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Influences of Maternal and Paternal PTSD on Epigenetic Regulation of the Glucocorticoid Receptor Gene in Holocaust Survivor Offspring
Abstract
Objective:
Differential effects of maternal and paternal posttraumatic stress disorder (PTSD) have been observed in adult offspring of Holocaust survivors in both glucocorticoid receptor sensitivity and vulnerability to psychiatric disorder. The authors examined the relative influences of maternal and paternal PTSD on DNA methylation of the exon 1F promoter of the glucocorticoid receptor (GR-1F) gene (NR3C1) in peripheral blood mononuclear cells and its relationship to glucocorticoid receptor sensitivity in Holocaust offspring.
Method:
Adult offspring with at least one Holocaust survivor parent (N=80) and demographically similar participants without parental Holocaust exposure or parental PTSD (N=15) completed clinical interviews, self-report measures, and biological procedures. Blood samples were collected for analysis of GR-1F promoter methylation and of cortisol levels in response to low-dose dexamethasone, and two-way analysis of covariance was performed using maternal and paternal PTSD as main effects. Hierarchical clustering analysis was used to permit visualization of maternal compared with paternal PTSD effects on clinical variables and GR-1F promoter methylation.
Results:
A significant interaction demonstrated that in the absence of maternal PTSD, offspring with paternal PTSD showed higher GR-1F promoter methylation, whereas offspring with both maternal and paternal PTSD showed lower methylation. Lower GR-1F promoter methylation was significantly associated with greater postdexamethasone cortisol suppression. The clustering analysis revealed that maternal and paternal PTSD effects were differentially associated with clinical indicators and GR-1F promoter methylation.
Conclusions:
This is the first study to demonstrate alterations of GR-1F promoter methylation in relation to parental PTSD and neuroendocrine outcomes. The moderation of paternal PTSD effects by maternal PTSD suggests different mechanisms for the intergenerational transmission of trauma-related vulnerabilities.
Supplementary resource (1)
... The study of the Bakusic et al. [102] builds upon the foundational work of Weaver et al. [99] and McGowan et al. [101] by extending the exploration of epigenetic regulation of stress responses to a clinical population with major depressive disorder (MDD). Unlike the earlier studies, which focused on maternal care in rats and childhood abuse in humans, this study examined the role of DNA methylation in both the glucocorticoid receptor gene (NR3C1) and the serotonin transporter gene (SLC6A4), highlighting a broader scope of epigenetic targets involved in HPA axis dysregulation. ...
... Unlike the earlier studies, which focused on maternal care in rats and childhood abuse in humans, this study examined the role of DNA methylation in both the glucocorticoid receptor gene (NR3C1) and the serotonin transporter gene (SLC6A4), highlighting a broader scope of epigenetic targets involved in HPA axis dysregulation. It also added a prospective clinical dimension by linking NR3C1 methylation at specific CpG sites to symptom improvement, emphasizing the potential of epigenetic markers for predicting treatment outcomes in MDD [102]. The incorporation of the Trier Social Stress Test (TSST) provided a direct measurement of HPA axis reactivity, allowing the study to quantify the functional impact of epigenetic dysregulation. ...
... The incorporation of the Trier Social Stress Test (TSST) provided a direct measurement of HPA axis reactivity, allowing the study to quantify the functional impact of epigenetic dysregulation. Importantly, the finding that NR3C1 and SLC6A4 methylation collectively explained a portion of the variability in cortisol responses bridges the gap between molecular changes and physiological stress regulation [102]. ...
