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BackgroundPTSD and depression commonly co-occur and have been associated with smaller hippocampal volumes compared to healthy and trauma-exposed controls. However, the hippocampus is heterogeneous, with subregions that may be uniquely affected in individuals with PTSD and depression.MethodsWe used random effects regressions and a harmonized neuroimaging protocol based on FreeSurfer (v6.0) to identify sub-structural hippocampal markers of current PTSD (C-PTSD), depression, and the interaction of these conditions across 31 cohorts worldwide (N=3,115;Mage=38.9±13.9 years). Secondary analyses tested these associations by sex and after modeling the simultaneous effects of remitted PTSD, childhood trauma, mild traumatic brain injury, and alcohol use disorder.ResultsA significant negative main effect of depression (n=800, vs. no depression, n=1456) was observed in the hippocampal tail (ß=−0.13) and CA1 (ß=−0.09) after adjusting for covariates and multiple testing (adjusted p’s (q)=0.028). A main effect of C-PTSD (n=1042 vs. control, n=1359) was not significant, but an interaction between C-PTSD and depression was significant in the CA1 (ß=−0.24, q=0.044). Pairwise comparisons revealed significantly smaller CA1 volumes in individuals with C-PTSD+Depression than controls (ß=−0.12, q=0.012), C-PTSD-only (ß=−0.17, q=0.001), and Depression-only (ß=−0.18, q=0.023). Follow-up analyses revealed sex effects in the hippocampal tail of depressed females, and an interaction effect of C-PTSD and depression in the fimbria of males.ConclusionsCollectively our results suggest that depression is a stronger predictor of hippocampal volumetry than PTSD, particularly in the CA1, and provide compelling evidence of more pronounced hippocampal phenotypes in comorbid PTSD and depression compared to either condition alone.

Background Maltreatment in childhood increases the risk of depression later in life. The influence of ethnicity and sex on this relationship is less well understood. Objective This paper examines ethnic and sex differences in rates of child maltreatment (CM) and depressed mood in adulthood and investigates whether the association between CM and depressed mood in adulthood is influenced by ethnicity and sex. Participants and setting Baseline data from the multiethnic HELIUS study (Amsterdam, the Netherlands) was analyzed and consisted of 22,551 participants aged 18–70 years from Dutch, African Surinamese, South Asian-Surinamese, Turkish, Moroccan, or Ghanaian ethnic backgrounds. Methods Physical, sexual and psychological abuse, and emotional neglect in childhood were self-reported and depressed mood was measured using the Patient Health Questionnaire-9. Results Logistic regression analyses demonstrated that emotional neglect and psychological abuse both have significant positive relationships with depressed mood. Furthermore, these associations were consistent across ethnic groups. The addition of ethnicity-by-maltreatment interaction terms to a main effects model revealed that Ghanaians who reported physical abuse in childhood were the only ethnic group with significantly increased odds for depressed mood (OR = 2.62, p = .001), with the same being true for Moroccans who experienced sexual abuse in childhood (OR = 1.91, p = .008). No sex differences were found in the relationships between CM and depressed mood. Conclusions The association between different types of CM and depressive symptoms may not always be uniform across ethnic groups. Greater understanding of the nuances present in these relationships is required to develop effective prevention and intervention strategies for multiethnic populations.

BACKGROUND: About 10% of trauma-exposed individuals develop PTSD. Although a growing number of studies have investigated resting-state abnormalities in PTSD, inconsistent results suggest a need for a meta-analysis and a systematic review. METHODS: We conducted a systematic literature search in four online databases using keywords for PTSD, functional neuroimaging, and resting-state. In total, 23 studies matched our eligibility criteria. For the meta-analysis, we included 14 whole-brain resting-state studies, reporting data on 663 participants (298 PTSD patients and 365 controls). We used the activation likelihood estimation approach to identify concurrence of whole-brain hypo- and hyperactivations in PTSD patients during rest. Seed-based studies could not be included in the quantitative meta-analysis. Therefore, a separate qualitative systematic review was conducted on nine seed-based functional connectivity studies. RESULTS: The meta-analysis showed consistent hyperactivity in the ventral anterior cingulate cortex and the parahippocampus/amygdala, but hypoactivity in the (posterior) insula, cerebellar pyramis and middle frontal gyrus in PTSD patients, compared to healthy controls. Partly concordant with these findings, the systematic review on seed-based functional connectivity studies showed enhanced salience network (SN) connectivity, but decreased default mode network (DMN) connectivity in PTSD. CONCLUSIONS: Combined, these altered resting-state connectivity and activity patterns could represent neurobiological correlates of increased salience processing and hypervigilance (SN), at the cost of awareness of internal thoughts and autobiographical memory (DMN) in PTSD. However, several discrepancies between findings of the meta-analysis and systematic review were observed, stressing the need for future studies on resting-state abnormalities in PTSD patients. Language: en

The neuropeptide oxytocin (OT) has been suggested as a promising pharmacological agent for medication-enhanced psychotherapy in posttraumatic stress disorder (PTSD) because of its anxiolytic and prosocial properties. We therefore investigated the behavioral and neurobiological effects of a single intranasal OT administration (40 IU) in PTSD patients. We conducted a randomized, placebo-controlled, cross-over resting-state fMRI study in male and female police officers with (n=37, 21 males) and without PTSD (n=40, 20 males). We investigated OT administration effects on subjective anxiety and functional connectivity of basolateral (BLA) and centromedial (CeM) amygdala subregions with prefrontal and salience processing areas. In PTSD patients, OT administration resulted in decreased subjective anxiety and nervousness. Under placebo, male PTSD patients showed diminished right CeM to left ventromedial prefrontal cortex (vmPFC) connectivity compared with male trauma-exposed controls, which was reinstated after OT administration. Additionally, female PTSD patients showed enhanced right BLA to bilateral dorsal anterior cingulate cortex (dACC) connectivity compared with female trauma-exposed controls, which was dampened after OT administration. Although caution is warranted, our findings tentatively suggest that OT has the potential to diminish anxiety and fear expression of the amygdala in PTSD, either via increased control of the vmPFC over the CeM (males) or via decreased salience processing of the dACC and BLA (females). Our findings add to accumulating evidence that OT administration could potentially enhance treatment response in PTSD.

