Faculty Bibliography

PURPOSE/OBJECTIVE:The Prospective Research in Stress-Related Military Operations (PRISMO) study was initiated to gain a better understanding of the long-term impact of military deployment on mental health, and to map the different biological and psychological factors that contribute to the development of stress-related mental health symptoms. PARTICIPANTS/METHODS:The PRISMO cohort consists of a convenience sample of Dutch military personnel deployed to Afghanistan between 2005 and 2008. Baseline data collection resulted in the recruitment of 1032 military men and women. Combat troops as well as non-combat support troops were recruited to increase the representativeness of the sample to the population as a whole. FINDINGS TO DATE/UNASSIGNED:The prevalence of various mental health symptoms increases after deployment in PRISMO cohort members, but symptom progression over time appears to be specific for various mental health symptoms. For post-traumatic stress disorder, we found a short-term symptom increase within 6 months after deployment (8.2%), and a long-term symptom increase at 5 years after deployment (12.9%). Several biological vulnerability factors associated with the development of stress-related conditions after deployment were identified, including predeployment glucocorticoid receptor sensitivity and predeployment testosterone level. Thus far, 34 publications have resulted from the cohort. FUTURE PLANS/UNASSIGNED:Various analyses are planned that will include the prevalence of mental health symptoms at 10 years postdeployment, as well as trajectory analyses that capture the longitudinal development of symptoms. Furthermore, we will use a machine learning approach to develop predictive and network models for several mental health symptoms, incorporating biological, psychological and social factors.

This paper reviews the military context of exposure to combat and deployment in Dutch soldiers. It does so by reviewing war victims and military psychiatry after WWII in the Netherlands, and describes Dutch deployments from the late 1970s to the present. 'Who is the Dutch soldier' is asked to articulate the mental load on the individual soldier before, during, and after deployment. The narrative review of this paper allows one to review how the armed forces personnel is challenged in relation to their specific assignment and in what respect the psychological dimensions are addressed and met in the face of risk and adversity. Finally, some critical considerations for future veterans care programmes are raised.

Background: Childhood trauma and combat-related trauma are both associated with decreased psychosocial functioning. Coping strategies play an important role in the adjustment to traumatic events. Objective: The present study examined childhood trauma and the mediating role of coping strategies in adult psychological symptoms in a non-clinical military population after deployment to Afghanistan. Additionally, the moderating role of coping strategies in vulnerability to combat events was explored. Method: Participants (N = 932) were drawn from a prospective study assessing psychological complaints (SCL-90), early trauma (ETISR-SF), combat-related events and coping strategies (Brief COPE). Mediation analyses via joint significance testing and moderation analyses were performed. Results: Childhood trauma is related to adult symptoms of general anxiety, depression and problems concerning interpersonal sensitivity through the mediation of self-blame as a coping strategy. Some evidence was found that self-blame moderated vulnerability to combat-related events resulting in psychological complaints, specifically symptoms of anxiety and depression. Conclusions: Military personnel should be made aware of self-criticizing maladaptive belief systems when dealing with aversive events. Negative beliefs about oneself and distorted trauma-related cognitions may have a basis in childhood events. Self-blame cognitions may be a potential mechanism of change in empirically supported trauma interventions such as cognitive processing therapy.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop upon exposure to a traumatic event. While most people are able to recover promptly, others are at increased risk of developing PTSD. However, the exact underlying biological mechanisms of differential susceptibility are unknown. Identifying biomarkers of PTSD could assist in its diagnosis and facilitate treatment planning. Here, we identified serum microRNAs (miRNAs) of subjects that underwent a traumatic event and aimed to assess their potential to serve as diagnostic biomarkers of PTSD. Next-generation sequencing was performed to examine circulating miRNA profiles of 24 members belonging to the Dutch military cohort Prospective Research in Stress-Related Military Operations (PRISMO). Three groups were selected: "susceptible" subjects who developed PTSD after combat exposure, "resilient" subjects without PTSD, and nonexposed control subjects (N = 8 per group). Differential expression analysis revealed 22 differentially expressed miRNAs in PTSD subjects compared to controls and 1 in PTSD subjects compared to resilient individuals (after multiple testing correction and a log2 fold-change cutoff of ≥|1|). Weighted Gene Coexpression Network Analysis (WGCNA) identified a module of coexpressed miRNAs which could distinguish between the three groups. In addition, receiver operating characteristic curve analyses suggest that the miRNAs with the highest module memberships could have a strong diagnostic accuracy as reflected by high areas under the curves. Overall, the results of our pilot study suggest that serum miRNAs could potentially serve as diagnostic biomarkers of PTSD, both individually or grouped within a cluster of coexpressed miRNAs. Larger studies are now needed to validate and build upon these preliminary findings.