Neuroinflammation is an inflammatory response that affects the central nervous system. This process involves the activation of immune cells like microglia and astrocytes, as well as the production of inflammatory chemicals like cytokines and chemokines. Neuroinflammation can be caused by a variety of circumstances, including trauma, infection, autoimmune illnesses, environmental factors, any stress scenario, and neurodegenerative diseases. Neuroinflammation is thought to be connected with a variety of psychiatric disorders. These illnesses include depression, anxiety disorders, schizophrenia, and bipolar disorder. Research in biological neuropsychiatry can assist in establishing future treatment options by demonstrating how neuroinflammation contributes to illness. This book chapter explains how neuroinflammation is a major contributor to mental illnesses, as well as how this topic is significant in study and therapy.
... Building on this, a host of research done by Yehuda and colleagues, provides strong evidence that PTSD-induced epigenetic changes can be inherited intergenerationally and may contribute to the manifestation of pathologies in the next generation [120][121][122][123]. Combat Veterans with PTSD have lower methylation levels in the promoter region of NR3C1-1F which is associated with lower urinary cortisol excretion, greater glucocorticoid sensitivity in peripheral blood mononuclear cells, and a greater decline in cortisol response following dexamethasone administration (DEX) [123]. ...
... What is particularly interesting about this research, is that the offspring effects are often dependent upon the parental exposure (maternal vs. paternal) and the offspring sex (sons vs. daughters). For example, when both parents experienced PTSD following Holocaust exposure, offspring exhibited lower DNA methylation of NR3C1-1F in peripheral blood cells, which was associated with enhanced cortisol suppression following DEX [122]. However, when only the father experienced PTSD, offspring exhibiter higher methylation of NR3C1-1F, and greater cortisol excretion and reduced GR sensitivity [122]. ...
... For example, when both parents experienced PTSD following Holocaust exposure, offspring exhibited lower DNA methylation of NR3C1-1F in peripheral blood cells, which was associated with enhanced cortisol suppression following DEX [122]. However, when only the father experienced PTSD, offspring exhibiter higher methylation of NR3C1-1F, and greater cortisol excretion and reduced GR sensitivity [122]. Moreover, paternal PTSD resulted in offspring with less adaptive attachment styles and higher rates of childhood trauma and sensitivity to violence, while maternal PTSD resulted in offspring with increased rates of depression and anxiety [122]. ...
Chronic pain is a public health problem that significantly reduces quality of life. Although the aetiology is often unknown, recent evidence suggests that susceptibility can be transmitted intergenerationally, from parent to child. Post-traumatic stress disorder (PTSD) is a debilitating psychological disorder, often associated with chronic pain, that has high prevalence rates in military personnel and Veterans. Therefore, we aimed to characterise the epigenetic mechanisms by which paternal trauma, such as PTSD, is transmitted across generations to confer risk in the next generation, specifically focusing on Veterans where possible. Numerous overlapping neurological pathways are implicated in both PTSD and chronic pain; many of which are susceptible to epigenetic modification, such as DNA methylation, histone modifications, and RNA regulation. Hence, epigenetic changes related to pain perception, inflammation, and neurotransmission may influence an individual’s predisposition to chronic pain conditions. We also examine the effects of PTSD on parenting behaviours and discuss how these variations could impact the development of chronic pain in children. We highlight the need for further research regarding the interactions between paternal trauma and epigenetic processes to ultimately generate effective prevention and therapeutic strategies for Veterans who have been affected by PTSD and chronic pain.
... U cilju prevencije oboljenja kod fetusa, potom deteta i odrasle osobe značajna je interakcija sa činiocima spoljnje sredine, te je tako od izuzetnog značaja ishrana majke, njena izloženost uticajima spoljašnje sredine, izloženost stresu i način na koji se na sve te činioce adaptirala, jer će se epigenetičke promene preneti i na generacije potomaka (1)(2)(3)(4)(5). ...
... Optimistična očekivanja da će naredne generacije tj. potomci živeti bolje iako su prethodne generacije živele u nepovoljnim uslovima, doživela su izmene, jer prema epigenetičkim saznanjima, epigenetičke promene sa prethodnih generacija se prenose na naredne generacije, te će tako naredne generacije nositi epigenetičke markere svojih predaka, čak i u nekoliko narednih generacija (4,5). ...
