Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.New methods for child psychiatric diagnosis and treatment outcome evaluatio

Preventing PTSD with oxytocin: Effects of oxytocin administration on fear neurocircuitry and PTSD symptom development in recently trauma-exposed individuals

The overall aim of the current PhD-thesis was to investigate the potential of intranasal oxytocin administration as early preventive intervention for PTSD, by assessing the effects of intranasal oxytocin early after trauma on functioning of the fear neurocircuitry and on PTSD symptom development in recently trauma-exposed individuals. To this end, we performed a functional magnetic resonance imaging (fMRI) study to assess the acute effects of a single administration of oxytocin on the functional fear neurocircuitry – consisting of the amygdala and (pre)frontal brain regions associated with fear extinction and emotion regulation – in recently trauma-exposed emergency department patients. In addition, we performed a randomized controlled trial to assess the efficacy of repeated intranasal oxytocin administration early after trauma for preventing the development of PTSD symptom. Furthermore, we investigated neurobiological correlates of PTSD and acute PTSD symptoms

Preventing PTSD with oxytoxin: Effects of oxytocin administration on fear neurocircuitry and PTSD symptom development in recently trauma-exposed individuals

The overall aim of the current PhD-thesis was to investigate the potential of intranasal oxytocin administration as early preventive intervention for PTSD, by assessing the effects of intranasal oxytocin early after trauma on functioning of the fear neurocircuitry and on PTSD symptom development in recently trauma-exposed individuals. To this end, we performed a functional magnetic resonance imaging (fMRI) study to assess the acute effects of a single administration of oxytocin on the functional fear neurocircuitry – consisting of the amygdala and (pre)frontal brain regions associated with fear extinction and emotion regulation – in recently trauma-exposed emergency department patients. In addition, we performed a randomized controlled trial to assess the efficacy of repeated intranasal oxytocin administration early after trauma for preventing the development of PTSD symptom. Furthermore, we investigated neurobiological correlates of PTSD and acute PTSD symptoms

Intranasal oxytocin as strategy for medication-enhanced psychotherapy of PTSD: Salience processing and fear inhibition processes

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 PTS

Process evaluation of a multifaceted intervention to improve cardiovascular disease prevention in general practice.

OBJECTIVES: To perform a process evaluation of a multifaceted intervention to improve cardiovascular and diabetes care in general practice. METHODS: The feasibility of the intervention, carried out by outreach visitors in 62 practices, was addressed by evaluating whether the intervention programme was performed as planned and the extent to which it was accepted by the practice team. In addition, the costs of the programme were determined. RESULTS: The intervention was largely carried out as planned, although the intervention period had to be extended by three months. Of the 18 topics that could be addressed during the intervention period, 12 (mean) were addressed. The number of outreach visits per practice was 15.2 (mean), each visit lasted about one hour. Most practice members endorsed both the key recommendations for clinical decision-making and cardiovascular risk profiling. The majority of GPs (range 63-98%) agreed with the guidelines for clinical decision-making, and 29-97% had a positive opinion about the guidelines for practice organisation. According to practice staff members, the outreach visitor had sufficient knowledge and skills to support them in changing the practice organisation. GPs were less positive about the outreach visitor's knowledge and skills in optimising clinical decision-making; however 78% believed that the outreach visitor contributed to effecting change in their clinical decision-making. The total costs of the intervention per practice were Euro 4317. CONCLUSIONS: This process evaluation demonstrated that the intervention was usually carried out as planned and achieved a high satisfaction rating from the participating practice members

Early posttraumatic autonomic and endocrine markers to predict posttraumatic stress symptoms after a preventive intervention with oxytocin

Background: Efficient prevention of posttraumatic stress disorder (PTSD) needs to target individuals with an increased risk for adverse outcome after trauma. Prognostic or prescriptive biological markers assessed early posttrauma may inform personalized treatment recommendations. Objective: To test prognostic and prescriptive effects of early (posttraumatic) autonomic and endocrine markers on PTSD symptom development. Method: Autonomic and endocrine markers were assessed within 12 days posttrauma and before treatment initiation within a randomized placebo-controlled trial investigating repeated oxytocin administration as preventive intervention for PTSD. Linear mixed effects models were used to test the effects of heart rate (variability), resting cortisol, morning cortisol and cortisol awakening response (CAR), cortisol suppression by dexamethasone and resting oxytocin on PTSD symptoms 1.5, 3 and 6 months posttrauma in men (n = 54), women using hormonal contraception (n = 27) and cycling women (n = 19). Results : We found significant prognostic effects of resting oxytocin and cortisol suppression. In women using hormonal contraception, higher oxytocin was associated with higher PTSD symptoms across follow-up. Stronger cortisol suppression by dexamethasone, reflecting increased glucocorticoid receptor feedback sensitivity, was associated with lower PTSD symptoms across follow-up in men, but with higher symptoms at 1.5 months in women using hormonal contraception. These effects were independent of treatment condition. No further significant prognostic or prescriptive effects were detected. Conclusion : Our exploratory study indicates that resting oxytocin and glucocorticoid receptor feedback sensitivity early posttrauma are associated with subsequent PTSD symptom severity. Notably, prognostic effects depended on sex and hormonal contraception use, emphasizing the necessity to consider these factors in biomedical PTSD research

Efficacy of oxytocin administration early after psychotrauma in preventing the development of PTSD: study protocol of a randomized controlled trial

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

Genetic variant in CACNA1C is associated with PTSD in traumatized police officers /631/208/176/1988 /692/499 /45 /45/61 /45/23 article

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