytes and T-cells was assessed prior to deployment and one and six months post-deployment. Differences in the longitudinal course of sensitivity for regulation by dexamethasone (DEX) of LPS-stimulated TNF-alpha production and PHA-stimulated T-cell proliferation between soldiers with and without subsequent symptom development were investigated using linear mixed models. Within the whole group, DEX-sensitivity of monocytes was significantly decreased at six months post-deployment compared to the assessments pre-deployment and one month post-deployment. The DEX-sensitivity of T-cells did not significantly change over time. Participants developing high levels of PTSD symptoms showed high DEX-sensitivity of T-cells, while participants developing high levels of depressive symptoms showed low DEX-sensitivity of T-cells before deployment that persisted at the two time points after return. In addition, participants developing severe fatigue had low DEX-sensitivity of monocytes at all assessments. Our finding that the previously observed pre-deployment group differences in peripheral GC-sensitivity persisted until at least six months after return indicates that in vitro GC-sensitivity of T-cells and monocytes may represent a persistent biological vulnerability factor for development of stress-related conditions PTSD, depression and fatigue.

Several studies have reported an association between traumatic stress and telomere length suggesting that traumatic stress has an impact on ageing at the cellular level. A newly derived tool provides an additional means to investigate cellular ageing by estimating epigenetic age based on DNA methylation profiles. We therefore hypothesise that in a longitudinal study of traumatic stress both indicators of cellular ageing will show increased ageing. We expect that particularly in individuals that developed symptoms of post-traumatic stress disorder (PTSD) increases in these ageing parameters would stand out. From an existing longitudinal cohort study, ninety-six male soldiers were selected based on trauma exposure and the presence of symptoms of PTSD. All military personnel were deployed in a combat zone in Afghanistan and assessed before and 6 months after deployment. The Self-Rating Inventory for PTSD was used to measure the presence of PTSD symptoms, while exposure to combat trauma during deployment was measured with a 19-item deployment experiences checklist. These groups did not differ for age, gender, alcohol consumption, cigarette smoking, military rank, length, weight, or medication use. In DNA from whole blood telomere length was measured and DNA methylation levels were assessed using the Illumina 450K DNA methylation arrays. Epigenetic ageing was estimated using the DNAm age estimator procedure. The association of trauma with telomere length was in the expected direction but not significant (B=-10.2, p=0.52). However, contrary to our expectations, development of PTSD symptoms was associated with the reverse process, telomere lengthening (B=1.91, p=0.018). In concordance, trauma significantly accelerated epigenetic ageing (B=1.97, p=0.032) and similar to the findings in telomeres, development of PTSD symptoms was inversely associated with epigenetic ageing (B=-0.10, p=0.044). Blood cell count, medication and premorbid early life trauma exposure did not confound the results. Overall, in this longitudinal study of military personnel deployed to Afghanistan we show an acceleration of ageing by trauma. However, development of PTSD symptoms was associated with telomere lengthening and reversed epigenetic ageing. These findings warrant further study of a perhaps dysfunctional compensatory cellular ageing reversal in PTSD.

OBJECTIVE: There is limited evidence on the association of the activity of HPG-axis with stress and symptoms of stress-related disorders. The aim of the current study was to assess the effect of deployment to a combat zone on plasma testosterone levels, and the possible association with the development of symptoms of posttraumatic stress disorder (PTSD). METHODS: A total of 918 males were included in the study before deployment to a combat zone in Afghanistan. The effect of deployment on testosterone was longitudinally assessed; starting prior to deployment and follow-up assessments were preformed at 1 and 6 months after return. Furthermore, the association with PTSD symptoms reported at 1 and 2 years post-deployment was assessed. RESULTS: Plasma testosterone levels were significantly increased after deployment compared with pre-deployment levels. Although no difference was found between individuals reporting high or low levels of PTSD symptoms, pre-deployment testosterone levels predicted the development of PTSD symptoms at 1 and 2 years post-deployment. CONCLUSION: This study provides evidence that not the alterations in testosterone levels shortly after deployment, but the pre-deployment testosterone levels are associated with PTSD symptoms, which is of value in the identification of biological vulnerability factors for the development of PTSD.

OBJECTIVES: Units deployed to armed conflicts are at high risk for exposure to combat events. Many battle casualties (BCs) have been reported in the recent deployment to Afghanistan. The long-term impact of these combat injuries, at their five-year end point, is currently unknown. To date, no systematic inventory has been performed of an identified group of BCs in comparison to non-injured service members from the same operational theatre. DESIGN: Observational cross-sectional cohort study. SETTING: Open online survey among Dutch BCs that deployed to Afghanistan (2006-2010). PARTICIPANTS: The Dutch BCs (n = 62) were compared to two control groups of non-injured combat groups (battle exposed [n = 53], and non-battle exposed [n = 73]). MAIN OUTCOME MEASURES: Participants rated their impact of trauma exposure (Impact of Events [IES]), post deployment reintegration (Post Deployment Reintegration Scale [PDRS]), general symptoms of distress (Symptom Checklist 90 [SCL-90]), as well as their current perceived quality of life (EuroQol-6D [EQ-6D]). Also cost effectiveness (Short From health survey [SF-36]) and care consumption were assessed (Trimbos/iMTA questionnaire). RESULTS: Over 90% of BCs were still in active duty. The mean scores of all questionnaires (IES, EQ-6D, SF-36, and SCL-90) of the BC group were significantly higher than in the control groups (p<0.05). The PDRS showed a significantly lower (p<0.05) outcome in the negative subscales. The mean consumption of care was triple that of both control groups. A lower score on quality of life was related to higher levels of distress and impact of trauma exposure. CONCLUSIONS: This study showed a clear long-term impact on a wide range of scales that contributes to a reduced quality of life in a group of BCs. Low perceived cost effectiveness matched with high consumption of care in the BC group in comparison to the control groups. These results warrant continuous monitoring of BCs.