... Kod trudnice, u isto vreme, istim uslovima okruženja (ishrana, hormoni, toksini, stres i dr.) direktno su izložene tri generacije: majka, fetus i reproduktivne ćelije fetusa. Epigenetički uticaji koji se prenose u četvrtu generaciju se mogu razmatrati kao nasleđeni a ne kao uticaji nastali drektnim izlaganjem spoljnjim činiocima (3)(4)(5)(6)(7)(8). ...
Epigenetika je oblast medicine koja se intenzivno razvija i saznanja iz ove oblasti se primenjuju u preventivnoj pedijatriji i drugim oblastima medicine. Primena epigenetičkih saznanja u preventivnoj pedijatriji je sve zastupljenija i interesantna sa više aspekata. U određenim okolnostima, s jedne strane uticaj epigenetičkih faktora može da izmeni ekspresiju gena i da dovede do ispoljavanja bolesti, a može svojim uticajem da deluje i preventivno, i da odloži ispoljavanje bolesti, poboljša kvalitet života i utiče na produženje života. Izmenom epigenetičkih faktora može se uticati na to da se pojava oboljenja odloži ili ne ispolji. Kako su epigenetičke promene reverzibilne, i nema primarnog oštećenja DNK sekvence niti promena na hromozomima, postoje velike mogućnosti za osmišljavanje strategije intervencije promenama životnog stila i samim tim primenama tzv. epigenetičke preventivne terapije.
... Another study identified notable hypermethylation at CpG sites within the oxytocin receptor (OXTR) in female PTSD patients compared to controls and male PTSD counterparts (Nawijn et al., 2019). Additionally, four studies examined maternal inheritance, identifying transmission of epigenetic signatures, such as heightened DNA methylation at crucial glucocorticoid binding sites or serotonin receptors, influenced by the trauma experienced by the mother prior to childbirth (Grasso et al., 2020;Schechter et al., 2015Schechter et al., , 2017Yehuda et al., 2014). Noteworthy is a study on pregnant survivors of the 1994 Tutsi genocide, which revealed higher methylation levels at the NR3C1 exon 1 promoter region in exposed mothers compared to those not exposed (Perroud et al., 2014). ...
... Despite this review highlighting consistent epigenetic, CpG, and miRNA markers along with bi-directional pathways in PTSD research, there remains a substantial gap in robustly linking these markers to gene expression. A significant number of studies (44 in total) did not correlate gene expression with measured epigenetic, CpG, or miRNA data, and among these, 12 failed to measure gene expression altogether (Bam, Yang, Zumbrun, et al., 2016;Bam et al., 2020;Busbee et al., 2021;Carvalho et al., 2023;Conrad et al., 2020;Crombach et al., 2024;Dean et al., 2020;Ensink et al., 2021;Gan et al., 2022;Guo et al., 2021;Hack et al., 2021;Houtepen et al., 2016;Katrinli et al., 2021Katrinli et al., , 2022Koenen et al., 2011;Krzyzewska et al., 2018;Linnstaedt et al., 2020;Logue et al., 2020;Lokhammer et al., 2022;Maddox et al., 2018;Marra et al., 2024;Mehta et al., 2019;Montalvo-Ortiz et al., 2022;Nothling et al., 2021;Occean et al., 2022;Pathak et al., 2022;Perroud et al., 2014;Schultebraucks et al., 2021;Serpeloni et al., 2019;Siegel et al., 2021;Smith et al., 2011Smith et al., , 2020Snijders et al., 2020;Swart et al., 2023;Vukojevic et al., 2020;Wani et al., 2021;Wingo et al., 2015;Xu et al., 2023;Yang et al., 2021;Yehuda et al., 2014;Zhou et al., 2014). The lack of correlation with the respective functional significance may potentially diminish the findings impact. ...