Background: Understanding the development of post-traumatic stress disorder (PTSD) is a precondition for efficient risk assessment and prevention planning. Studies to date have been site and sample specific. Towards developing generalizable models of PTSD development and prediction, the International Consortium to Predict PTSD (ICPP) compiled data from 13 longitudinal, acute-care based PTSD studies performed in six different countries. Objective: The objectives of this study were to describe the ICPP’s approach to data pooling and harmonization, and present cross-study descriptive results informing the longitudinal course of PTSD after acute trauma. Methods: Item-level data from 13 longitudinal studies of adult civilian trauma survivors were collected. Constructs (e.g. PTSD, depression), measures (questions or scales), and time variables (days from trauma) were identified and harmonized, and those with inconsistent coding (e.g. education, lifetime trauma exposure) were recoded. Administered in 11 studies, the Clinician Administered PTSD Scale (CAPS) emerged as the main measure of PTSD diagnosis and severity. Results: The pooled data set included 6254 subjects (39.9% female). Studies’ average retention rate was 87.0% (range 49.1–93.5%). Participants’ baseline assessments took place within 2 months of trauma exposure. Follow-up durations ranged from 188 to 1110 days. Reflecting studies’ inclusion criteria, the prevalence of baseline PTSD differed significantly between studies (range 3.1–61.6%), and similar differences were observed in subsequent assessments (4.3–38.2% and 3.8–27.0% for second and third assessments, respectively). Conclusion: Pooling data from independently collected studies requires careful curation of individual data sets for extracting and optimizing informative commonalities. However, it is an important step towards developing robust and generalizable prediction models for PTSD and can exceed findings of single studies. The large differences in prevalence of PTSD longitudinally cautions against using any individual study to infer trauma outcome. The multiplicity of instruments used in individual studies emphasizes the need for common data elements in future studies.

Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder that has been associated with lower white matter integrity of tracts connecting the prefrontal cortex with limbic regions. However, previous diffusion tensor imaging (DTI) findings have been inconsistent, showing high variability in the exact location and direction of effects.We performed probabilistic tractography of the bilateral uncinate fasciculus, cingulum and superior longitudinal fasciculus (both temporal and parietal projections) in male and female police officers with and without PTSD.We included 38 (21 men) police officers with and 39 (20 men) without PTSD in our analyses. Compared with trauma-exposed controls, patients with PTSD showed significantly higher mean diffusivity of the right uncinate fasciculus, the major white matter tract connecting the amygdala to the prefrontal cortex (Our specific sample of trauma-exposed police officers limits the generalizability of our findings to other PTSD patient groups (e.g., civilian trauma).Patients with PTSD showed diminished structural connectivity between the amygdala and vmPFC, which was correlated with higher anxiety symptoms and increased functional activity of these brain regions. Our findings provide additional evidence for the prevailing neurocircuitry model of PTSD, postulating that ineffective communication between the amygdala and vmPFC underlies decreased top-down control over fear responses.

Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder that may develop after a traumatic event. Here we aimed to identify epigenetic and genetic loci associated with PTSD. We included 73 traumatized police officers with extreme phenotypes regarding symptom severity despite similar trauma history: n = 34 had PTSD and n = 39 had minimal PTSD symptoms. Epigenetic and genetic profiles were based on the Illumina HumanMethylation450 BeadChip. We searched for differentially methylated probes (DMPs) and differentially methylated regions (DMRs). For genetic associations we analyzed the CpG-SNPs present on the array. We detected no genome-wide significant DMPs and we did not replicate previously reported DMPs associated with PTSD. However, GSE analysis of the top 100 DMPs showed enrichment of three genes involved in the dopaminergic neurogenesis pathway. Furthermore, we observed a suggestive association of one relatively large DMR between patients and controls, which was located at the PAX8 gene and previously associated with other psychiatric disorders. Finally, we validated five PTSD-associated CpG-SNPs identified with the array using sanger sequencing. We subsequently replicated the association of one common SNP (rs1990322) in the CACNA1C locus with PTSD in an independent cohort of traumatized children. The CACNA1C locus was previously associated with other psychiatric disorders, but not yet with PTSD. Thus, despite the small sample size, inclusion of extreme symptom severity phenotypes in a highly homogenous traumatized cohort enabled detection of epigenetic and genetic loci associated with PTSD. Moreover, here we showed that genetically confounded 450K probes are informative for genetic association analysis.

Background There are currently few preventive interventions available for posttraumatic stress disorder (PTSD). Intranasal oxytocin administration early after trauma may prevent PTSD, because oxytocin administration was previously found to beneficially impact PTSD vulnerability factors, including neural fear responsiveness, peripheral stress reactivity, and socioemotional functioning. Therefore, we investigated the effects of intranasal oxytocin administration early after trauma on subsequent clinician-rated PTSD symptoms. We then assessed whether baseline characteristics moderated the intervention's effects. Methods We performed a multicenter, randomized, double-blind, placebo-controlled clinical trial. Adult emergency department patients with moderate to severe acute distress ( n = 120; 85% accident victims) were randomized to intranasal oxytocin (8 days/40 IU twice daily) or placebo (8 days/10 puffs twice daily), initiated within 12 days posttrauma. The Clinician-Administered PTSD Scale (CAPS) was administered at baseline (within 10 days posttrauma) and at 1.5, 3, and 6 months posttrauma. The intention-to-treat sample included 107 participants (oxytocin: n = 53; placebo: n = 54). Results We did not observe a significant group difference in CAPS total score at 1.5 months posttrauma (primary outcome) or across follow-up (secondary outcome). Secondary analyses showed that participants with high baseline CAPS scores receiving oxytocin had significantly lower CAPS scores across follow-up than participants with high baseline CAPS scores receiving placebo. Conclusions Oxytocin administration early after trauma did not attenuate clinician-rated PTSD symptoms in all trauma-exposed participants with acute distress. However, participants with high acute clinician-rated PTSD symptom severity did show beneficial effects of oxytocin. Although replication is warranted, these findings suggest that oxytocin administration is a promising preventive intervention for PTSD for individuals with high acute PTSD symptoms.

