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1.  Psychotrauma research in the Netherlands 
European Journal of Psychotraumatology  2013;4:10.3402/ejpt.v4i0.20873.
doi:10.3402/ejpt.v4i0.20873
PMCID: PMC3644054  PMID: 23671758
2.  Psychotraumatology in the Netherlands 
European Journal of Psychotraumatology  2013;4:10.3402/ejpt.v4i0.20832.
The contribution to psychotrauma literature from Dutch authors has a long tradition. The relatively high lifetime prevalence of trauma and posttraumatic stress disorder (PTSD) is not unique for the Netherlands and does not fully explain the interest in trauma and its consequences. In this overview of psychotraumatology in the Netherlands, we will discuss some of the key events and processes that contribute to the current interest. We outlined the historical basis and development of the field in the Netherlands, including the impact of World War II, the effects of major man-made or natural disasters, engagement in military conflicts, as well as smaller scale traumatic events like sexual abuse and traffic accidents. The liberal and open culture may have reduced stigma to trauma, while other sociocultural aspects may have contributed to increased prevalence. Finally, we describe Dutch psychotraumatology today and how history and culture have shaped the current scientific basis.
doi:10.3402/ejpt.v4i0.20832
PMCID: PMC3644061  PMID: 23671764
psychotraumatology; PTSD; Netherlands; history; review
3.  Police officers: a high-risk group for the development of mental health disturbances? A cohort study 
BMJ Open  2013;3(1):e001720.
Objectives
Policing is generally considered a high-risk profession for the development of mental health problems, but this assumption lacks empirical evidence. Research question of the present study is to what extent mental health disturbances, such as (very) severe symptoms of anxiety, depression and hostility are more prevalent among police officers than among other occupational groups.
Design
Multicomparative cross-sectional study using the data of several cross-sectional and longitudinal studies in the Netherlands.
Participants
Two samples of police officers (N=144 and 503), employees of banks (N=1113) and employees of banks who were robbed (N=144); employees of supermarkets (N=335), and a psychiatric hospital (N=219), employees of a governmental social welfare organisation (N=76), employees who followed a training based on rational-motive therapy to strengthen their assertiveness (N=710), soldiers before deployment (N=278) and before redeployment (N=236) and firefighters (N=123). The numbers refer to respondents with complete data.
Primary outcomes
Prevalence of severe (subclinical level) and very severe symptoms (clinical level) were computed using the Dutch norm tables (80th percentile and 95th percentile, respectively) of the Symptom Check List Revised (SCL-90-R). All comparisons were controlled for age, gender and education.
Results
Multivariate logistic regression and analyses showed that the prevalence of clinical and subclinical levels of symptoms of anxiety, depression and hostility among police officers were not significantly higher than among comparison groups. The same pattern was found for the other SCL-90-R subscales.
Conclusions
We found no indications that self-reported mental health disturbances were more prevalent among police officers than among groups of employees that are not considered high-risk groups, such as employees of banks, supermarkets, psychiatric hospital and soldiers before deployment.
doi:10.1136/bmjopen-2012-001720
PMCID: PMC3563131  PMID: 23355659
Mental Health; Psychiatry; Occupational & Industrial Medicine
4.  Use of a Web Portal for Support and Research After a Disaster: Opportunities and Lessons Learned 
Background
In this report we describe the development and use of a web portal in the aftermath of the 2004 tsunami. This large scale disaster confronted many displaced people with death, despair and need for information and support. Awareness and insight in the emotional impact of disasters can provide opportunities for surveillance and early treatment. Moreover, online support systems can contribute to community building, empowerment of victims and resilience.
Objective
We evaluate the development and use of a multilingual web portal that combined a platform for information, emotional support, self assessment and referral with research opportunities. The rapid development, use, advantages, difficulties and learning points are discussed.
Methods
A multidisciplinary working group from the University Medical Centre Utrecht, the Major Incident Hospital and the Central Military Hospital developed a web portal for tsunami victims. The webportal combined: (1) a forum aimed at community building, (2) self assessment tools that in the same time function as a reseach survey, (3) e-consultation, and (4) an information portal.
