Research Center Military Mental Healthcare

The Hague, Netherlands

Research Center Military Mental Healthcare

The Hague, Netherlands
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Boks M.P.,University Utrecht | Rutten B.P.F.,Maastricht University | Geuze E.,University Utrecht | Geuze E.,Research Center Military Mental Healthcare | And 7 more authors.
Neuropsychopharmacology | Year: 2016

Genomic variation in the SKA2 gene has recently been identified as a promising suicide biomarker. In light of its role in glucocorticoid receptor transactivation, we investigated whether SKA2 DNA methylation influences cortisol stress reactivity and is involved in the development of post-traumatic stress disorder (PTSD). Increased SKA2 methylation was significantly associated with lower cortisol stress reactivity in 85 healthy individuals exposed to the Trier Social Stress Test (B=-173.40, t=-2.324, p-value=0.023). Next, we observed that longitudinal decreases in SKA2 methylation after deployment were associated with the emergence of post-deployment PTSD symptoms in a Dutch military cohort (N=93; B=-0.054, t=-3.706, p-value=3.66 × 10-4). In contrast, exposure to traumatic stress during deployment by itself resulted in longitudinal increases in SKA2 methylation (B=0.037, t=4.173, p-value=6.98 × 10-5). Using pre-deployment SKA2 methylation levels and childhood trauma exposure, we found that the previously published suicide prediction rule significantly predicted post-deployment PTSD symptoms (AUC=0.66, 95% CI: 0.53-0.79) with an optimal sensitivity of 0.81 and specificity of 0.91. Permutation analysis using random methylation loci supported these findings. Together, these data establish the importance of SKA2 for cortisol stress responsivity and the development of PTSD and provide further evidence that SKA2 is a promising biomarker for stress-related disorders including PTSD. © 2016 American College of Neuropsychopharmacology. All rights reserved.


Rapcencu A.E.,Research Center Military Mental Healthcare | Rapcencu A.E.,Netherlands Institute for Forensic Psychiatry and Psychology | Gorter R.,Research Center Military Mental Healthcare | Gorter R.,University Utrecht | And 4 more authors.
Psychoneuroendocrinology | Year: 2017

Dysfunction of the HPA-axis has frequently been found in the aftermath of trauma exposure with or without PTSD. Decreasing HPA-axis reactivity to different stress cues has been reported during PTSD treatment. The cortisol awakening response (CARi) is a well-validated, standardized measure of HPA-axis reactivity which can be easily acquired in the clinical setting. Whether CARi changes over time in traumatized individuals are specific to PTSD treatment is unknown. Furthermore, a possible role for the baseline CARi in predicting symptom reduction after treatment in PTSD has not been examined before. To answer these questions, a cohort study was conducted in which the awakening cortisol was measured in both PTSD (N = 41) and non-PTSD (N = 25) combat-exposed male subjects. Measurements took place at inclusion and 6–8 months after inclusion for both the PTSD and the non-PTSD group. During the 6–8 months interval, PTSD patients received trauma-focused focused psychotherapy, whereas non-PTSD patients received no treatment. We found a decrease in the CARi over time in both groups, suggesting it was not specific to PTSD or the effect of treatment. Therefore, caution is warranted when attributing diminished HPA-axis reactivity over time to effects of PTSD treatment. Second, CARi prior to treatment predicted PTSD symptom reduction (CAPS score change) after treatment, and accounted for 10% of the variance, even when adjusted for changes in depressive symptoms and medication use during the study period. A putative role emerges for CARi as a predictive biomarker of symptom reduction in male individuals with combat-related PTSD. © 2017 Elsevier Ltd


Kennis M.,Research Center Military Mental Healthcare | Kennis M.,University Utrecht | Rademaker A.R.,Research Center Military Mental Healthcare | Rademaker A.R.,University Utrecht | And 2 more authors.
Neuroscience and Biobehavioral Reviews | Year: 2013

This review examines the neural correlates of Gray's model (. Gray and McNaughton, 2000; McNaughton and Corr, 2004), supplemented by a fourth dimension: constraint (. Carver, 2005). The purpose of this review is to summarize findings from fMRI studies that tap on neural correlates of personality aspects in healthy subjects, in order to provide insight into the neural activity underlying human temperament. BAS-related personality traits were consistently reported to correlate positively to activity of the ventral and dorsal striatum and ventral PFC in response to positive stimuli. FFFS and BIS-related personality traits are positively correlated to activity in the amygdala in response to negative stimuli. There is limited evidence that constraint is associated with PFC and ACC activity. In conclusion, functional MRI research sheds some light on the specific neural networks underlying personality. It is clear that more sophisticated task paradigms are required, as well as personality questionnaires that effectively differentiate between BAS, FFFS, BIS, and constraint. Further research is proposed to potentially reveal new insight in the neural subsystems governing basic human behavior. © 2012 Elsevier Ltd.