SummaryIn this review we summarize the results and conclusions of five studies as presented in a symposium at the 42nd annual meeting of the International Society for Psychoneuroendocrinology, in New York in September 2012. Oxytocin administration has received increasing attention for its role in promoting positive social behavior and stress regulation, and its potential as a therapeutic intervention for addressing various aspects of psychiatric disorders. However, it has been noted that the observed effects are not uniformly beneficial. In this paper we present five new studies each concluding that contextual and interindividual factors moderate the effects of oxytocin, as well as peripheral oxytocin levels. These findings are in accordance with the recent idea that oxytocin administration may increase sensitivity to social salience cues and that the interpretation of these cues may be influenced by contextual (i.e. presence of a stranger versus friend) or interindividual factors (i.e. sex, attachment style, or the presence of psychiatric symptoms). When social cues in the environment are interpreted as “safe” oxytocin may promote prosociality but when the social cues are interpreted as “unsafe” oxytocin may promote more defensive and, in effect, “anti-social” emotions and behaviors. Likewise, oxytocin appears to promote such agonistic tendencies in individuals who are chronically pre-disposed to view the social milieu in uncertain and/or in negative terms (e.g., those with borderline personality disorder, severe attachment anxiety and/or childhood maltreatment). In all, these studies in pre-clinical animal, healthy humans and patients samples further reinforce the importance of considering both contextual and interindividual factors when trying to understand the role of oxytocin as a biological substrate underlying social bonding and stress regulatory processes and when studying the effects of oxytocin administration in particular in patients with (increased risk for) psychiatric disorders.

Military personnel exposed to combat are at risk for experiencing post-traumatic distress that can progress over time following deployment. We hypothesized that progression of post-traumatic distress may be related to enhanced susceptibility to post-deployment stressors. This study aimed at examining the concept of stress sensitization prospectively in a sample of Dutch military personnel deployed in support of the conflicts in Afghanistan. In a cohort of soldiers (N = 814), symptoms of post-traumatic stress disorder (PTSD) were assessed before deployment as well as 2, 7, 14, and 26 months (N = 433; 53 %) after their return. Data were analyzed using latent growth modeling. Using multiple group analysis, we examined whether high combat stress exposure during deployment moderated the relation between post-deployment stressors and linear change in post-traumatic distress after deployment. A higher baseline level of post-traumatic distress was associated with more early life stressors (standardized regression coefficient = 0.30, p < 0.001). In addition, a stronger increase in posttraumatic distress during deployment was associated with more deployment stressors (standardized coefficient = 0.21, p < 0.001). A steeper linear increase in posttraumatic distress post-deployment (from 2 to 26 months) was predicted by more post-deployment stressors (standardized coefficient = 0.29, p < 0.001) in high combat stress exposed soldiers, but not in a less combat stress exposed group. The group difference in the predictive effect of post-deployment stressors on progression of post-traumatic distress was significant (χ²(1) = 7.85, p = 0.005). Progression of post-traumatic distress following combat exposure may be related to sensitization to the effects of post-deployment stressors during the first year following return from deployment

BACKGROUND: A significant proportion of soldiers return from deployment with symptoms of fatigue, sleep difficulties, and posttraumatic complaints. Disrupted sleep has been proposed as a contributing factor for the development of posttraumatic stress disorder (PTSD). This study investigates the impact of impaired sleep and nightmares before deployment on the development of PTSD symptoms. METHOD: We collected reports on insomnia symptoms and nightmares in 453 Dutch service members prior to military deployment to Afghanistan. PTSD symptoms were assessed at 6 months postdeployment. The predictive value of insomnia symptoms and nightmares on the development of PTSD symptoms was assessed with a logistic regression analyses, in which was controlled for predeployment mood and anxiety symptoms. RESULTS: Self-reported predeployment nightmares predicted PTSD symptoms at 6 months (odds ratio 2.992, 95% confidence interval (CI) 1.096-8.551, P .05). CONCLUSION: In conclusion, this prospective longitudinal cohort study indicates that the existence of predeployment nightmares is associated with an increased risk for the development of PTSD symptoms. Nightmares may be related to hampered fear extinction memory consolidation, which has been associated with REM sleep. Language: en

We review current knowledge on how posttraumatic stress disorder (PTSD) is associated with dysregulation of the most commonly studied markers of the endocrine and immune systems pre-, peri- and post-trauma. Lower basal cortisol output, enhanced glucocorticoid receptor function, and a proinflammatory state have been most consistently found in PTSD, with considerable variability among studies and participants. Longitudinal research is scarce, but there is converging evidence that biological dysregulation is present before PTSD onset. Biological dysregulation may become more apparent with increasing time since trauma, and may be reversible with and predict effective treatment. However, considering the variability of findings and the complex interplay of these systems with other factors, the current clinical application of these findings remains limited.

Approximately 10% of trauma-exposed individuals go on to develop post-traumatic stress disorder (PTSD). Neural emotion regulation may be etiologically involved in PTSD development. Oxytocin administration early post-trauma may be a promising avenue for PTSD prevention, as intranasal oxytocin has previously been found to affect emotion regulation networks in healthy individuals and psychiatric patients. In a randomized double-blind placebo-controlled between-subjects functional magnetic resonance (fMRI) study, we assessed the effects of a single intranasal oxytocin administration (40 IU) on seed-based amygdala resting-state FC with emotion regulation areas (ventromedial prefrontal cortex (vmPFC), ventrolateral prefrontal cortex (vlPFC)), and salience processing areas (insula, dorsal anterior cingulate cortex (dACC)) in 37 individuals within 11 days post trauma. Two resting-state scans were acquired; one after neutral- and one after trauma-script-driven imagery. We found that oxytocin administration reduced amygdala-left vlPFC FC after trauma script-driven imagery, compared with neutral script-driven imagery, whereas in PL-treated participants enhanced amygdala-left vlPFC FC was observed following trauma script-driven imagery. Irrespective of script condition, oxytocin increased amygdala–insula FC and decreased amygdala–vmPFC FC. These neural effects were accompanied by lower levels of sleepiness and higher flashback intensity in the oxytocin group after the trauma script. Together, our findings show that oxytocin administration may impede emotion regulation network functioning in response to trauma reminders in recently trauma-exposed individuals. Therefore, caution may be warranted in administering oxytocin to prevent PTSD in distressed, recently trauma-exposed individuals.

Background Anhedonia is a significant clinical problem in post-traumatic stress disorder (PTSD). PTSD patients show reduced motivational approach behavior, which may underlie anhedonic symptoms. Oxytocin administration is known to increase reward sensitivity and approach behavior. We therefore investigated whether oxytocin administration affected neural responses during motivational processing in PTSD patients and trauma-exposed controls. Methods 35 police officers with PTSD (21 males) and 37 trauma-exposed police officers without PTSD (19 males) were included in a within-subjects, randomized, placebo-controlled fMRI study. Neural responses during anticipation of monetary reward and loss were investigated with a monetary incentive delay task (MID) after placebo and oxytocin (40 IU) administration. Results Oxytocin increased neural responses during reward and loss anticipation in PTSD patients and controls in the striatum, dorsal anterior cingulate cortex and insula, key regions in the reward pathway. Although PTSD patients did not differ from controls in motivational processing under placebo, anhedonia severity in PTSD patients was negatively related to reward responsiveness in the ventral striatum. Furthermore, oxytocin effects on reward processing in the ventral striatum were positively associated with anhedonia. Conclusions Oxytocin administration increased reward pathway sensitivity during reward and loss anticipation in PTSD patients and trauma-exposed controls. Thus, oxytocin administration may increase motivation for goal-directed approach behavior in PTSD patients and controls, providing evidence for a neurobiological pathway through which oxytocin could potentially increase motivation and reward sensitivity in PTSD patients.