Molecular studies identifying alterations associated with PTSD have predominantly focused on candidate genes or conducted genome-wide analyses, often encountering issues with replicability. this review aims to identify robust bi-directional epigenetic and microRNA (miRNA) regulators focusing on their functional impacts on post-traumatic stress disorder (PTSD) and their utility in clinical diagnosis, whilst examining knowledge gaps in the existing research. A systematic search was conducted across multiple databases, including web of Science, Scopus, Global Health (CABI), and PubMed, augmented by grey literature, yielding 3465 potential articles. Ultimately, 92 studies met the inclusion criteria and were analysed to pinpoint significant epigenetic changes with clinically relevant potential in PTSD. the selected studies explored histone modifications, CpG sites, single nucleotide polymorphisms (SNPs), and miRNA biomarkers. Specifically, nine studies examined epigenetic markers, detailing the influence of methylation on chromatin accessibility at histone positions H3K4, H3K9, and H3K36 within a PTSD context. Seventy-three studies investigated DNA methylation, identifying 20 hypermethylated and five hypomethylated cpG islands consistently observed in PtSD participants. Nineteen studies linked 88 SNPs to PtSD, with only one SNP replicated within these studies. Furthermore, sixteen studies focused on miRNAs, with findings indicating 194 downregulated and 24 upregulated miRNAs were associated with PTSD. Although there are epigenetic mechanisms that are significantly affected by PTSD, a granular deconstruction of these mechanisms elucidates the need to incorporate more nuanced approaches to identifying the factors that contribute to PTSD. technological advances in diagnostic tools are driving the need to integrate detailed participant characteristics, trauma type, genetic susceptibilities, and best practices for robust reporting. this comprehensive approach will be crucial for enhancing the translational potential of PTSD research for clinical application.
... Epigenetic modifications have been linked to the development and persistence of PTSD symptoms. Studies have shown that trauma exposure can lead to changes in DNA methylation patterns in genes associated with the stress response, such as the glucocorticoid receptor gene (Yehuda et al., 2014). Additionally, alterations in histone modifications and non-coding RNAs have been observed in PTSD patients (Zovkic et al., 2013). ...
... For example, studies have identified specific DNA methylation patterns associated with depression, schizophrenia, and PTSD (Mill et al., 2008;Yehuda et al., 2014). These epigenetic modifications could serve as biomarkers for the early detection and diagnosis of these disorders. ...
Epigenetics in Psychiatry: Implications for Genomics, Evolution, Inheritance Patterns, and Biomarker Development
... Indeed, the notion of intergenerational trauma transmission, as examined by Yehuda et al. (2014), offers valuable understanding of how the unresolved childhood trauma experienced by the younger brother might impact his own family. His emotional disengagement and incapacity to demonstrate affection imply that he may be inadvertently maintaining a pattern of psychological susceptibility, impacting not just his own welfare but also the emotional growth of his unborn kid. ...
... The lack of resolution of psychological problems within the family poses a danger for the child to be exposed to the intergenerational transfer of trauma. The transmission of trauma, as proposed by Yehuda et al. (2014), encompasses not just firsthand experiences but also behavioural patterns, emotional reactions, and even biological processes. The emotional repression shown by the father and the anguish experienced by the mother may provide an emotionally unstable atmosphere, therefore causing the kid to internalize comparable patterns of emotional suppression, anxiety, or avoidance. ...
This case study employed a comprehensive, multidisciplinary diagnostic approach to assess the psychological, physiological, and social impacts on the two brothers. The methods used were: • Clinical Interviews: Semi-structured clinical interviews were conducted with both brothers to gather detailed information about their childhood experiences, emotional 1
... Some of these intergenerational effects have been linked to altered DNA methylation linked specifically to the presence of maternal or paternal PTSD in Holocaust survivors. For example, DNA methylation of the exon 1F promotor of the glucocorticoid receptor gene (nr3c1) was greater in adult offspring with paternal PTSD in the absence of maternal PTSD (Yehuda et al. 2014). In contrast, DNA methylation of this same locus was reduced in offspring with both paternal and maternal PTSD. ...