Results
Within 3 weeks after the tsunami, the working group launched an open, online service (www.TISEI.org. Tsunami Intrenational Survey on Emotional Impact) to foster community) support in the aftermath of the disaster. It combined four functionalities that were earlier previously only used separately. The portal had over 36.800 unique visitors in the first two years. At least 31% (144/464) percent of the Dutch surviving victims could be reached for a survey through the site. The TISEI-environment was available in 15 languages and visitors came from all over the world. Ninety-five percent of all visitors came from Europe or the United States. Subsequent to immediate disaster support, the web portal also served as a memorial archive for anniversary meetings and follow-up incentives. Difficulties we experienced were lack of funding, time pressure, victim-anonymisation, international collaboration and long term maintenance.
Conclusions
A multilingual website with combined modalities for emotional care and research after a natural disaster proved feasible. Web based services like www.TISEI.org in the aftermath of mass disasters can help community building and deliver low level, patient centred and easily accessible information and care. A multilingual website with combined modalities for emotional care and research after a natural disaster proved feasible. Growing Internet penetration world wide and especially the rapid expansion and influence of online communities enables delivery of care and perform research with the internetInternet as a platform. The unpredictable nature of disaster does put time pressure on the development of online solutions and influenced the yield of our site. This highlights the necessity of developing methods and (inter) national collaborations in advance, secure funding, and learn from earlier initiatives.
doi:10.2196/ijmr.1588
PMCID: PMC3626128  PMID: 23612349
Disaster medicine; Stress Disorders; Post-Traumatic; Internet; mental health; health surveys; stress, psychological; Online Systems; Self-Help groups
5.  IL-1β reactivity and the development of severe fatigue after military deployment: a longitudinal study 
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.
doi:10.1186/1742-2094-9-205
PMCID: PMC3485092  PMID: 22908999
Fatigue; Stress; Inflammation; Cytokine; Interleukin-1; Receptor; Reactivity; Military; LPS; Interleukin-8
7.  Neuroendocrine and immune responses to a cognitive stress challenge in veterans with and without PTSD 
European Journal of Psychotraumatology  2012;3:10.3402/ejpt.v3i0.16206.
Background
PTSD has been associated with altered hypothalamus–pituitary–adrenal-axis (HPA-axis), immune and sympathetic nervous system (SNS) regulation. The purpose of this study was to evaluate the effect of cognitive stress on these systems in PTSD patients and controls.
Methods
The subjective units of distress score (SUDS), NK-cell response, plasma levels of noradrenalin and ACTH in response to cognitive stress were assessed in male veterans with PTSD (n=15) and age, region and year of deployment matched veterans without psychopathology (n=15).
Results
The challenge induced an increase in SUDS, noradrenalin, ACTH and NK-cell response in both groups. Baseline levels of ACTH were lower in PTSD patients. The test was experienced as more stressful by PTSD patients and resulted in an augmented ACTH response in patients. The noradrenalin and NK-cell responses showed no group differences. The ACTH response correlated with the severity of symptoms in patients, and the noradrenalin response correlated with the ACTH and NK-cell response in controls, but not in patients.
Discussion
PTSD patients experience more distress and present with an exaggerated pituitary response to this stressor. In addition, our results suggest an altered interaction between the HPA-axis, SNS and immune system in PTSD.
doi:10.3402/ejpt.v3i0.16206
PMCID: PMC3402140  PMID: 22893842
cognitive stress challenge; PTSD; HPA axis; NK-cell activity; catecholamines; ACTH; cortisol
8.  Obstructive sleep apnea in combat-related posttraumatic stress disorder: a controlled polysomnography study  
European Journal of Psychotraumatology  2011;2:10.3402/ejpt.v2i0.8451.
Background
Obstructive sleep apnea (OSA) may be highly prevalent in posttraumatic stress disorder (PTSD) and may exacerbate PTSD complaints.
Objective
Our objective was to determine whether the prevalence of OSA was high in a sample of Dutch veterans with PTSD as compared to age- and trauma-matched controls, and whether OSA was associated with more severe PTSD complaints.
Methods
We determined the apnea hypopnea indices (AHI) with polysomnographic registrations in 20 veterans with PTSD, 24 veterans without PTSD, and 17 healthy controls. PTSD severity and nightmare complaints were assessed with the Clinician-Administered PTSD Scale (CAPS).
Results
The prevalence of an AHI>10 was 29% in PTSD, 21% in trauma controls, and 29% in healthy controls (χ2= 0.60, df=2, p=n.s.). The mean CAPS score in patients with OSA (n=6) was significantly higher than in patients without OSA (p<0.05), while nightmare severity was similar in PTSD patients with OSA as compared to PTSD patients without OSA (p=n.s.). Furthermore, there was a significant correlation between AHI and CAPS score in PTSD patients (r=0.46, p<0.05, df=14).