UNLABELLED There is a need for effective, early post-trauma preventive interventions for post-traumatic stress disorder (PTSD). Attenuating amygdala hyperreactivity early post-trauma, a likely PTSD vulnerability factor, may decrease PTSD risk. Since oxytocin modulates amygdala reactivity to emotional stimuli, oxytocin administration early post-trauma may be a promising candidate for PTSD prevention. In a randomized double-blind placebo-controlled fMRI study, we investigated effects of a single intranasal oxytocin administration (40 IU) on amygdala reactivity to happy, neutral and fearful faces in 41 recently trauma-exposed men and women showing moderate to high distress after initial post-trauma screening. We explored treatment interactions with sex. Participants were scanned within 11 days post-trauma. Compared with placebo, oxytocin significantly increased right amygdala reactivity to fearful faces. There was a significant treatment by sex interaction on amygdala reactivity to neutral faces, with women showing increased left amygdala reactivity after oxytocin. These findings indicate that a single oxytocin administration may enhance fearful faces processing in recently trauma-exposed individuals and neutral faces processing in recently trauma-exposed women. These observations may be explained by oxytocin-induced increased salience processing. Clinical implications of these findings for PTSD prevention should be further investigated. TRIAL REGISTER Netherlands Trial Registry; Boosting Oxytocin after trauma: Neurobiology and the Development of Stress-related psychopathology (BONDS); NTR3190; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 3190.

Traumatic stress can have severe consequences for both mental and physical health. Furthermore, both psychological and biological traces of trauma increase as a function of accumulating traumatic experiences. Neurobiological research may aid in limiting the impact of traumatic stress, by leading to advances in preventive and treatment interventions. To promote the possibility for clinical implementation of novel research findings, this brief review describes timely conceptual and methodological challenges and directions in neurobiological trauma research on behalf of the Task Force “Neurobiology of Traumatic Stress” of the European Society for Traumatic Stress Studies (ESTSS). The most important conceptual challenges are the heterogeneity of disorders and existence of subtypes across diagnostic categories: differential latent profiles and trajectories regarding symptom expression and neural correlates are being unraveled; however, similar latent classes’ approaches for treatment response and neurobiological data remain scarce thus far. The key to improving the efficacy of currently available preventive interventions and treatments for trauma-related disorders lies in a better understanding and characterization of individual differences in response to trauma and interventions. This could lead to personalized treatment strategies for trauma-related disorders, based on objective information indicating whether individuals are expected to benefit from them. The most important methodological challenge identified here is the need for large consortia and meta-analyses or, rather, mega-analyses on existent data as a first step. In addition, large multicenter studies, combining novel methods for repeated sampling with more advanced statistical modeling techniques, such as machine learning, should aim to translate identified disease mechanisms into molecular blood-based biomarker combinations to predict disorder vulnerability and treatment responses. Keywords: Trauma; PTSD; vulnerability; resilience; neurobiology (Published: 18 March 2016) Responsible Editor: Marit Sijbrandij, VU University, Netherlands. This paper is part of the Special Issue: Trauma occurs in social contexts. More papers from this issue can be found at www.ejpt.net For the abstract or full text in other languages, please see Supplementary files under ‘Article Tools’ Citation: European Journal of Psychotraumatology 2016, 7 : 29453 - http://dx.doi.org/10.3402/ejpt.v7.29453

Contains fulltext : 108044.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Individuals who are exposed to a traumatic event are at increased risk of developing psychiatric disorders such as posttraumatic stress disorder (PTSD). Studies have shown that increased amygdala activity is frequently found in patients with PTSD. In addition, pre-trauma glucocorticoid receptor (GR) number in peripheral blood mononuclear cells (PBMCs) has been found to be a significant predictor for the development of PTSD symptoms. Research in rodents has shown that the response of basolateral amygdala neurons to corticosterone is mediated by GR. However, to the best of our knowledge, no previous study has investigated GR number in PBMCs and amygdala function in humans. METHODS: To investigate whether peripheral GR number is related to amygdala functioning, we assessed GR number in PBMCs of healthy soldiers before their deployment to Afghanistan. Amygdala functioning was assessed with fMRI before and after deployment. RESULTS: We found that pre-deployment GR number was significantly negatively correlated to pre-deployment amygdala activity. More importantly, pre-deployment GR number predicted the increase in amygdala activity by deployment. DISCUSSION: Our results demonstrate that peripheral GR number is associated with amygdala functioning and predicts the increase in amygdala activity following military deployment in healthy individuals who did not develop PTSD. It is uncertain how this relationship is mediated mechanistically, but future studies should examine the relation of GR and amygdala activity to determine whether this is part of a common pathway leading to increased vulnerability to stress-related disorders.

Background Biological correlates of posttraumatic stress disorder (PTSD) have mostly been studied using cross-sectional or posttrauma prospective designs. Therefore, it remains largely unknown whether previously observed biological correlates of PTSD precede trauma exposure. We investigated whether glucocorticoid receptor (GR) pathway components assessed in leukocytes before military deployment represent preexisting vulnerability factors for development of PTSD symptoms. Methods Four hundred forty-eight male soldiers were assessed before and 6 months after deployment to a combat zone. Participants were assigned to the PTSD or comparison group based on Self-Rating Inventory for PTSD scores after deployment. Logistic regression analysis was applied to predict development of a high level of PTSD symptoms based on predeployment GR number, messenger (m)RNA expression of GR target genes FKBP5 , GILZ , and SGK1 , plasma cortisol, and childhood trauma. We also investigated whether predeployment GR number and FKBP5 mRNA expression were associated with single nucleotide polymorphisms in the GR and FKBP5 genes, either alone or in interaction with childhood trauma. Results Several GR pathway components predicted subsequent development of a high level of PTSD symptoms: predeployment high GR number, low FKBP5 mRNA expression, and high GILZ mRNA expression were independently associated with increased risk for a high level of PTSD symptoms. Childhood trauma also independently predicted development of a high level of PTSD symptoms. Additionally, we observed a significant interaction effect of GR haplotype B cl I and childhood trauma on GR number. Conclusions Collectively, our results indicate that predeployment GR pathway components are vulnerability factors for subsequent development of a high level of PTSD symptoms.