BACKGROUND: A subgroup of servicemen can be identified that seek a disproportionally amount of health care in comparison to diagnostic and therapeutic perspectives. This group can be identified on the basis of an absence of a structural medical explanation for their symptoms. The symptoms manifest predominantly as fatigue and pain, and are often chronic. Patients with medical unexplained medical symptoms (MUPS) often have multiple and complex problems that would be best treated by a multidisciplinary team of medical specialists and paramedics. The military is characterized by high loyalty towards peers and leadership, leading to neglect for personal care. OBJECTIVE: While consensus on the biological basis for these complaints is lacking, awareness on the need for effective treatments for this patient group is high. METHOD: Based on reviews, expert recommendations and clinical demand, a specialized treatment program for soldiers with MUPS has recently been developed and implemented in the system of health care in the Netherlands Armed Forces. We developed a functional rehabilitation program with blended care elements of cognitive behavioral therapy (CBT), physical therapy, case management, and psychoeducation, embedded in a day treatment setting. RESULTS: The program received high scores on participant as well as team satisfaction. The program is illustrated by two clinical vignettes. CONCLUSION: The blended care program for MUPS that focused on allostatic load awareness offered a more holistic and preventive approach that contributed to a reduction of unnecessary medical consumption, and increased job participation. We recommend that the development of guidelines for diagnoses and treatment of these complaints in military settings will improve the quality of patient care, reduce disability, facilitate reintegration, and encourage scientific research.

BACKGROUND: The North Atlantic Treaty Organization (NATO) coalition forces remain heavily committed on combat operations overseas. Understanding the prevalence and characteristics of battlefield injury of coalition partners is vital to combat casualty care performance improvement. The aim of this systematic review was to evaluate the prevalence and characteristics of battle casualties from NATO coalition partners in Iraq and Afghanistan. The primary outcome was mechanism of injury and the secondary outcome anatomical distribution of wounds. METHODS: This systematic review was performed based on all cohort studies concerning prevalence and characteristics of battlefield injury of coalition forces from Iraq and Afghanistan up to December 20th 2013. Studies were rated on the level of evidence provided according to criteria by the Centre for Evidence Based Medicine in Oxford. The methodological quality of observational comparative studies was assessed by the modified Newcastle-Ottawa Scale. RESULTS: Eight published articles, encompassing a total of n=19,750 battle casualties, were systematically analyzed to achieve a summated outcome. There was heterogeneity among the included studies and there were major differences in inclusion and exclusion criteria regarding the target population among the included trials, introducing bias. The overall distribution in mechanism of injury was 18% gunshot wounds, 72% explosions and other 10%. The overall anatomical distribution of wounds was head and neck 31%, truncal 27%, extremity 39% and other 3%. CONCLUSIONS: The mechanism of injury and anatomical distribution of wounds observed in the published articles by NATO coalition partners regarding Iraq and Afghanistan differ from previous campaigns. There was a significant increase in the use of explosive mechanisms and a significant increase in the head and neck region compared with previous wars.

INTRODUCTION: Care for battle casualties demands special skills from surgeons and anesthesiologists. The experiences of Dutch military surgeons and anesthesiologists that deployed to South Afghanistan provided an opportunity to evaluate predeployment training and preparation of military medical specialists. METHOD: A survey was conducted among all surgeons and anesthesiologists (n = 40) that deployed to South Afghanistan between February 2006 and November 2010. They were asked about their medical preparedness, deployment experience, and postdeployment impact. RESULTS: Most (35/40) participants reported high levels of preparedness before their deployment. All (40/40) surgeons and anesthesiologists described a positive influence of their deployment on their professional skills and 33/40 described a positive effect on their personal development. Knowledge of maxillofacial, ophthalmic, neurological, urological, gynecological, vascular, and thoracic surgery scored below average. Impact on mental health and social support network was reported as negative by 11/40 participants, 24/40 reported a neutral, and 5/40 a positive effect. CONCLUSION: A standardized predeployment training program to prepare Dutch surgeons and anesthesiologists for combat surgery is currently lacking. These results emphasize the need for a standardized predeployment medical training, despite high levels of perceived preparedness. Also, the high mental and psychological impact on the deployed surgeons and anesthesiologists warrants further assessment.

Several lines of research have demonstrated that memories for fearful events become transiently labile upon re-exposure. Activation of molecular mechanisms is required in order to maintain retrieved information. This process is called reconsolidation. Targeting reconsolidation - as in exposure-based psychotherapy - offers therefore a potentially interesting tool to manipulate fear memories, and subsequently to treat disorders such as post-traumatic stress disorder (PTSD). In this paper we discuss the evidence for reconsolidation in rodents and humans and highlight recent studies in which clinical research on normal and abnormal fear extinction reduction of the expression of fear was obtained by targeting the process of reconsolidation. We conclude that reconsolidation presents an interesting opportunity to modify or alter fear and fear-related memories. More clinical research on normal and abnormal fear extinction is required.