Boks M.P.,University Utrecht | Mierlo H.C.V.,University Utrecht | Rutten B.P.F.,Maastricht University | Radstake T.R.D.J.,University Utrecht | And 9 more authors.
Psychoneuroendocrinology | Year: 2015

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. © 2014 Elsevier Ltd.


Van Liempt S.,Research Center Military Mental Healthcare | Van Liempt S.,Rudolf Magnus Institute of Neuroscience | Vermetten E.,Research Center Military Mental Healthcare | Lentjes E.,University Utrecht | And 2 more authors.
Psychoneuroendocrinology | Year: 2011

Background: Healthy sleep facilitates the consolidation of newly acquired memories. Although patients with posttraumatic stress disorder (PTSD) often complain of sleep disturbances and memory deficits, the interrelatedness of these symptoms is not well understood. Sleep may be disturbed in PTSD by increased awakenings during sleep, which has been associated with decreased growth hormone (GH) secretion. We conducted a controlled study in which we assessed sleep fragmentation, nocturnal secretion of GH, and memory consolidation in patients with PTSD. Methods: While sleep EEG was being monitored, 13 veterans with PTSD, 15 trauma controls (TC) and 15 healthy controls (HC) slept with an iv catheter, through which blood was collected every 20. min from 23:00. h to 08:00. h. Declarative memory encoding was assessed with the 15 word task before sleep, and consolidation was assessed the next morning by a free recall. Results: Sleep was more fragmented in patients with PTSD, with more awakenings in the first half of the night (p<0.05). Plasma levels of GH during the night were significantly decreased in PTSD compared with HC (p<0.05). Furthermore, GH secretion and awakenings were independent predictors for delayed recall, which was lower in PTSD compared to HC (p<0.05). Conclusions: These data show that PTSD is associated with increased awakenings during sleep and decreased nocturnal GH secretion. Furthermore, decreased GH secretion may be related to sleep fragmentation and both variables may exert a negative effect on sleep dependent memory consolidation. © 2011 Elsevier Ltd.


Van Rooij S.J.H.,University Utrecht | Van Rooij S.J.H.,Research Center Military Mental Healthcare | Geuze E.,University Utrecht | Geuze E.,Research Center Military Mental Healthcare | And 4 more authors.
Neuropsychopharmacology | Year: 2015

Thirty to fifty percent of posttraumatic stress disorder (PTSD) patients do not respond to treatment. Understanding the neural mechanisms underlying treatment response could contribute to improve response rates. PTSD is often associated with decreased inhibition of fear responses in a safe environment. Importantly, the mechanism of effective treatment (psychotherapy) relies on inhibition and so-called contextual cue processing. Therefore, we investigate inhibition and contextual cue processing in the context of treatment. Forty-one male war veterans with PTSD and 22 healthy male war veterans (combat controls) were scanned twice with a 6-to 8-month interval, in which PTSD patients received treatment (psychotherapy). We distinguished treatment responders from nonresponders on the base of percentage symptom decrease. Inhibition and contextual cue processing were assessed with the stop-signal anticipation task. Behavioral and functional MRI measures were compared between PTSD patients and combat controls, and between responders and nonresponders using repeated measures analyses. PTSD patients showed behavioral and neural deficits in inhibition and contextual cue processing at both time points compared with combat controls. These deficits were unaffected by treatment; therefore, they likely represent vulnerability factors or scar aspects of PTSD. Second, responders showed increased pretreatment activation of the left inferior parietal lobe (IPL) during contextual cue processing compared with nonresponders. Moreover, left IPL activation predicted percentage symptom improvement. The IPL has an important role in contextual cue processing, and may therefore facilitate the effect of psychotherapy. Hence, increased left IPL activation may represent a potential predictive biomarker for PTSD treatment response. © 2015 American College of Neuropsychopharmacology.


Reijnen A.,Research Center Military Mental Healthcare | Reijnen A.,University Utrecht | Reijnen A.,Leiden University | Geuze E.,Research Center Military Mental Healthcare | And 5 more authors.
Psychoneuroendocrinology | Year: 2015

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. © 2014 Elsevier Ltd.