Aim: Posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and severe fatigue may develop in response to severe stress and trauma. These conditions have all been shown to be associated with altered sensitivity of leukocytes for regulation by glucocorticoids (GCs). However, it remains unknown whether sensitivity of leukocytes for GCs is a pre-existing vulnerability factor, or whether GC-sensitivity of leukocytes alters as a consequence of stress and stress-related conditions. Our aim was to investigate whether sensitivity of T-cells and monocytes for regulation by GCs (i.e. dexamethasone: DEX) assessed before military deployment predicts high levels of PTSD, depressive, and/or fatigue symptoms 6 months after return from deployment. Methods: We included 526 male military personnel before deployment to Afghanistan. Logistic regression analysis was performed to predict fatigue, depressive, and PTSD symptoms 6 months after deployment based on sensitivity of LPS-induced TNF-alpha production and PHA-induced T-cell proliferation to DEX-inhibition before deployment. Results: Severe fatigue 6 months after deployment was independently associated with low DEX-sensitivity of monocyte TNF-alpha production before deployment. A high level of depressive symptoms after deployment was independently associated with a low DEX-sensitivity of T-cell proliferation. In contrast, a high level of PTSD symptoms after deployment was independently associated with a high DEX-sensitivity of T-cell proliferation before deployment, but only in individuals who reported PTSD symptoms without depressive symptoms. The predictive value of DEX-sensitivity was independent of childhood trauma and GR number, GR subtype and GR target gene mRNA expression in leukocytes. Conclusions: We present here for the first time that the sensitivity of leukocytes for GCs prior to deployment is a predictive factor for the development of PTSD, depressive and fatigue symptomatology in response to deployment. Notably, PTSD, depressive and fatigue symptoms were differentially associated with GC-sensitivity of monocytes and T-cells and therefore may have different biological underpinnings. (c) 2012 Elsevier Ltd. All rights reserved

Psychological trauma and prolonged stress may cause mental disorders such as posttraumatic stress disorder (PTSD). Pretrauma personality is an important determinant of posttraumatic adjustment. Specifically, trait neuroticism has been identified as a risk factor for PTSD. Additionally, the combination of high negative affectivity or neuroticism with marked social inhibition or introversion, also called Type D personality (Denollet, 2000), may compose a risk factor for PTSD. There is no research available that examined pretrauma Type D personality in relation to PTSD. The present study examined the predictive validity of the Type D personality construct in a sample of Dutch soldiers. Data were collected prior to and 6 months after military deployment to Afghanistan. Separate multiple regression analyses were performed to examine the predictive validity of Type D personality. First, Type D personality was defined as the interaction between negative affect and social inhibition (Na × Si). In a second analysis, Type D was defined following cutoff criteria recommended by Denollet (2000). Results showed that negative affectivity was a significant predictor of PTSD symptoms. Social inhibition and the interaction Na × Si did not add to the amount of explained variance in postdeployment PTSD scores over the effects of childhood abuse, negative affectivity, and prior psychological symptoms. A second analysis showed that Type D personality (dichotomous) did not add to the amount of explained variance in postdeployment PTSD scores over the effects of childhood abuse, and prior psychological symptoms. Therefore, Type D personality appears to be of limited value to explain development of combat-related PTSD symptoms.

About 10% of trauma-exposed individuals develop PTSD. Although a growing number of studies have investigated resting-state abnormalities in PTSD, inconsistent results suggest a need for a meta-analysis and a systematic review.We conducted a systematic literature search in four online databases using keywords for PTSD, functional neuroimaging, and resting-state. In total, 23 studies matched our eligibility criteria. For the meta-analysis, we included 14 whole-brain resting-state studies, reporting data on 663 participants (298 PTSD patients and 365 controls). We used the activation likelihood estimation approach to identify concurrence of whole-brain hypo- and hyperactivations in PTSD patients during rest. Seed-based studies could not be included in the quantitative meta-analysis. Therefore, a separate qualitative systematic review was conducted on nine seed-based functional connectivity studies.The meta-analysis showed consistent hyperactivity in the ventral anterior cingulate cortex and the parahippocampus/amygdala, but hypoactivity in the (posterior) insula, cerebellar pyramis and middle frontal gyrus in PTSD patients, compared to healthy controls. Partly concordant with these findings, the systematic review on seed-based functional connectivity studies showed enhanced salience network (SN) connectivity, but decreased default mode network (DMN) connectivity in PTSD.Combined, these altered resting-state connectivity and activity patterns could represent neurobiological correlates of increased salience processing and hypervigilance (SN), at the cost of awareness of internal thoughts and autobiographical memory (DMN) in PTSD. However, several discrepancies between findings of the meta-analysis and systematic review were observed, stressing the need for future studies on resting-state abnormalities in PTSD patients.

Post-traumatic stress disorder (PTSD) is a disabling psychiatric disorder. As a substantial part of PTSD patients responds poorly to currently available psychotherapies, pharmacological interventions boosting treatment response are needed. Because of its anxiolytic and pro-social properties, the neuropeptide oxytocin (OT) has been proposed as promising strategy for treatment augmentation in PTSD. As a first step to investigate the therapeutic potential of OT in PTSD, we conducted a double-blind, placebo-controlled, cross-over functional MRI study examining OT administration effects (40 IU) on amygdala reactivity toward emotional faces in unmedicated male and female police officers with (n=37, 21 males) and without (n=40, 20 males) PTSD. Trauma-exposed controls were matched to PTSD patients based on age, sex, years of service and educational level. Under placebo, the expected valence-dependent amygdala reactivity (ie, greater activity toward fearful-angry faces compared with happy-neutral faces) was absent in PTSD patients. OT administration dampened amygdala reactivity toward all emotional faces in male and female PTSD patients, but enhanced amygdala reactivity in healthy male and female trauma-exposed controls, independent of sex and stimulus valence. In PTSD patients, greater anxiety prior to scanning and amygdala reactivity during the placebo session were associated with greater reduction of amygdala reactivity after OT administration. Taken together, our results indicate presumably beneficial neurobiological effects of OT administration in male and female PTSD patients. Future studies should investigate OT administration in clinical settings to fully appreciate its therapeutic potential.

Summary 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-α 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.

