Epigenetic modifications and transgenerational inheritance in women victims of violence (EWVV)

Mindfulness-based interventions for women victims of interpersonal violence: A systematic review

Identifying the molecular mechanisms that underlie learning and memory is one of the major challenges in neuroscience. Synapses are highly specialized intercellular junctions specialized for transmission of signals between neuron and its target cells. One of the most profound characteristics of synapses is the extraordinary degree of morphological and functional plasticity under basal conditions and also in response to neuronal activity. Synaptic plasticity is a long studied mechanism that is thought to be in the center of memory formation and maintenance. The significance of synapse morphological dynamics for the synaptic plasticity and therefore memory still remains unclear. Taken the advantages of the nematode C. elegans, we investigated α-adducin (add-1) in aversive olfactory associative learning and memory. Loss of add-1 function selectively impaired short- and long-term memory without causing acquisition, sensory or motor deficits. We showed that α-adducin is required for consolidation of synaptic plasticity, for sustained synaptic increase of AMPA-type glutamate receptor (GLR-1) content and altered GLR-1 turnover dynamics. ADD-1 controlled the storage of memories presumably through actin capping activity in a splice form and tissue specific manner. In support of the C. elegans results, genetic variability of the human ADD1 gene was significantly associated with episodic memory performance in healthy young subjects. Finally, human ADD1 expression in nematodes restored loss of C. elegans add-1 gene function. Taken together, our findings support a role for α-adducin in memory from nematodes to humans. Studying the molecular and genetic underpinnings of memory over distinct species may be helpful in the development of novel strategies to treat memory-related diseases. In contrast to a relatively deep understanding of how memories are formed, is our limited understanding of how these same memories are maintained. Epigenetic modifications of DNA could be crucial for understanding the molecular basis of complex phenotypes. In the second project we tried to underpin the link between traumatic memories and posttraumatic stress disorder (PTSD) in genocide survivors and DNA methylation. Stress induces a complex set of mechanisms that affect the entire organism. The primary function of those changes is to prepare the organism for the direct consequences of stressful events and to ensure a quick return to homeostasis. Additionally, stress is triggering long-term adaptive responses, which result in enhanced memory of stressful events. Failing to recover from the initial response and to keep the adaptive biological alterations under control leads to impaired homeostasis, results in disorders like PTSD. One of the critical symptoms is loss of the auto-regulation of the stress-induced alterations in HPA (hypothalamic-pituitary- adrenal axis) signaling and increased inhibition of the HPA axis. These changes are maintained over a long period of time, although the underlying mechanisms remain unclear. We investigated epigenetic alterations of the glucocorticoid receptor (GR) gene promoter in saliva samples from survivors of the Rwandan genocide. We found a strong, negative correlation of PTSD symptoms like intrusions, avoidance, and PTSD diagnosis with DNA methylation of the GR gene promoter in genocide survivors. Furthermore, the epigenetic changes were specific to the NGFI transcriptional factor-binding site of the GR promoter and also correlate with GR gene expression. Additionally, we detected a significant negative correlation of LINE-1 element methylation with PTSD risk and avoidance symptoms. Together, our data suggests that epigenetic alterations of glucocorticoid receptor gene and genome-wide in LINE-1 elements could be important for pathophysiology of PTSD and may offer new targets for PTSD diagnosis and treatment. This study also suggests an intriguing possibility of using peripheral tissues for finding epigenetic signatures of some life experiences and complex memory processes. Finally, we took one-step ‘’back’’ to the context of the genomic DNA sequence. This revealed the association of genetic variation in the de-novo DNA methyltransferase 3B gene (DNMT3B) with PTSD symptom clusters and risk. Thus, our study suggests a possible mechanism that loops genetic variation and epigenetic mechanisms as driving forces of the phenotypic plasticity, with development, adaptation and disease. But, instead of revealing a simple predictive code that is shared by many genes, in-depth observation of epigenomic patterns highlights the unique complexity of each transcriptional unit and its associated transcriptional regulatory machinery.