Conclusions
Our results indicate that PTSD is not necessarily associated with a higher prevalence of OSA. However, PTSD severity was related to OSA, which may possibly mean that comorbid OSA leads to an increase in PTSD complaints. However, future research should indicate whether OSA exerts a negative influence on PTSD, and treatment of OSA alleviates PTSD symptoms.
doi:10.3402/ejpt.v2i0.8451
PMCID: PMC3402109  PMID: 22893807
PTSD; sleep; OSA; polysomnography; apnea
9.  Disaster-related injury and predictors of health complaints after exposure to a natural disaster: an online survey 
BMJ Open  2011;1(2):e000248.
Objectives
To study short- and long-term effects of experiencing a disaster in repatriated injured survivors and the differential effect of injury, need for medical treatment, loss of loved ones and danger to life on both physical and mental health.
Design
Prospective online study.
Setting
Open online survey among Dutch survivors of the 2004 Asian tsunami.
Participants
Of the estimated total of 464 Dutch survivors, the authors recruited 144 unique respondents (59 men and 85 women) with a total of 175 assessments made in various time periods.
Main outcome measures
Health outcomes were Symptom Checklist 90 (SCL-90), Impact of Event Scale (original version, in Dutch) and Beck Depression Inventory II. Correlations were calculated with socio-demographic as well as disaster-related factors: physical injury, medical care, loss of loved ones and duration of threat to life. Assessments were clustered in four post-disaster time periods (0–3, 4–6, 7–30 and 31–48 months).
Results
Across these periods, SCL-90 scores were significantly higher than the reference population (p<0.001), with a significant linear downward trend between the groups over time (p=0.001). The same pattern occurred for the Impact of Event Scale (p<0.001) and the Beck Depression Inventory II (p=0.002). Physical injury, medical care or loss of loved ones was not associated with higher total SCL-90 scores or somatic subscores. Both duration of threat to life and female sex were correlated with all measured outcome parameters.
Conclusions
Exposure to the 2004 Asian tsunami had significant short- and long-term impacts on health complaints in a group of repatriated Dutch tsunami victims. Cross-sectionally, there was a trend towards recovery over 4 years, although 22% still reported high psychological and physical distress 4 years post-disaster. Duration of danger to life and female sex were associated with more physical and mental health complaints. In this study, neither disaster-related injury nor loss of loved ones resulted in negative health outcomes.
Article summary
Article focus
Disasters are traumatic events that may result in a wide range of physical and mental health consequences. The aim of this paper was to study short- and long-term effects in injured disaster survivors.
Our hypothesis was that physical injury and psychological trauma (eg, loss of loved ones) would be determinants for physical and mental health outcomes after the disaster.
Key messages
Despite a trend towards recovery between the cross-sectional groups over 4 years, the 2004 tsunami had significant short- and long-term impacts on health complaints in a Dutch group of tsunami victims.
Physical injury or loss of loved ones did not necessarily result in negative health outcomes.
Duration of danger to life was a predictor for traumatic stress symptoms, general health complaints as well as depressive symptoms over a 4-year period.
Strengths and limitations of this study
One of the few studies of long-term physical and mental health impact of natural disasters and the differential effects of being wounded, danger to life and loss of loved ones.
Combined approach: research on physical as well as mental health—unique set up with a survey on an online post-disaster web service, combined with other features.
Limitations: post-disaster study limited options for longitudinal research.
doi:10.1136/bmjopen-2011-000248
PMCID: PMC3244663  PMID: 22185804
10.  Cytokine Production by Leukocytes of Military Personnel with Depressive Symptoms after Deployment to a Combat-Zone: A Prospective, Longitudinal Study 
PLoS ONE  2011;6(12):e29142.
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.
doi:10.1371/journal.pone.0029142
PMCID: PMC3237604  PMID: 22195009
11.  A Positron Tomographic Emission Study of Olfactory Induced Emotional Recall in Veterans with and without Combat-related Posttraumatic Stress Disorder 
Psychopharmacology bulletin  2007;40(1):8-30.
OBJECTIVE
Memory for odors is often associated with highly emotional experiences, and odors have long been noted by clinicians to be precipitants of trauma symptoms in PTSD. Primitive brain systems involved in fear responsivity and survival also mediate smell, including the olfactory cortex and amygdala. The purpose of this study was to measure neural correlates of olfaction in PTSD.