... However, genes affected by maternal and paternal PTSD were regulated in opposite directions, suggesting sex-specific parent-of-origin effects in the intergenerational effects to be observed in the children. That finding validated previously reported parent-oforigin epigenomic effects in studies of Holocaust survivors including the methylation modifications of the glucocorticoid receptor exon 1F promoter, which is downregulated by maternal PTSD and upregulated by paternal PTSD (Yehuda et al. 2014). Daskalakis et al. also highlighted a downregulation in gene expression of matrix metalloproteinase-8 (MMP-8) in Holocaust offspring (Daskalakis et al. 2021). ...
A close relationship between immune regulation and neuropsychiatric disorders is becoming more apparent. Studies have now uncovered key mechanisms for stress to manifest as physiological maladaptations. Stress is a persistent issue with broad-ranging implications for the mental and physical health of society, including its broad impact on immune health. Evidence shows that stress activates pro-inflammatory cytokine pathways that contribute to the long-term dysregulation of the hypothalamus-pituitary-adrenal axis. Within the past decade, preclinical discoveries have demonstrated multigenerational impacts of stress transmitted via the male germ line. While similar epigenetic processes exist in humans, the occurrence of intergenerational epigenetic inheritance in humans remains highly controversial. However, there is mounting evidence that a parental history of stress can be a risk factor for developing anxiety and depressive traits, leading to a more recent hypothesis that the parental history of exposures to stress also influences offspring immune function via epigenetic inheritance. In this regard, greater progress has been made in understanding the maternal influence while little is known of the paternal contribution. In this review, we will discuss the potential for non-genetic environmental factors (e.g. stress exposures) to compromise the male germline epigenetic constitution (e.g. non-coding RNA content and extent of DNA methylation) resulting in a compromised immunological state of health of their offspring.
... Further investigations on GR pathways demonstrated that the GR pathways can also control stress response across generations. Yehuda et al. conducted one of the pioneering studies in this field where the team revealed that offspring of fathers with PTSD exhibited higher GR-1F promoter methylation in the absence of maternal PTSD, whereas offspring of both parents with PTSD showed lower methylation levels [53]. Clustering analysis confirmed distinct effects of maternal and paternal PTSD on clinical outcomes, indicating differential mechanisms in the intergenerational transmission of trauma. ...
Over the past decade, numerous reports have highlighted intergenerational and even transgenerational epigenetic effects resulting from parental exposure to diets, toxins, and stress. In many cases, these parentally induced phenotypes do not seem to confer an obvious benefit, making it challenging to understand the evolutionary drivers behind them. In this perspective, we discuss recent observations in humans and rodents indicating that a parental infection or vaccination can enhance the offspring's ability to cope with infections. Such parental priming of their offspring's immune system and cellular defense would provide immediate protection to the newborn, offering a clear evolutionary advantage. Here, focusing mainly on paternal effects, we propose that a parentally induced inflammatory memory in the offspring could be the underlying mechanism for many of the reported inter‐ and transgenerational effects. Sperm‐borne RNA could be a triggering signal to initiate inflammatory pathways in early embryogenesis. This gene‐regulatory state would then be maintained via epigenetic mechanisms throughout each mitosis and last for the individual's lifetime. The accumulating understanding that diet, stress, toxins, and infections affect offspring health raises important questions about public health policies. There is an urgent need to understand what consequences different exposures during sensitive time windows have on future generations.
... 3 The dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, as reflected in altered cortisol (a glucocorticoid stress-regulating hormone) levels, has been proposed as a transmission mechanism that underlies the intergenerational transmission of trauma. 4,5 Most of the studies on this topic were conducted among the children of Holocaust survivors and focused primarily on maternal PTSD. 6,7 In this study, we sought to extend this line of research to an African sample by investigating the relationship between mothers' PTSD and depression, and their adult offspring's cortisol levels in Rwanda. ...