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder. An important diagnostic feature of PTSD is anhedonia, which may result from deficits in reward functioning. This has however never been studied systematically in PTSD. To determine if PTSD is associated with reward impairments, we conducted a systematic review of studies in which reward functioning was compared between PTSD patients and healthy control participants, or investigated in relation to PTSD symptom severity. A total of 29 studies were included, covering reward anticipation and approach ('wanting'), and hedonic responses to reward ('liking'). Overall, results were mixed, although decreased reward anticipation and approach and reduced hedonic responses were repeatedly observed in PTSD patients compared to healthy controls. Decreased reward functioning was seen more often in female than in male PTSD samples and most often in response to social positive stimuli. Though more research is needed, these findings are a first step in understanding the possible mechanisms underlying anhedonia in PTSD.

Summary 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.

BACKGROUND: Currently few evidence based interventions are available for the prevention of PTSD within the first weeks after trauma. Increased risk for PTSD development is associated with dysregulated fear and stress responses prior to and shortly after trauma, as well as with a lack of perceived social support early after trauma. Oxytocin is a potent regulator of these processes. Therefore, we propose that oxytocin may be important in reducing adverse consequences of trauma. The 'BONDS' study is conducted in order to assess the efficacy of an early intervention with intranasal oxytocin for the prevention of PTSD. METHODS/DESIGN: In this multicenter double-blind randomized placebo-controlled trial we will recruit 220 Emergency Department patients at increased risk of PTSD. Trauma-exposed patients are screened for increased PTSD risk with questionnaires assessing peri-traumatic distress and acute PTSD symptoms within 7 days after trauma. Baseline PTSD symptom severity scores and neuroendocrine and psychophysiological measures will be collected within 10 days after trauma. Participants will be randomized to 7.5 days of intranasal oxytocin (40 IU) or placebo twice a day. Follow-up measurements at 1.5, 3 and 6 months post-trauma are collected to assess PTSD symptom severity (the primary outcome measure). Other measures of symptoms of psychopathology, and neuroendocrine and psychophysiological disorders are secondary outcome measures. DISCUSSION: We hypothesize that intranasal oxytocin administered early after trauma is an effective pharmacological strategy to prevent PTSD in individuals at increased risk, which is both safe and easily applicable. Interindividual and contextual factors that may influence the effects of oxytocin treatment will be considered in the analysis of the results. TRIAL REGISTRATION: Netherlands Trial Registry: NTR3190.

Summary About ten percent of people experiencing a traumatic event will subsequently develop post-traumatic stress disorder (PTSD). PTSD is characterized by an exaggerated fear response which fails to extinguish over time and cannot be inhibited in safe contexts. The neurobiological correlates of PTSD involve enhanced salience processing (i.e. amygdala, dorsal anterior cingulate cortex (dACC) and anterior insula (AI) hyperactivity), and reduced top-down inhibitory control over this fear response (i.e. dorsal and ventromedial prefrontal cortex (vmPFC) hypoactivity and diminished structural and functional connectivity between the vmPFC, hippocampus and amygdala). Therefore, dampening the exaggerated fear response (i.e. by reducing amygdala hyperactivity) and enhancing top-down inhibitory control (i.e. by promoting prefrontal control over the amygdala) during psychotherapy is an important target for medication-enhanced psychotherapy (MEP) in PTSD patients. Since the neuropeptide oxytocin (OT) has been found to act on these two processes, we propose that OT is a promising pharmacological agent to boost treatment response in PTSD. Human fMRI studies indicate that intranasal OT attenuates amygdala (hyper)activity and enhances connectivity of the amygdala with the vmPFC and hippocampus, resulting in increased top-down control over the fear response. In addition, intranasal OT was found to attenuate amygdala–brainstem connectivity and to change activity and connectivity in nodes of the salience network (i.e. AI and dACC). Furthermore, OT administration may modulate hypothalamus–pituitary–adrenal (HPA) axis and autonomic nervous system (ANS) function and may enhance social behaviour, which could be beneficial in the therapeutic alliance. We also discuss contextual and interindividual factors (e.g. gender and social context) which may influence the effectiveness of OT in MEP. In all, we propose that intranasal OT given prior to each psychotherapy session may be an effective additive treatment to boost treatment response in PTSD.

Rationale: Deployed military personnel are at risk for (mental) health problems, including post traumatic stress disorder (PTSD), major depressive disorder (MDD), and fatigue. We hypothesized that development of these conditions is associated with biological vulnerability factors. Therefore, we assessed whether the development of PTSD, depressive and/or fatigue symptoms in response to military deployment could be predicted by glucocorticoid (GC) signalling in leukocytes and the capacity of peripheral blood cells to produce cytokines. Methods: We included 1,032 Dutch military personnel prior to deployment to Afghanistan. Symptom severity was assessed 6 months after return. In blood collected prior to deployment, we assessed GC signalling in leukocytes (glucocorticoid receptor [GR] number, target gene mRNA expression, and GC-sensitivity) and cytokine production upon stimulation with LPS, PHA, or IL-1β. Results: We identified different vulnerability factors for development of a high level of PTSD, depressive, and fatigue symptoms. PTSD symptom development was predicted by high GC signalling in leukocytes. In contrast, depressive symptom development was associated with low GC signalling in T-cells and high T-cell cytokine production capacity. Finally, development of fatigue was associated with low GC signalling in monocytes prior to deployment and high reactivity of monocytes to IL-1β after deployment. Conclusions: The identified vulnerability factors for the development of high levels of PTSD, depressive, and fatigue symptoms were condition specific. This indicates PTSD, depression, and fatigue have different underlying biological mechanisms. Moreover, the results suggest that the biological profile prior to stress/trauma exposure may not only determine if a stress-related condition will develop but also which specific stress-related condition will develop.

Rationale : Currently, there are no effective interventions that prevent the development of posttraumatic stress disorder (PTSD) in recently traumatized individuals. The neuropeptide oxytocin is a potent regulator of two important processes disturbed in PTSD: it regulates physiological and behavioural stress and fear responses. In addition, oxytocin administration influences socio-emotional processes. Interestingly, high levels of acute distress after trauma and a lack of social support are risk factors for developing PTSD. Therefore, oxytocin administration appears to be a promising preventive treatment for PTSD, by hypothetically ameliorating dysregulated stress and fear responses as well as facilitating adaptive social functioning. Methods : We have initiated a randomized controlled trial (RCT) to investigate the effectiveness of an intranasal oxytocin treatment regimen in preventing the development of PTSD in recently traumatized individuals at increased risk for PTSD. In addition, in the same population we are conducting an fMRI study, which will create deeper insights into the neural mechanisms through which oxytocin and social context may regulate fear responses to traumatic stress. Results : In this presentation, the rationale behind stimulation of the oxytocin system in recently trauma-exposed individuals at risk for PTSD will be discussed, and an outline of the RCT will be presented. In addition, preliminary pilot data of the RCT will be shown.