METHODS
We exposed male combat veterans with PTSD (N=8) and without PTSD (N=8) to a set of smells, including diesel (related to traumatic memories of combat), and three other types of smells: odorless air, vanilla/coconut and hydrogen sulfide (H2S) (resp. a neutral, positive, and negative hedonic non-traumatic smell) in conjunction with PET imaging of cerebral blood flow and assessment of psychophysiological and behavioral symptoms. All subjects also underwent a baseline of olfactory acuity.
RESULTS
PTSD patients rated diesel as unpleasant and distressing, resulting in increased PTSD symptoms and anxiety in PTSD versus combat controls. Exposure to diesel resulted in an increase in regional blood flow (rCBF) in amygdala, insula, medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC), and decreased rCBF in lateral prefrontal cortex (lPFC) in PTSD in comparison to combat controls. Combat controls showed less rCBF changes on any smell, and did not show amygdala activation upon diesel exposure.
CONCLUSIONS
These data support the hypothesis that in PTSD trauma-related smells can serve as strong emotional reminders. The findings indicate the involvement of a neural circuitry that shares olfactory elements and memory processing regions when exposed to trauma-related stimuli.
PMCID: PMC3236699  PMID: 17285093
PTSD; brain imaging techniques; olfaction; memory; amygdala
12.  Effects of antidepressant treatment on neural correlates of emotional and neutral declarative verbal memory in depression 
Journal of affective disorders  2006;101(1-3):99-111.
Background
Multiple studies have documented deficits in verbal declarative memory function in depression that improve with resolution of symptoms; imaging studies show deficits in anterior cingulate function in depression, a brain area that mediates memory. No studies to date have examined neural correlates of emotionally valenced declarative memory using affectively negative (sad) verbal material that is clinically relevant to understanding depression. Also no studies have examined the effects of treatment on neural correlates of verbal declarative memory. The purpose of this study was to examine the effects of treatment with antidepressants on verbal declarative memory in patients with depression.
Methods
Subjects with (N =18) and without (N=9) mid-life major depression underwent positron emission tomography (PET) imaging during verbal declarative memory tasks with both neutral paragraph encoding compared to a control condition, and emotional (sad) word pair retrieval compared to a control condition. Imaging was repeated in 13 subjects with depression after treatment with antidepressants.
Results
Patients with untreated depression had a failure of anterior cingulate activation relative to controls during retrieval of emotional word pairs. Antidepressant treatment resulted in increased anterior cingulate function compared to the untreated baseline for both neutral and emotional declarative memory.
Limitations
Limitations include a small sample size and variety of antidepressants used.
Conclusions
These results are consistent with alterations in anterior cingulate function that are reversible with treatment in patients with depression. These findings may have implications for understanding the mechanism of action of antidepressants in the treatment of depression.
doi:10.1016/j.jad.2006.10.028
PMCID: PMC3233752  PMID: 17182108
PET; Memory; Depression; Cingulate; Frontal cortex
13.  Hippocampal and Amygdalar Volumes in Dissociative Identity Disorder 
The American journal of psychiatry  2006;163(4):630-636.
Objective
Smaller hippocampal volume has been reported in several stress-related psychiatric disorders, including posttraumatic stress disorder (PTSD), borderline personality disorder with early abuse, and depression with early abuse. Patients with borderline personality disorder and early abuse have also been found to have smaller amygdalar volume. The authors examined hippocampal and amygdalar volumes in patients with dissociative identity disorder, a disorder that has been associated with a history of severe childhood trauma.
Method
The authors used magnetic resonance imaging to measure the volumes of the hippocampus and amygdala in 15 female patients with dissociative identity disorder and 23 female subjects without dissociative identity disorder or any other psychiatric disorder. The volumetric measurements for the two groups were compared.
Results
Hippocampal volume was 19.2% smaller and amygdalar volume was 31.6% smaller in the patients with dissociative identity disorder, compared to the healthy subjects. The ratio of hippocampal volume to amygdalar volume was significantly different between groups.
Conclusions
The findings are consistent with the presence of smaller hippocampal and amygdalar volumes in patients with dissociative identity disorder, compared with healthy subjects.
doi:10.1176/appi.ajp.163.4.630
PMCID: PMC3233754  PMID: 16585437
14.  Positron emission tomographic imaging of neural correlates of a fear acquisition and extinction paradigm in women with childhood sexual-abuse-related post-traumatic stress disorder 
Psychological medicine  2005;35(6):791-806.