Induction of FOS expression by acute immobilization stress is reduced in locus coeruleus and medial amygdala of Wistar–Kyoto rats compared to Sprague–Dawley rats

Anxiety disorders are among the most common of all mental disorders and their pathogenesis is a major topic in psychiatry, both for prevention and treatment. Early stressful life events and alterations of hypothalamic pituitary adrenal (HPA) axis function seem to have a significant role in the onset of anxiety. Existing data appear to support the mediating effect of the HPA axis between childhood traumata and posttraumatic stress disorder. Findings on the HPA axis activity at baseline and after stimuli in panic disordered patients are inconclusive, even if stressful life events may have a triggering function in the development of this disorder. Data on the relationship between stress, HPA axis functioning and obsessive-compulsive disorder (OCD) are scarce and discordant, but an increased activity of the HPA axis is reported in OCD patients. Moreover, normal basal cortisol levels and hyper-responsiveness of the adrenal cortex during a psychosocial stressor are observed in social phobics. Finally, abnormal HPA axis activity has also been observed in generalized anxiety disordered patients. While several hypothesis have attempted to explain these findings over time, currently the most widely accepted theory is that early stressful life events may provoke alterations of the stress response and thus of the HPA axis, that can endure during adulthood, predisposing individuals to develop psychopathology. All theories are reviewed and the authors conclude that childhood life events and HPA abnormalities may be specifically and transnosographically related to all anxiety disorders, as well as, more broadly, to all psychiatric disorders.

PTSD and the HPA axis: Differences in response to the cold pressor task among individuals with child vs. adult trauma

Suicidality, posttraumatic stress, and depressive reactions after earthquake and maltreatment: A cross-sectional survey of a random sample of 6132 chinese children and adolescents

Post-traumatic stress disorder (PTSD) confers an increased risk for disorders with an inflammatory etiology. PTSD-related dysregulation of the sympathetic nervous system (SNS) and hypothalamic-pituitary adrenal (HPA) axis and associated alterations in inflammatory activity may contribute to this increased risk. However, little is known about convergent SNS, HPA and inflammatory signaling at the level of the immune cell transcriptome in PTSD. To explore such signaling, we examined the prevalence of specific transcription factor binding motifs in the promoter regions of differentially expressed genes in monocytes from individuals with PTSD and matched controls. Participants included 49 men (24 PTSD+ and 25 trauma-exposed controls) and 18 women (10 PTSD+ and 8 controls). Men with PTSD showed up-regulation of target genes for the NF-κB/Rel family of transcription factors, which convey inflammatory signals, up-regulation of target genes for CREB/ATF transcription factors, which convey adrenergic signals from the SNS, and down-regulation of target genes for the glucocorticoid receptor, which conveys glucocorticoid signals from the HPA axis. Women with PTSD also showed significant up-regulation of target genes for NF-κB and non-significant down-regulation of target genes for GR, but significant down-regulation of target genes for CREB/ATF. Altered transcriptional control of monocyte gene expression could contribute to exaggerated inflammatory activity in PTSD.

Post-traumatic stress disorder (PTSD) confers an increased risk for disorders with an inflammatory etiology. PTSD-related dysregulation of the sympathetic nervous system (SNS) and hypothalamic-pituitary adrenal (HPA) axis and associated alterations in inflammatory activity may contribute to this increased risk. However, little is known about convergent SNS, HPA and inflammatory signaling at the level of the immune cell transcriptome in PTSD. To explore such signaling, we examined the prevalence of specific transcription factor binding motifs in the promoter regions of differentially expressed genes in monocytes from individuals with PTSD and matched controls. Participants included 49 men (24 PTSD+ and 25 trauma-exposed controls) and 18 women (10 PTSD+ and 8 controls). Men with PTSD showed up-regulation of target genes for the NF-κB/Rel family of transcription factors, which convey inflammatory signals, up-regulation of target genes for CREB/ATF transcription factors, which convey adrenergic signals from the SNS, and down-regulation of target genes for the glucocorticoid receptor, which conveys glucocorticoid signals from the HPA axis. Women with PTSD also showed significant up-regulation of target genes for NF-κB and non-significant down-regulation of target genes for GR, but significant down-regulation of target genes for CREB/ATF. Altered transcriptional control of monocyte gene expression could contribute to exaggerated inflammatory activity in PTSD.