Mesial temporal lobe epilepsy (mTLE) is a chronic and often treatment-refractory brain disorder characterized by recurrent seizures originating from the hippocampus. The pathogenic mechanisms underlying mTLE remain largely unknown. Recent clinical and experimental evidence supports a role of various inflammatory mediators in mTLE. Here, we performed protein expression profiling of 40 inflammatory mediators in surgical resection material from mTLE patients with and without hippocampal sclerosis, and autopsy controls using a multiplex bead-based immunoassay. In mTLE patients we identified 21 upregulated inflammatory mediators, including 10 cytokines and 7 chemokines. Many of these upregulated mediators have not previously been implicated in mTLE (for example, CCL22, IL-7 and IL-25). Comparing the three patient groups, two main hippocampal expression patterns could be distinguished, pattern I (for example, IL-10 and IL-25) showing increased expression in mTLE + HS patients compared to mTLE-HS and controls, and pattern II (for example, CCL4 and IL-7) showing increased expression in both mTLE groups compared to controls. Upregulation of a subset of inflammatory mediators (for example, IL-25 and IL-7) could not only be detected in the hippocampus of mTLE patients, but also in the neocortex. Principle component analysis was used to cluster the inflammatory mediators into several components. Follow-up analyses of the identified components revealed that the three patient groups could be discriminated based on their unique expression profiles. Immunocytochemistry showed that IL-25 IR (pattern I) and CCL4 IR (pattern II) were localized in astrocytes and microglia, whereas IL-25 IR was also detected in neurons. Our data shows co-activation of multiple inflammatory mediators in hippocampus and neocortex of mTLE patients, indicating activation of multiple pro- and anti-epileptogenic immune pathways in this disease.

Background It has been suggested that pro-inflammatory cytokine signaling to the brain may contribute to severe fatigue. We propose that not only the level of circulating cytokines, but also increased reactivity of target cells to cytokines contributes to the effect of cytokines on behavior. Based on this concept, we assessed the reactivity of peripheral blood cells to IL-1β in vitro as a novel approach to investigate whether severe fatigue is associated with increased pro-inflammatory signaling. Methods We included 504 soldiers before deployment to a combat-zone. We examined fatigue severity and the response to in vitro stimulation with IL-1β prior to deployment (T0), and 1 (T1) and 6 months (T2) after deployment. IL-8 production was used as read-out. As a control we determined LPS-induced IL-8 production. The presence of severe fatigue was assessed with the Checklist Individual Strength (CIS-20R). Differences in dose–response and the longitudinal course of IL-1β and LPS-induced IL-8 production and fatigue severity were investigated using repeated measures ANOVA. Results At T2, the group who had developed severe fatigue (n = 65) had significantly higher IL-1β-induced IL-8 production than the non-fatigued group (n = 439). This group difference was not present at T0, but developed over time. Longitudinal analysis revealed that in the non-fatigued group, IL-1β-induced IL-8 production decreased over time, while IL-1β-induced IL-8 production in the fatigued group had not decreased. To determine whether the observed group difference was specific for IL-1β reactivity, we also analyzed longitudinal LPS-induced IL-8 production. We did not observe a group difference in LPS-induced IL-8 production. Conclusions Collectively, our findings indicate that severe fatigue is associated with a higher reactivity to IL-1β. We propose that assessment of the reactivity of the immune system to IL-1β may represent a promising novel method to investigate the association between behavioral abnormalities and pro-inflammatory cytokine signaling.

A significant proportion of soldiers return from deployment with symptoms of fatigue, sleep difficulties, and posttraumatic complaints. Disrupted sleep has been proposed as a contributing factor for the development of posttraumatic stress disorder (PTSD). This study investigates the impact of impaired sleep and nightmares before deployment on the development of PTSD symptoms.We collected reports on insomnia symptoms and nightmares in 453 Dutch service members prior to military deployment to Afghanistan. PTSD symptoms were assessed at 6 months postdeployment. The predictive value of insomnia symptoms and nightmares on the development of PTSD symptoms was assessed with a logistic regression analyses, in which was controlled for predeployment mood and anxiety symptoms.Self-reported predeployment nightmares predicted PTSD symptoms at 6 months (odds ratio 2.992, 95% confidence interval (CI) 1.096-8.551, P.05), while predeployment insomnia complaints did not (odds ratio 0.976, 95% CI 0.862-1.155, P.05).In conclusion, this prospective longitudinal cohort study indicates that the existence of predeployment nightmares is associated with an increased risk for the development of PTSD symptoms. Nightmares may be related to hampered fear extinction memory consolidation, which has been associated with REM sleep.

Background: As of yet, no collective agreement has been reached regarding the precise factor structure of posttraumatic stress disorder (PTSD). Several alternative factor-models have been proposed in the last decades.Objective: The current study examined the fit of a hierarchical adaptation of the Simms et al. (2002) dysphoria model and compared it to the fit of the PTSD model as depicted in the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition (DSM-IV), a correlated four-factor emotional numbing, and a correlated four-factor dysphoria model.Methods: Data were collected using the Clinician-Administered PTSD Scale in a mixed-trauma sample of treatment-seeking PTSD patients (N=276).Results: All examined models provided superior fit to the three-factor model of DSM-IV. The hierarchical four-factor solution provided a better fit than competing models.Conclusion: The present study provides empirical support for a conceptualization of PTSD that includes a higher-order PTSD factor that encompasses re-experiencing, arousal, and effortful avoidance sub-factors and a dysphoria factor.Keywords: PTSD; confirmatory factor analysis; trauma; distress disorders; dysphoriaFor the abstract or full text in other languages, please see Supplementary files in the column to the right (under Article Tools)(Published: 13 December 2012)Citation: European Journal of Psychotraumatology 2012, 3: 17580 - http://dx.doi.org/10.3402/ejpt.v3i0.17580

Few prospective studies on pre-trauma predictors for subsequent development of posttraumatic stress disorder (PTSD) have been conducted. In this study we prospectively investigated whether pre-deployment personality and the cortisol awakening response (CAR) predicted development of PTSD symptoms in response to military deployment. Furthermore, we hypothesized that potential effects of age, childhood trauma and previous deployment on development of PTSD symptoms were mediated via pre-deployment personality, CAR and PTSD symptoms. Path analysis was performed on data from 470 male soldiers collected before and six months after a 4-month deployment to Afghanistan. Before deployment, personality was assessed with the short-form Temperament-Character Inventory and the Cook-Medley Hostility scale. In addition, pre-deployment saliva sampling for assessment of the CAR was performed immediately after awakening and 15, 30 and 60 min thereafter. Pre-deployment high hostility and low self-directedness represented intrinsic vulnerabilities for development of PTSD symptoms after deployment. The CAR assessed before deployment did not predict PTSD symptoms after deployment. Pre-deployment low-to-moderate PTSD symptoms were associated with PTSD symptoms after deployment. As hypothesized, the effects of age and childhood trauma on PTSD symptoms after deployment were mediated via personality and pre-deployment PTSD symptoms. However, the number of previous deployments was not related to development of PTSD symptoms. The total model explained 24% of variance in PTSD symptoms after military deployment.