Background
In the conditioned fear paradigm, repeated pairing of an aversive unconditioned stimulus (US) (e.g. electric shock) with a neutral conditioned stimulus (CS) (e.g. bright light) results in a conditioned fear response to the light alone. Animal studies have shown that the amygdala plays a critical role in acquisition of conditioned fear responses, while the medial prefrontal cortex (including anterior cingulate), through inhibition of amygdala responsiveness, has been hypothesized to play a role in extinction of fear responses. No studies have examined neural correlates of fear conditioning and extinction in patients with post-traumatic stress disorder (PTSD).
Method
Women with early childhood sexual-abuse-related PTSD (n=8) and women without abuse or PTSD (n=11) underwent measurement of psychophysiological (skin conductance) responding as well as positron emission tomographic (PET) measurement of cerebral blood flow during habituation, acquisition and extinction conditions. During habituation subjects were repeatedly exposed to a blue square on a screen. During acquisition, exposure to the blue square (CS) was paired with an electric shock to the forearm (US). With extinction, subjects were again exposed to the blue squares without shock. On a different day subjects went through the same procedure with electric shocks administered randomly in the absence of the blue square.
Results
Skin conductance responding to the CS was consistent with the development of conditioned responses with this paradigm. PTSD patients had increased left amygdala activation with fear acquisition, and decreased anterior cingulate function during extinction, relative to controls.
Conclusions
These findings implicate amygdala and anterior cingulate in the acquisition and extinction of fear responses, respectively, in PTSD.
PMCID: PMC3233760  PMID: 15997600
15.  Long-Term Treatment with Paroxetine Increases Verbal Declarative Memory and Hippocampal Volume in Posttraumatic Stress Disorder 
Biological psychiatry  2003;54(7):693-702.
Background
Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD.
Methods
Declarative memory was assessed with the Wechsler Memory Scale–Revised and Selective Reminding Test before and after 9–12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI. Of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testing. Twenty patients were able to complete MRI imaging.
Results
Patients with PTSD showed a significant improvement in PTSD symptoms with treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume.
Conclusions
These findings suggest that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD.
PMCID: PMC3233762  PMID: 14512209
Posttraumatic stress disorder; memory; hippocampus; stress; paroxetine; selective serotonin reuptake inhibitors
16.  Regional Brain Metabolic Correlates of α-Methylparatyrosine–Induced Depressive Symptoms 
Context
We previously used positron emission tomography (PET) measurement of brain metabolism with 18fluorodeoxyglucose to show that patients receiving selective serotonin reuptake inhibitors (SSRIs) who have a tryptophan depletion–induced return of depressive symptoms have an acute decrease in metabolism in orbitofrontal cortex, dorsolateral prefrontal cortex, and thalamus. Many patients with depression in remission while taking norepinephrine reuptake inhibitors (NRIs) (but not SSRIs) experience a return of depressive symptoms with depletion of norepinephrine and dopamine using α-methylparatyrosine (AMPT).
Objective
To assess brain metabolic correlates of AMPT administration in patients with depression in remission while receiving NRIs.
Design, Setting, and Participants
Randomized, controlled, double-blind trial in which 18 patients recruited in 1997–2000 from the general community who had depression in remission while taking NRIs had PET imaging in a psychiatric research unit following AMPT and placebo administration.
Interventions
After initial medication with desipramine and follow-up until response, patients underwent active AMPT (five 1-g doses administered orally over 28 hours) and placebo (diphenhydramine hydrochloride, five 50- mg doses administered similarly) catecholamine depletion challenges in randomized order of assignment, after which PET imaging was performed on day 3 of each condition. Both study conditions were performed 1 week apart.
Main Outcome Measures
Regional brain metabolism rates in patients with and without AMPT-induced return of depressive symptoms.
Results
AMPT-induced return of depressive symptoms was experienced by 11 of the 18 patients and led to decreased brain metabolism in a number of cortical areas, with the greatest magnitude of effects in orbitofrontal (P=.002) and dorsolateral prefrontal (P=.03) cortex and thalamus (P=.006). Increased resting metabolism in prefrontal and limbic areas predicted vulnerability to return of depressive symptoms.
Conclusions
Different neurochemical systems that mediate depression may have effects on a common brain circuitry. Baseline metabolism in successfully treated depressed patients may predict vulnerability to future episodes of depression.
doi:10.1001/jama.289.23.3125
PMCID: PMC3233764  PMID: 12813118
17.  Childhood Trauma Associated With Smaller Hippocampal Volume in Women With Major Depression 
The American journal of psychiatry  2002;159(12):2072-2080.