Traumatic stress results in hypothalamic pituitary adrenal (HPA) axis abnormalities and an increased risk to both suicidal behaviors and post-traumatic stress disorder (PTSD). Previous work out of our laboratory identified SKA2 DNA methylation associations with suicidal behavior in the blood and brain of multiple cohorts. Interaction of SKA2 with stress predicted suicidal behavior with ~80% accuracy. SKA2 is hypothesized to reduce the ability to suppress cortisol following stress, which is of potentially high relevance in traumatized populations. Our objective was to investigate the interaction of SKA2 and trauma exposure on HPA axis function, suicide attempt and PTSD. SKA2 DNA methylation at Illumina HM450 probe cg13989295 was assessed for association with suicidal behavior and PTSD metrics in the context of Child Trauma Questionnaire (CTQ) scores in 421 blood and 61 saliva samples from the Grady Trauma Project (GTP) cohort. Dexamethasone suppression test (DST) data were evaluated for a subset of 209 GTP subjects. SKA2 methylation interacted with CTQ scores to predict lifetime suicide attempt in saliva and blood with areas under the receiver operator characteristic curve (AUCs) of 0.76 and 0.73 (95% confidence interval (CI): 0.6–0.92, P=0.003, and CI: 0.65–0.78, P<0.0001) and to mediate the suppression of cortisol following DST (β=0.5±0.19, F=1.51, degrees of freedom (df)=12/167, P=0.0096). Cumulatively, the data suggest that epigenetic variation at SKA2 mediates vulnerability to suicidal behaviors and PTSD through dysregulation of the HPA axis in response to stress.

Cortisol secretions serve as the barometer of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates and controls responses to stress. Studies of cortisol secretions in patients with posttraumatic stress disorder (PTSD) reveal inconsistent results. Current research on HPA axis functioning in PTSD is examined to elucidate the neuroendocrine contributions in the disorder, identify current treatment's impact on the HPA axis, and consider implications for nursing care and areas for future research. There is evidence for HPA dysregulation in PTSD, which contributes to widespread impairment in functions such as memory and stress reactivity and to physical morbidity via processes such as allostatic load. There is limited, but building, evidence that dehydroepiandrosterone (DHEA), which is released simultaneously with cortisol, may provide anti-glucocorticoid and neuroprotective effects. Current treatments such as selective serotonin reuptake inhibitors and psychotherapy may have a beneficial impact on the HPA axis in PTSD populations. Somatic approaches to treating PTSD have not yet been studied in relation to their impact on HPA axis parameters in PTSD patients. Treatment studies of DHEA or glucocorticoids have not yet used HPA axis endpoints. PTSD treatment studies that include measures of HPA axis target mechanisms and consider HPA axis regulation as an additional treatment outcome are warranted.

Although a number of theorists have hypothesized a link between negative experiences during childhood (e.g., abuse) and the presence of psychopathology in adults, little is known about the relative specificity of childhood emotional, physical, or sexual abuse to different forms of psychopathology. In this study, we hypothesized that adult psychiatric outpatients' reports of childhood emotional abuse would exhibit a specific relationship with diagnoses of depression. Analyses partially supported our hypothesis. Specifically, diagnoses of major depression were significantly more strongly related to reports of childhood emotional abuse than to physical or sexual abuse. However, the same effect was observed for social phobia. In addition, patients with major depression reported equivalent levels of childhood emotional abuse as patients with social phobia, but lower levels of emotional abuse than those with posttraumatic stress disorder.

Background: Childhood maltreatment is associated with various psychiatric disorders, including post-traumatic stress disorder (PTSD) and personality disorders (PDs). Previous research has suggested that PTSD and PD are highly comorbid. However, the impact of different types of childhood maltreatment on the severity of PTSD and PD symptoms in a clinical population with PTSD/PD symptoms remains unclear. Objective: We aimed to clarify the role of (a) the overall severity and (b) the severity of subtypes of childhood maltreatment on the severity of (a) PTSD and (b) comorbid PD symptoms. Methods: Data was collected from participants (N = 197) seeking treatment for PTSD with comorbid PD symptoms at a trauma expertise centre in the Netherlands. We assessed childhood maltreatment using the Childhood Trauma Questionnaire-short form (CTQ-sf), PTSD severity with the Clinician-administered PTSD Scale for DSM-5 (CAPS-5), and PD severity with the Structured Clinical Interview for DSM-5 Personality Disorders (SCID-5-PD). Data were analyzed using linear and Poisson regression. Results: We found that emotional neglect was the most prevalent form of childhood maltreatment (80.7%), followed by emotional abuse (72.6%). Sexual and emotional abuse shared independent associations with the severity of PTSD. The overall maltreatment severity and emotional abuse were significantly associated with the severity of comorbid borderline PD symptoms. Sexual abuse was significantly associated with the severity of comorbid avoidant PD symptoms. None of the childhood maltreatment types were significantly associated with the severity of comorbid obsessive-compulsive PD symptoms. Conclusions: We demonstrated the relationship between childhood sexual and emotional abuse and PTSD severity in people with PTSD and comorbid PD symptoms. This has important implications since emotional abuse usually does not fulfil the A-criterion required for the diagnosis of PTSD. We recommend routinely assessing emotional abuse in trauma- and PD treatment, and investigating the effectiveness of adapting trauma treatment for emotional abuse. Trial registration: ClinicalTrials.gov identifier: NCT03833453.