Kennis M.,University Utrecht | Kennis M.,Research Center Military Mental Healthcare | Van Rooij S.J.H.,University Utrecht | Van Rooij S.J.H.,Research Center Military Mental Healthcare | And 8 more authors.
Neuropsychopharmacology | Year: 2015

Posttraumatic stress disorder (PTSD) is a debilitating disorder that has been associated with brain abnormalities, including white matter alterations. However, little is known about the effect of treatment on these brain alterations. To investigate the course of white matter alterations in PTSD, we used a longitudinal design investigating treatment effects on white matter integrity using diffusion tensor imaging (DTI). Diffusion tensor and magnetization transfer images were obtained pre- and posttreatment from veterans with (n=39) and without PTSD (n=22). After treatment, 16 PTSD patients were remitted, and 23 had persistent PTSD based on PTSD diagnosis. The dorsal and hippocampal cingulum bundle, stria terminalis, and fornix were investigated as regions of interest. Exploratory whole-brain analyses were also performed. Groups were compared with repeated-measures ANOVA for fractional anisotropy (FA), and magnetization transfer ratio. Persistently symptomatic PTSD patients had increasing FA of the dorsal cingulum over time, and at reassessment these FA values were higher than both combat controls and the remitted PTSD group. Group-by-time interactions for FA were found in the hippocampal cingulum, fornix, and stria terminalis, posterior corona radiata, and superior longitudinal fasciculus. Our results indicate that higher FA of the dorsal cingulum bundle may be an acquired feature of persistent PTSD that develops over time. Furthermore, treatment might have differential effects on the hippocampal cingulum, fornix, stria terminalis, posterior corona radiata, and superior longitudinal fasciculus in remitted vs persistent PTSD patients. This study contributes to a better understanding of the neural underpinnings of PTSD treatment outcome. © 2015 American College of Neuropsychopharmacology.


Van Rooij S.J.H.,University Utrecht | Van Rooij S.J.H.,Research Center Military Mental Healthcare | Van Rooij S.J.H.,Emory University | Kennis M.,University Utrecht | And 4 more authors.
Neuropsychopharmacology | Year: 2016

In about 30-50% of patients with posttraumatic stress disorder (PTSD), symptoms persist after treatment. Although neurobiological research has advanced our understanding of PTSD, little is known about the neurobiology underlying persistence of PTSD. Two functional MRI scans were collected from 72 war veterans with and without PTSD over a 6-To 8-month interval, during which PTSD patients received trauma-focused therapy. All participants performed a trauma-unrelated emotional processing task in the scanner. Based on post-Treatment symptom severity, a distinction was made between remitted and persistent patients. Behavioral and imaging measures of trauma-unrelated emotional processing were compared between the three groups (remitted patients, N=21; persistent patients, N=22; and combat controls, N=25) with repeated-measures (pre-and post-Treatment) analyses. Second, logistic regression was used to predict treatment outcome. Before and after treatment, persistent patients showed a higher dorsal anterior cingulate cortex (dACC) and insula response to negative pictures compared with remitted patients and combat controls. Before treatment, persistent patients showed increased amygdala activation in response to negative pictures compared with remitted patients. The remitted patients and combat controls did not differ on the behavioral or imaging measures. Finally, higher dACC, insula, and amygdala activation before treatment were significant predictors of symptom persistence. Our results highlight a pattern of brain activation that may predict poor response to PTSD treatment. These findings can contribute to the development of alternative or additional therapies. Further research is needed to elucidate the heterogeneity within PTSD and describe how differences in neural function are related to treatment outcome. Such approaches are critical for defining parameters to customize PTSD treatment and improve treatment response rates. © 2016 American College of Neuropsychopharmacology.


Kennis M.,Research Center Military Mental Healthcare | Kennis M.,University Utrecht | Rademaker A.R.,Research Center Military Mental Healthcare | Rademaker A.R.,University Utrecht | And 5 more authors.
Human Brain Mapping | Year: 2015

Post-traumatic stress disorder (PTSD) is an anxiety disorder that is associated with structural and functional alterations in several brain areas, including the anterior cingulate cortex (ACC). Here, we examine resting state functional connectivity of ACC subdivisions in PTSD, using a seed-based approach. Resting state magnetic resonance images were obtained from male veterans with (n=31) and without (n=25) PTSD, and healthy male civilian controls (n=25). Veterans with and without PTSD (combat controls) had reduced functional connectivity compared to healthy controls between the caudal ACC and the precentral gyrus, and between the perigenual ACC and the superior medial gyrus and middle temporal gyrus. Combat controls had increased connectivity between the rostral ACC and precentral/middle frontal gyrus compared to PTSD patients and healthy civilian controls. The resting state functional connectivity differences in the perigenual ACC network reported here indicate that veterans differ from healthy controls, potentially due to military training, deployment, and/or trauma exposure. In addition, specific alterations in the combat controls may potentially be related to resilience. These results underline the importance of distinguishing trauma-exposed (combat) controls from healthy civilian controls when studying PTSD. Hum Brain Mapp, 36:99-109, 2015. © 2014 Wiley Periodicals, Inc. © 2014 Wiley Periodicals, Inc. 36 1 January 2015 10.1002/hbm.22615 Research Article Research Articles © 2014 Wiley Periodicals, Inc..

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