Objective
Smaller hippocampal volume has been reported only in some but not all studies of unipolar major depressive disorder. Severe stress early in life has also been associated with smaller hippocampal volume and with persistent changes in the hypothalamic-pituitary-adrenal axis. However, prior hippocampal morphometric studies in depressed patients have neither reported nor controlled for a history of early childhood trauma. In this study, the volumes of the hippocampus and of control brain regions were measured in depressed women with and without childhood abuse and in healthy nonabused comparison subjects.
Method
Study participants were 32 women with current unipolar major depressive disorder—21 with a history of prepubertal physical and/or sexual abuse and 11 without a history of prepubertal abuse—and 14 healthy nonabused female volunteers. The volumes of the whole hippocampus, temporal lobe, and whole brain were measured on coronal MRI scans by a single rater who was blind to the subjects’ diagnoses.
Results
The depressed subjects with childhood abuse had an 18% smaller mean left hippocampal volume than the nonabused depressed subjects and a 15% smaller mean left hippocampal volume than the healthy subjects. Right hippocampal volume was similar across the three groups. The right and left hippocampal volumes in the depressed women without abuse were similar to those in the healthy subjects.
Conclusions
A smaller hippocampal volume in adult women with major depressive disorder was observed exclusively in those who had a history of severe and prolonged physical and/or sexual abuse in childhood. An unreported history of childhood abuse in depressed subjects could in part explain the inconsistencies in hippocampal volume findings in prior studies in major depressive disorder.
PMCID: PMC3230324  PMID: 12450959
18.  Alterations in Stress Reactivity After Long-Term Treatment with Paroxetine in Women with Posttraumatic Stress Disorder 
Posttraumatic stress disorder (PTSD) is typically accompanied by both acute and chronic alterations in the stress response. These alterations have mostly been described in individuals under baseline conditions, but studies have also used a challenge model to assess the role of the hypothalamic-pituitary-adrenal (HPA) axis in the stress response. The purpose of this article was to assess the effect of long-term treatment with the selective reuptake inhibitor (SSRI), paroxetine, on stress reactivity in patients with PTSD. We assessed diurnal salivary cortisol and urinary cortisol as well as cortisol, heart rate, and behavioral responses to a standardized cognitive stress challenge, in 13 female patients with chronic PTSD before and after 12 months of paroxetine treatment. Treatment resulted in a significant decrease in PTSD symptoms. Twenty-four-hour urinary cortisol was lower compared to base line after successful treatment. Treatment resulted in a decrease of salivary cortisol levels on all time points on a diurnal curve. Despite similar stress perception, cortisol response to the cognitive stress challenge resulted in a 26.5% relative decrease in stress-induced salivary cortisol with treatment. These results suggest that successful treatment with SSRI in chronic PTSD is associated with a trend for a decrease in baseline diurnal cortisol and with reduced cortisol reactivity to stress.
doi:10.1196/annals.1364.014
PMCID: PMC3230329  PMID: 16891570
cortisol; PTSD; stress; paroxetine; SSRI; challenge; HPA axis
19.  Magnetic Resonance Imaging-Based Measurement of Hippocampal Volume in Posttraumatic Stress Disorder Related to Childhood Physical and Sexual Abuse—A Preliminary Report 
Biological psychiatry  1997;41(1):23-32.
We have previously reported smaller hippocampal volume and deficits in short-term memory in patients with combat-related posttraumatic stress disorder (PTSD) relative to comparison subjects. The purpose of this study was to compare hippocampal volume in adult survivors of childhood abuse to matched controls. Magnetic resonance imaging was used to measure volume of the hippocampus in adult survivors of childhood abuse (n = 17) and healthy subjects (n = 17) matched on a case-by-case basis for age, sex, race, handedness, years of education, body size, and years of alcohol abuse. All patients met criteria for PTSD secondary to childhood abuse. PTSD patients had a 12% smaller left hippocampal volume relative to the matched controls (p < .05), without smaller volumes of comparison regions (amygdala, caudate, and temporal lobe). The findings were significant after controlling for alcohol, age, and education, with multiple linear regression. These findings suggest that a decrease in left hippocampal volume is associated with abuse-related PTSD.