Toward the Predeployment Detection of Risk for PTSD

Background: Trauma-focused treatments for post-traumatic stress disorder (PTSD) are effective for many patients. However, relapse may occur when acquired extinction memories fail to generalize beyond treatment contexts. A subgroup of PTSD patients – potentially with substantial exposure to early-life adversity (ELA) – show dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, which results in lower cortisol levels. Glucocorticoids, including cortisol, appear to facilitate strength and generalization of emotional memories. Objective: We describe the protocol of an integrated PTSD study. We investigate (A) associations between HPA-axis dysregulation, ELA, epigenetic markers, and PTSD treatment outcome (observational study); and (B) effects of exogenous glucocorticoids on strength and generalization of extinction memories and associated neural mechanisms [pharmacological intervention study with functional magnetic resonance imaging (fMRI)]. The objective is to provide proof of concept that PTSD patients with HPA-axis dysregulation often experienced ELA and may show improved strength and generalization of extinction learning after glucocorticoid administration. Method: The observational study (n = 160 PTSD group, n = 30 control group) assesses ELA, follow-up PTSD symptoms, epigenetic markers, and HPA-axis characteristics (salivary cortisol levels during low-dose dexamethasone suppression test and socially evaluated cold-pressor test). The pharmacological intervention study (n = 80 PTSD group, with and without HPA-axis dysregulation) is a placebo-controlled fMRI study with a crossover design. To investigate strength and generalization of extinction memories, we use a differential fear acquisition, extinction, and extinction recall task with spatial contexts within a virtual environment. Prior to extinction learning, 20 mg hydrocortisone or placebo is administered. During next-day recall, strength of the extinction memory is determined by recovery of skin conductance and pupil dilation differential responding, whereas generalization is assessed by comparing responses between different spatial contexts. Conclusion: The integrated study described in the current protocol paper could inform a personalized treatment approach in which these PTSD patients may receive glucocorticoids as a treatment enhancer in trauma-focused therapies. Trial registration: The research project is registered in the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database, https://eudract.ema.europa.eu/, EudraCT number 2020-000712-30.

Context In Europe, at least one in three women experience physical and/or sexual violence in her lifetime. This gender-based violence affects the victim's physical and mental health. Women victims of violence are at risk of developing mental health disorders such as post-traumatic stress disorder (PTSD) and traumatic dissociation. However, few recent studies have examined the prevalence of PTSD and other mental health problems among women victim of violence, making the development of research interventions to manage these symptoms challenging. Methods and implications The “Maison des Femmes” institute (MdF; Women's Home) is the only one of its kind in France. It provides care and support for women victim of violence. The multidimensional services provided at MdF consists of physical and mental health care as well as social and judicial support in a confidential and secure environment. “AVeC-L”(Accompagnement des femmes Victimes de ViolenCes à La Maison des Femmes), is an intervention research project (pilot study + comparative trial) which aims to examine and compare the mental health of adult women consulting at MdF and in two local health centers. In the currently ongoing pilot study, we measure the presence of PTSD and its intensity using the PTSD Checklist for DSM-5 in 80 participants. We also measure traumatic dissociative symptoms, and quality of life, and substance use. Using qualitative research, we also examine the women's perception of the effect of the care provided at MdF and at the two others local health centers. Expected results and implications The “Avec-L” pilot study will estimate the prevalence of PTSD and dissociative symptoms among women victims of violence who consult at MdF. It will also provide information on women's perception of the provided care. These results will contribute to the design of a larger intervention trial (pre and post comparison) evaluating the effect of the multidimensional support and care at MdF on women's mental health.