Background
Most studies on the influence of mothers’ trauma-related psychopathology on their offspring’s hypothalamic-pituitary-adrenal (HPA) axis functioning have been conducted in Western contexts. Furthermore, those studies have focused on the association between mothers’ post-traumatic stress disorder (PTSD) and their offspring’s HPA axis functioning. More research is needed among African populations exposed to mass violence to mitigate the intergenerational transmission of trauma.
Aim
To investigate the link between mothers’ PTSD and depression and their offspring’s basal cortisol level.
Setting
This cross-sectional study was conducted in two provinces of Rwanda (Kigali City and the Southern Province) among families of survivors of the 1994 genocide perpetrated against the Tutsi.
Methods
A total of 45 dyads of mothers and their adult offspring were recruited. They answered questionnaires that measured sociodemographic characteristics, trauma exposure, PTSD and depression symptoms. Participants also provided saliva samples for cortisol extraction.
Results
Mothers’ depression was negatively associated with their offspring’s overall basal cortisol level. There was no link between mothers’ PTSD and their offspring’s overall basal cortisol level. The relationship between the offspring’s overall basal cortisol level and their own psychopathology was not significant.
Conclusion
These preliminary findings showed an HPA axis disruption among offspring of mass violence-exposed and depressed mothers.
Contribution
This study contributes to the literature by showing that depression is a relevant correlate of neuroendocrine functioning and should be investigated more consistently in research on the intergenerational consequences of trauma exposure.
... This suggests that DNAm may be leveraged as a biomarker to identify those at highest risk of PTSD, even before trauma has occurred. Relatedly, a growing literature has provided evidence that prenatal exposures may shape differential risk for/resilience to PTSD [26][27][28] and/or leave DNAm imprints of trauma exposure that persist postnatally [29][30][31][32][33]. Of note, many of the persistent differences associated with prenatal trauma exposure occur in genes related to glucocorticoid signaling and hypothalamic-pituitaryadrenal (HPA) axis functioning [30][31][32]. ...
... For adults, therapy and long-term behavioral management strategies are essential to prevent the intergenerational and transgenerational transmission of trauma to offspring. 69,70 These approaches ensure a comprehensive strategy for addressing the impact of trauma across the lifespan. ...
The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss the diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry. Prim Care Companion CNS Disord 2025;27(3):24f03894. Author affiliations are listed at the end of this article.
... Low levels of cortisol and a high level of the enzyme that breaks it down in the bodies of children of war victims make them less adapted to life in their environment than their peers. This explains the fact that descendants of war survivors are more likely to develop post-traumatic stress disorder 50 . It would therefore be worthwhile to investigate in future studies whether children of mothers with low cortisol levels in early pregnancy are more susceptible to the negative consequences of stress. ...
The first months after childbirth are a tremendous challenge for women and, consequently, a time when women’s mental health problems often arise. Knowledge of the prenatal predictors of these problems is of fundamental importance in preventing them. This study aimed to test whether first trimester hair cortisol influenced maternal postpartum depressive symptoms. The women ( N = 75) were tested twice: in the first trimester of pregnancy and within three months after giving birth. In the first trimester, they had hair samples taken and were examined using a sociodemographic survey and questionnaires: the Edinburgh Postnatal Depression Scale (EPDS), the Perceived Stress Scale (PSS-10), and the Zimbardo Time Perspective Inventory. After delivery, women completed a survey about the course of delivery and their child’s health, EPDS, and PSS-10. Low hair cortisol concentration in the first trimester was a predictor of a high level of postpartum depressive symptoms. This relationship was mediated by fatalistic time perspective. The results suggest that low hair cortisol concentration in the first trimester of pregnancy indicates a high probability of postpartum depression, and that low levels of cortisol may be associated with passivity, a sense of lack of control, and helplessness.