PMCID: PMC3229101  PMID: 8988792
Hippocampus; stress; posttraumatic stress disorder; cortisol; childhood abuse
20.  Emotion Modulation in PTSD: Clinical and Neurobiological Evidence for a Dissociative Subtype 
The American journal of psychiatry  2010;167(6):640-647.
In this article, the authors present evidence regarding a dissociative subtype of PTSD, with clinical and neurobiological features that can be distinguished from nondissociative PTSD. The dissociative subtype is characterized by overmodulation of affect, while the more common undermodulated type involves the predominance of reexperiencing and hyperarousal symptoms. This article focuses on the neural manifestations of the dissociative subtype in PTSD and compares it to those underlying the reexperiencing/hyperaroused subtype. A model that includes these two types of emotion dysregulation in PTSD is described. In this model, reexperiencing/hyperarousal reactivity is viewed as a form of emotion dysregulation that involves emotional undermodulation, mediated by failure of prefrontal inhibition of limbic regions. In contrast, the dissociative subtype of PTSD is described as a form of emotion dysregulation that involves emotional overmodulation mediated by midline prefrontal inhibition of the same limbic regions. Both types of modulation are involved in a dynamic interplay and lead to alternating symptom profiles in PTSD. These findings have important implications for treatment of PTSD, including the need to assess patients with PTSD for dissociative symptoms and to incorporate the treatment of dissociative symptoms into stage-oriented trauma treatment.
doi:10.1176/appi.ajp.2009.09081168
PMCID: PMC3226703  PMID: 20360318
21.  Structural and functional plasticity of the human brain in posttraumatic stress disorder 
Progress in brain research  2008;167:171-186.
Posttraumatic stress disorder (PTSD) is associated with long-term changes in neurobiology. Brain areas involved in the stress response include the medial prefrontal cortex, hippocampus, and amygdala. Neurohormonal systems that act on the brain areas to modulate PTSD symptoms and memory include glucocorticoids and norepinephrine. Dysfunction of these brain areas is responsible for the symptoms of PTSD. Brain imaging studies show that PTSD patients have increased amygdala reactivity during fear acquisition. Other studies show smaller hippocampal volume. A failure of medial prefrontal/anterior cingulate activation with re-experiencing of the trauma is hypothesized to represent a neural correlate of the failure of extinction seen in PTSD. The brain has the capacity for plasticity in the aftermath of traumatic stress. Antidepressant treatments and changes in environment can reverse the effects of stress on hippocampal neurogenesis, and humans with PTSD showed increased hippocampal volume with both paroxetine and phenytoin.
doi:10.1016/S0079-6123(07)67012-5
PMCID: PMC3226705  PMID: 18037014
PET; depression; cortisol; glucocorticoids; stress; PTSD
22.  Fear conditioning and early life vulnerabilities: two distinct pathways of emotional dysregulation and brain dysfunction in PTSD 
European Journal of Psychotraumatology  2010;1:10.3402/ejpt.v1i0.5467.
The newly proposed criteria for posttraumatic stress disorder (PTSD) in the Diagnostic and Statistical Manual (DSM-V) include dysregulation of a variety of emotional states including fear, anger, guilt, and shame, in addition to dissociation and numbing. Consistent with these revisions, we postulate two models of emotion dysregulation in PTSD in which fear is not the prevailing emotion but is only one of several components implicated in a dysregulated emotional system that also mediates problems regulating anger, guilt, shame, dissociation, and numbing.
We discuss whether there is a relationship between fear and other emotion regulation systems that may help further our understanding of PTSD and its underlying neurocircuitry. Two pathways describing the relationship between fear and other emotion regulation systems in PTSD are proposed. The first pathway describes emotion dysregulation as an outcome of fear conditioning through stress sensitization and kindling. The second pathway views emotion dysregulation as a distal vulnerability factor and hypothesizes a further exacerbation of fear and other emotion regulatory problems, including the development of PTSD after exposure to one or several traumatic event(s) later in life. Future research and treatment implications are discussed.
doi:10.3402/ejpt.v1i0.5467
PMCID: PMC3401986  PMID: 22893793
Anterior cingulate cortex; medial prefrontal cortex; amygdale; DSM-V; emotion; attachment; HPA-axis; infant; development
23.  Type D Personality, Temperament, and Mental Health in Military Personnel Awaiting Deployment 
Background
The Type D (distressed) personality refers to a general propensity to psychological distress defined by the combination of negative affectivity and social inhibition. Type D personality predicts poor mental and physical health in cardiac patients, but it has been argued that its assessment is affected by the state of illness. Therefore, validation of the Type D construct in healthy adults remains essential.