The development of posttraumatic stress disorder (PTSD) is influenced by preexisting vulnerability factors. The authors aimed at identifying a preexisting biomarker representing a vulnerability factor for the development of PTSD. To that end, they determined whether the dexamethasone binding capacity of leukocytes, as a measure of glucocorticoid receptor (GR) number, before exposure to trauma was a predictor of development of PTSD symptoms. In addition, the authors analyzed mRNA expression for GR subtypes and GR target genes. Participants were selected from a large prospective study on deployment-related disorders, in which peripheral blood mononuclear cells (PBMCs) were obtained prior to and 1 and 6 months after military deployment. Participants included armed forces personnel with high levels of PTSD symptoms 6 months after deployment (N=34) and comparison subjects without high levels of PTSD or depressive symptoms (N=34) matched for age, rank, previous deployments, educational level, and function during deployment. Before military deployment, the GR number in PBMCs was significantly higher in participants who developed high levels of PTSD symptoms after deployment relative to matched comparison subjects. Logistic regression analysis showed that the risk for inclusion in the PTSD group after deployment increased 7.5-fold with each GR increase of 1,000. No group differences were observed in mRNA expression of GR-α, GR-P, GR-β, glucocorticoid-induced leucine zipper (GILZ), serum and glucocorticoid-inducible kinase-1 (SGK-1), and FKBP5. The higher GR number in the PTSD group was maintained at 1 and 6 months after deployment. These results demonstrate that a preexisting high GR number in PBMCs is a vulnerability factor for subsequent development of PTSD symptoms

Severe fatigue and co-morbid depressive symptoms are frequently reported by recently deployed military personnel. Stress can induce lasting changes in the negative feedback regulation of the hypothalamic-pituitary-adrenal axis (HPA-axis) and the regulation of the immune system by cortisol. Since these actions of cortisol are modulated via glucocorticoid receptors (GR), we investigated the effect of deployment and of deployment-related fatigue on glucocorticoid binding to peripheral blood mononuclear cells (PBMCs) in a prospective design. Psychological assessments and blood sample collection took place before and one and six months after deployment. Participants were selected from a larger group and assigned to three groups based on their level of fatigue and depressive symptoms six months after deployment. We compared fatigued participants without depressive symptoms (n=21), fatigued participants with depressive symptoms (n=14) and non-fatigued participants without depressive symptoms (n=21). Fatigued participants with depressive symptoms at six months after deployment had higher glucocorticoid binding to PMBCs than the other two groups at all three time points. Notably, this difference was already present before deployment. There was no effect of deployment on glucocorticoid binding to PBMCs. The observed differences in glucocorticoid binding were not related to pre-existing group differences in psychological symptoms. No group differences were observed in the composition of the PBMC population and plasma cortisol levels. These results indicate that high glucocorticoid binding to PBMCs might represent a vulnerability factor for the development of severe fatigue with depressive symptoms after a sustained period of stress, such as deployment.

Rationale : PTSD is associated with changes in the glucocorticoid receptor (GR) pathway. We hypothesized that altered functioning of the GR pathway is already present before development of PTSD and thus represents a biological vulnerability factor for the development of PTSD. Therefore, we investigated the predictive value of several GR pathway components for the development of high levels of PTSD symptoms. Methods : We included a cohort of 1,032 Dutch soldiers prior to deployment to Afghanistan. GR pathway components were assessed in blood collected prior to deployment. PTSD symptoms were assessed 6 months after return. Results : A high GR number, high GILZ mRNA expression, and low FKBP5 mRNA expression in leukocytes prior to deployment were independently associated with development of high levels of PTSD symptoms. In addition, sensitivity of T-cells for regulation by the synthetic glucocorticoid dexamethasone was associated with development of high levels of PTSD symptoms. However, the direction of the association between dexamethasone-sensitivity and PTSD depended on the presence of co-morbid depressive symptoms. Conclusions : Altered functioning of the GR pathway in leukocytes is a vulnerability factor for development of high levels of PTSD symptoms. The identification of such biological vulnerability factors for PTSD could facilitate the selection of individuals for preventive treatment within groups at risk for trauma-exposure.

Major depressive disorder (MDD) is frequently diagnosed in military personnel returning from deployment. Literature suggests that MDD is associated with a pro-inflammatory state. To the best of our knowledge, no prospective, longitudinal studies on the association between development of depressive symptomatology and cytokine production by peripheral blood leukocytes have been published. The aim of this study was to investigate whether the presence of depressive symptomatology six months after military deployment is associated with the capacity to produce cytokines, as assessed before and after deployment. 1023 military personnel were included before deployment. Depressive symptoms and LPS- and T-cell mitogen-induced production of 16 cytokines and chemokines in whole blood cultures were measured before (T0), 1 (T1), and 6 (T2) months after return from deployment. Exploratory structural equation modeling (ESEM) was used for data reduction into cytokine patterns. Multiple group latent growth modeling was used to investigate differences in the longitudinal course of cytokine production between individuals with (n = 68) and without (n = 665) depressive symptoms at T2. Individuals with depressive symptoms after deployment showed higher T-cell cytokine production before deployment. Moreover, pre-deployment T-cell cytokine production significantly predicted the presence of depressive symptomatology 6 months after return. There was an increase in T-cell cytokine production over time, but this increase was significantly smaller in individuals developing depressive symptoms. T-cell chemokine and LPS-induced innate cytokine production decreased over time and were not associated with depressive symptoms. These results indicate that increased T-cell mitogen-induced cytokine production before deployment may be a vulnerability factor for development of depressive symptomatology in response to deployment to a combat-zone. In addition, deployment to a combat-zone affects the capacity of T-cells and monocytes to produce cytokines and chemokines until at least 6 months after return.