... ( continued on next page ) Elevated cortisol levels cause stress-related memory recall, which connects maternal trauma with postpartum suffering [ 30 ]. ...
This study introduces the BPS Materno-Semiotics Framework, an innovative methodological approach that combines the Biopsychosocial (BPS) Model (Engel, 1977) with Semiotic Analysis (Barthes, 1964) to examine how films construct maternal distress. The portrayal of maternal or postpartum mental health in films continues to be crucial yet an underexplored area in the interdisciplinary studies. Studies that already exist don't combine cultural symbolism or psychological realism into a single analytical framework (Mayang & Aziz, 2023). This study bridges the gap and uses the movie Nightbitch (2024) as an example to show how biological, psychological, and social factors interact with cultural ideas about motherhood in film narratives.
This comprehensive tool is useful for academics and filmmakers to evaluate how film influences public views of motherhood. It is flexible to be modified to analyse themes including mental health, workplace stress, and gender roles on other media portrayals.•This study offers a multifaceted methodology for the analysis of motherhood and mental health topics.
•By integrating clinical psychology and cultural studies, this study provides an interdisciplinary framework.
•This holistic tool enables to perform a dual-lens analysis that examines the psychological realities of parental inadequacies and the socio-cultural myths weaved into film portrayals.
... Moreover, maternal HPA axis dysregulation and increased maternal stress, for example, resulting from sequelae of maternal childhood trauma, such as psychiatric disorders, might result in an unfavourable intrauterine environment for the fetus, which could lead to the de novo production of epigenetic marks (Buss et al. 2017;Lindsay et al. 2020). Indeed, previous research has found associations between maternal stress during pregnancy, in the form of trauma exposure or a psychiatric disorder, to be associated with epigenetic alterations of the glucocorticoid receptor gene (NR3C1) (Palma-Gudiel et al. 2015;Yehuda et al. 2014). Such alterations could then affect HPA axis development and thus postnatal HPA axis functioning in children of childhood trauma-exposed mothers. ...
Childhood trauma experiences can carry over to the next generation, affecting the health and behavior of survivors’ children. However, the mechanisms underlying these intergenerational effects of childhood trauma are not yet clear. One mechanism may be changes in children's hypothalamic–pituitary–adrenal (HPA) axis. This preregistered longitudinal study examined associations between 170 mothers’ childhood trauma experiences (maltreatment, family and peer violence) and their children's cortisol reactivity and total circadian cortisol output at 12 months and 6 years of age. Multilevel regression analyses revealed that maternal childhood trauma was not significantly associated with child cortisol reactivity or total circadian cortisol output, neither at 12 months nor at 6 years of age. Thus, we found no evidence in this community sample that maternal childhood trauma impacts young children's HPA axis functioning. Exploratory analyses revealed moderation effects of maternal prenatal psychopathology and prenatal circadian cortisol slope: in mothers with high prenatal psychopathology or circadian cortisol slope, maternal childhood trauma was positively associated with child total circadian cortisol output, while this association was negative in mothers with low psychopathology or circadian cortisol slope. Future research should replicate these findings in older children and more severely trauma‐exposed populations and further explore moderators of this intergenerational association.
... Rachel Yehuda, a New York-i Mount Sinai Egyetem orvosi karának idegtudomány-és pszichiátriaprofesszora jelentős munkássággal rendelkezik e téren. A holokauszt-túlélőknél és utódjaiknál vizsgálta a PTSD neurobiológiáját (Yehuda, Daskalakis, Lehrner, Desarnaud, Bader, Makotkine, Flory, Bierer és Meaney, 2014). Wolynn könyvében olvashatjuk a következőt Yehuda eredményeiről: "Yehuda és csapata leírta, hogy a PTSD-ben szenvedő holokauszt-túlélők gyermekei a szüleikhez hasonlóan alacsony kortizolszinttel születtek, ami hajlamossá teszi őket a korábbi generáció PTSD-tüneteinek újraélésére" (2016. ...