Purpose
The objectives of this study were (1) to validate Type D personality against temperament and character dimensions in young, healthy adults and (2) to investigate the association between Type D personality and pre-deployment mental health.
Method
Type D personality, temperament, and questionnaires on mental health were filled out by 86 healthy male Dutch military personnel before UN deployment to Afghanistan.
Results
Type D personality was present in 16% of healthy military personnel before deployment. The Type D components social inhibition (α = 0.89) and negative affectivity (α = 0.85) correlated positively with harm avoidant temperament (r = 0.66 and 0.46) and negatively with self-directed character (r = −0.33 and −0.57). In addition, these four traits loaded on the same broad personality dimension. Military men with a Type D personality not only reported significantly less self-directedness and more harm avoidance as compared to non-Type D men (p < 0.001) but also more symptoms of PTSD, general emotional distress, and hostility (all p < 0.012).
Conclusions
Type D personality was associated with harm avoidance, low self-directedness, and increased symptoms of PTSD and hostility in men awaiting deployment. This association was not caused by any somatic confounding in these young, healthy men.
doi:10.1007/s12529-010-9096-7
PMCID: PMC3088830  PMID: 20473600
Type D; Mental health; Pre-deployment; Validation studies; Temperament; Risk factors
24.  Does neuroimaging research examining the pathophysiology of posttraumatic stress disorder require medication-free patients? 
Background
In an attempt to avoid unknown influence, most neuroimaging studies examining the pathophysiology of posttraumatic stress disorder (PTSD) exclude patients taking medications. Here we review the empirical evidence for relevant medications having a confounding effect on task performance or cerebral blood flow (CBF) in this population. The evidence for potentially confounding effects of psychotherapy in PTSD are also discussed.
Methods
The literature that we reviewed was obtained through a PubMed search from 1980 to 2009 using the search terms posttraumatic stress disorder, PTSD, psychotropic medications, neuroimaging, functional magnetic resonance imaging, positron emission tomography, cerebral blood flow, CBF, serotonin-specific reuptake blocker, benzodiazepine, ketamine, methamphetamine, lamotrigine and atypical antipsychotic agents.
Results
The empirical evidence for relevant medications having a confounding effect on task performance or CBF in relevant areas remains sparse for most psychotropic medications among patients with PTSD. However, considerable evidence is accumulating for 2 of the most commonly prescribed medication classes (serotonin-specific reuptake inhibitors and benzodiazepines) in healthy controls. Compelling data for the potentially confounding effects on brain areas relevant to PTSD for psychotherapeutic interventions are also accumulating.
Conclusion
Neuroimaging studies examining the pathophysiology of PTSD should ideally recruit both medicated (assuming that the medication treatment has not resulted in the remission of symptoms) and unmedicated participants, to allow the findings to be generalized with greater confidence to the entire population of patients with PTSD. More research is needed into the independent effects of medications on task performance and CBF in regions of interest in PTSD. Neuro-imaging studies should also take into account whether patients are currently engaged in psychotherapeutic treatment.
doi:10.1503/jpn.090047
PMCID: PMC2834789  PMID: 20184804
25.  Hippocampus and amygdala volumes in patients with borderline personality disorder with or without posttraumatic stress disorder 
Background
Several studies have investigated volumetric brain changes in patients with posttraumatic stress disorder (PTSD) and borderline personality disorder (BPD). Both groups exhibit volume reductions of the hippocampus and amygdala. Our aim was to investigate the influence of comorbid PTSD on hippocampus and amygdala volumes in patients with BPD.
Methods
We compared 2 groups of unmedicated female patients with BPD (10 with and 15 without comorbid PTSD) and 25 healthy female controls. We used T1- and T2-weighted magnetic resonance images for manual tracing and 3-dimensional reconstruction of the hippocampus and amygdala.
Results
Hippocampus volumes of patients with BPD and PTSD were smaller than those of healthy controls. However, there was no significant difference between patients with BPD but without PTSD and controls. Impulsiveness was positively correlated with hippocampus volumes in patients with BPD.
Limitations
Our study did not allow for disentangling the effects of PTSD and traumatization. Another limitation was the relatively small sample size.
Conclusion
Our findings highlight the importance of classifying subgroups of patients with BPD. Comorbid PTSD may be related to volumetric alterations in brain regions that are of central importance to our understanding of borderline psychopathology.
PMCID: PMC2702446  PMID: 19568480

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