Mirjam van Zuiden

Predicting PTSD: Pre-existing vulnerabilities in glucocorticoid-signaling and implications for preventive interventions

Posttraumatic stress disorder (PTSD) is an anxiety disorder that may develop in response to a traumatic event. Approximately 10% of trauma-exposed individuals subsequently develop PTSD. It is hypothesized that the development of PTSD is associated with biological vulnerability factors, which are already present prior to the onset of symptoms. In this review we present an overview of currently identified vulnerability factors in the glucocorticoid (GC) signaling pathway for the development of PTSD. In addition, the implications of the identified vulnerability factors for potential preventive intervention strategies, including glucocorticoid receptor (GR) agonists and oxytocin, are discussed. Summarized, the findings of these studies indicate that individuals vulnerable for development of PTSD have dysregulations on various levels of the GC-signaling cascade: i.e. low levels of circulating levels of cortisol shortly after trauma, high GR number in peripheral blood mononuclear cells (PBMCs), high GILZ mRNA expression and low FKBP5 expression in PBMCs prior to trauma, and high sensitivity of T-cells for regulation by GCs prior to trauma. Furthermore, single nucleotide polymorphisms in the GR and FKBP5 genes have been found to be associated with increased risk for PTSD. Collectively, the identified vulnerability factors tentatively suggest that the development of PTSD may be preceded by a high sensitivity of various cells for regulation by GCs. The identification of these vulnerability factors may ultimately aid selective targeting of preventive interventions towards individuals at risk for PTSD. In addition, the identification of these vulnerability factors may eventually result in new preventive pharmacological strategies for PTSD.

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 PTSD.

ABERRANT RESTING-STATE BRAIN ACTIVITY IN POSTTRAUMATIC STRESS DISORDER: A META-ANALYSIS AND SYSTEMATIC REVIEW.

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.

Social support, oxytocin and PTSD

Background A lack of social support and recognition by the environment is one of the most consistent risk factors for posttraumatic stress disorder (PTSD), and PTSD patients will recover faster with proper social support. The oxytocin system has been proposed to underlie beneficial effects of social support as it is implicated in both social bonding behavior and reducing stress responsivity, notably amygdala reactivity (Koch et al., 2014; Olff et al., 2010; Olff, 2012). The amygdala is found to be hypersensitive in people with PTSD. Method In order to investigate neurobiological mechanisms underlying potential preventive and therapeutic effects of intranasal oxytocin, we performed a series of fMRI studies (funded with a prestigious NWO TOP grant): BONDS standing for “Boosting Oxytocin after trauma: Neurobiology and the Development of Stress-related psychopathology” in acutely traumatized persons admitted to the emergency department (Frijling et al., 2014); BOOSTER “Boosting oxytocin after trauma: the effects of intranasal oxytocin administration on emotional and motivational processing and neural activity in PTSD” in police officers with and without PTSD. Results In this presentation, we present the BOOSTER results on the effects of a single oxytocin administration on amygdala reactivity in response to emotional faces in PTSD patients versus traumatized controls. We found significantly decreased bilateral amygdala reactivity towards emotional faces in PTSD patients compared to traumatized controls. Conclusions These promising results call for intervention studies such as studying the effects of medication (oxytocin) enhanced psychotherapy in PTSD patients.

Intranasal oxytocin enhances neural processing of monetary reward and loss in post-traumatic stress disorder and traumatized controls.

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.

Pre-deployment differences in glucocorticoid sensitivity of leukocytes in soldiers developing symptoms of PTSD, depression or fatigue persist after return from military deployment.

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.

Cytokine production as a putative biological mechanism underlying stress sensitization in high combat exposed soldiers

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.

Intranasal oxytocin increases neural responses to social reward in post-traumatic stress disorder

Abstract Therapeutic alliance and perceived social support are important predictors of treatment response for post-traumatic stress disorder (PTSD). Intranasal oxytocin administration may enhance treatment response by increasing sensitivity for social reward and thereby therapeutic alliance and perceived social support. As a first step to investigate this therapeutical potential, we investigated whether intranasal oxytocin enhances neural sensitivity to social reward in PTSD patients. Male and female police officers with (n = 35) and without PTSD (n = 37) were included in a double-blind, randomized, placebo-controlled cross-over fMRI study. After intranasal oxytocin (40 IU) and placebo administration, a social incentive delay task was conducted to investigate neural responses during social reward and punishment anticipation and feedback. Under placebo, PTSD patients showed reduced left anterior insula (AI) responses to social rewards (i.e. happy faces) compared with controls. Oxytocin administration increased left AI responses during social reward in PTSD patients, such that PTSD patients no longer differed from controls under placebo. Furthermore, in PTSD patients, oxytocin increased responses to social reward in the right putamen. By normalizing abberant insula responses and increasing putamen responses to social reward, oxytocin administration may enhance sensitivity for social support and therapeutic alliance in PTSD patients. Future studies are needed to investigate clinical effects of oxytocin.

Neuroendocrine and neuroimmune markers in PTSD: pre-, peri- and post-trauma glucocorticoid and inflammatory dysregulation

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.

Early interventions: from e-health to neurobiology

No abstract available. (Published: 11 June 2015) Citation: European Journal of Psychotraumatology 2015, 6 : 28545 - http://dx.doi.org/10.3402/ejpt.v6.28545 This abstract is part of the Special Issue: the Swedish Psychotrauma Society scientific conference – selected abstracts . More abstracts from this issue can be found atwww.ejpt.net