BACKGROUND:Recent studies examining the association between posttraumatic stress disorder (PTSD) and accelerated aging, as defined by DNA methylation-based estimates of cellular age that exceed chronological age, have yielded mixed results. METHODS:We conducted a meta-analysis of trauma exposure and PTSD diagnosis and symptom severity in association with accelerated DNA methylation age using data from 9 cohorts contributing to the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (combined N = 2186). Associations between demographic and cellular variables and accelerated DNA methylation age were also examined, as was the moderating influence of demographic variables. RESULTS:Meta-analysis of regression coefficients from contributing cohorts revealed that childhood trauma exposure (when measured with the Childhood Trauma Questionnaire) and lifetime PTSD severity evidenced significant, albeit small, meta-analytic associations with accelerated DNA methylation age (ps = 0.028 and 0.016, respectively). Sex, CD4T cell proportions, and natural killer cell proportions were also significantly associated with accelerated DNA methylation age (all ps < 0.02). PTSD diagnosis and lifetime trauma exposure were not associated with advanced DNA methylation age. There was no evidence of moderation of the trauma or PTSD variables by demographic factors. CONCLUSIONS:Results suggest that traumatic stress is associated with advanced epigenetic age and raise the possibility that cells integral to immune system maintenance and responsivity play a role in this. This study highlights the need for additional research into the biological mechanisms linking traumatic stress to accelerated DNA methylation age and the importance of furthering our understanding of the neurobiological and health consequences of PTSD.

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.

The therapeutic application of human-animal interaction has gained interest recently. One form this interest takes is the use of service dogs as complementary treatment for veterans with Post-Traumatic Stress Disorder (PTSD). Many reports on the positive effect of PTSD Service Dogs (PSDs) on veterans exist, though most are indirect, anecdotal, or based on self-perceived welfare by veterans. They therefore only give a partial insight into PSD effect. To gain a more complete understanding of whether PSDs can be considered an effective complementary treatment for PTSD, a scoping literature review was performed on available studies of PSDs. The key search words were 'dog', 'canine', 'veteran', and 'PTSD'. This yielded 126 articles, of which 19 matched the inclusion criteria (six empirical studies). Recurrent themes in included articles were identified for discussion of methodology and/or results. It was found that results from most included studies were either applicable to human-animal interaction in general or other types of service animals. They therefore did not represent PSDs specifically. Studies which did discuss PSDs specifically only studied welfare experience in veterans, but used different methodologies. This lead us to conclude there is currently no undisputed empirical evidence that PSDs are an effective complementary treatment for veterans with PTSD other than reports on positive welfare experience. Additionally, the lack of development standardization and knowledge regarding welfare of PSDs creates risks for both human and animal welfare. It is therefore recommended that a study on the effect of PSDs be expanded to include evaluation methods besides self-perceived welfare of assisted humans. Future studies could include evaluations regarding human stress response and functioning, ideally conducted according to validated scientific methodologies using objective measurement techniques to identify the added value and mechanisms of using PSDs to assist treatment of PTSD in humans.

Compelling evidence suggests that epigenetic mechanisms such as DNA methylation play a role in stress regulation and in the etiologic basis of stress related disorders such as Post traumatic Stress Disorder (PTSD). Here we describe the purpose and methods of an international consortium that was developed to study the role of epigenetics in PTSD. Inspired by the approach used in the Psychiatric Genomics Consortium, we brought together investigators representing seven cohorts with a collective sample size of N = 1147 that included detailed information on trauma exposure, PTSD symptoms, and genome-wide DNA methylation data. The objective of this consortium is to increase the analytical sample size by pooling data and combining expertise so that DNA methylation patterns associated with PTSD can be identified. Several quality control and analytical pipelines were evaluated for their control of genomic inflation and technical artifacts with a joint analysis procedure established to derive comparable data over the cohorts for meta-analysis. We propose methods to deal with ancestry population stratification and type I error inflation and discuss the advantages and disadvantages of applying robust error estimates. To evaluate our pipeline, we report results from an epigenome-wide association study (EWAS) of age, which is a well-characterized phenotype with known epigenetic associations. Overall, while EWAS are highly complex and subject to similar challenges as genome-wide association studies (GWAS), we demonstrate that an epigenetic meta-analysis with a relatively modest sample size can be well-powered to identify epigenetic associations. Our pipeline can be used as a framework for consortium efforts for EWAS.