A deviáns viselkedések kialakulásának folyamatát számos tényező befolyásolja. Jelen tanulmány középpontjában a családi hatások állnak, melyek meghatározó szerepet játszanak az egyén személyiségfejlődésében. A családi közegben szerzett tapasztalatok, a nevelési stílusok és a kötődési minták mind jelentős mértékben formálják viselkedésünket és személyiségünket. Különösen fontos szerepet kap a tanulmányban az epigenetika, amely a genetikai változások szintjén vizsgálja a családi hatások hatásmechanizmusait. Ezen kívül a transzgenerációs vonatkozások is kiemelt figyelmet kapnak, mivel bemutatják a múltbeli események és élmények hosszú távú hatását az egyéni fejlődésre. A kutatás célja tehát annak bemutatása, hogy a családi hatások döntő szerepet játszanak a devianciák kialakulásában.
... Bhattacharya et al. (2019) identified DNA methylation as pivotal in epigenetic transmission, where environmental trauma modifies gene expression without altering DNA sequences. Yehuda et al. (2014) provided compelling evidence from Holocaust survivors' offspring, revealing increased vulnerability to stress disorders due to glucocorticoid receptor gene methylation. Mbarki (2024) highlights methylation changes that manifest in people living with PTSD, with enduring effects on offspring. ...
Afghan refugees are at the forefront of international attention amidst the unfolding global refugee crisis. Having borne witnesses to the horrors of war, fled their homeland, and endured the tragic loss of loved ones, they suffered a psychological trauma that reshaped their cognitive and emotional frameworks. This cross-sectional survey explores the prevalence and comorbidity of posttraumatic stress disorder and posttraumatic obsessive-compulsive disorder among Afghan refugees living in Haripur, Pakistan, and the intergenerational transmission of PTSD across their three generations. Researchers collected data from 48 male participants representing three generations of 16 Afghan refugee families using the Obsessive-Compulsive Inventory-Revised and the Posttraumatic Diagnostic Scale for DSM-5-TR. The findings revealed a significant positive correlation between posttraumatic obsessive-compulsive disorder and posttraumatic stress disorder, indicating a substantial co-occurrence of posttraumatic obsessive-compulsive disorder and posttraumatic stress disorder. About 79.20% of total participants were diagnosed with posttraumatic obsessive-compulsive disorder, and it was more prevalent among the first generation (87.5%) than in the second and third generations (75.0%) each—additionally, significant variability across generations in the prevalence of PTSD. The first-generation refugees experienced severe and very severe symptoms (12.5%), the second-generation experienced moderate symptoms, and the third-generation experienced mild symptoms (16.6%). These results emphasize the importance of addressing the comorbidity of both disorders in refugee communities to underscore their intergenerational adverse mental health outcomes.
... Social and interpersonal relationships suffer as well, with individuals experiencing social defeat stress often struggling with trust issues and social withdrawal (Heinrich & Gullone, 2006). Furthermore, the intergenerational effects of chronic social stress, potentially transmitted through epigenetic mechanisms, suggest that the children of affected individuals may also be at higher risk for mental health problems (Yehuda et al., 2014). ...
The World Health Organization anticipated major depressive disorder to become the primary contributor to the global burden of disease by 2023. Chronic psychological stress directly impacts synaptic plasticity and the formation of stress-associated memories, contributing to a predisposition to depression. Conversely, research suggests that environmental enrichment, promoting physical activity, social interaction, and sensory stimulation, positively influences neurocognitive functions. However, there is a paucity of studies examining the effects of environmental enrichment on learning and memory in chronic social defeat stress (CSDS) models. Male C57BL/6N mice were (n=5) housed in enriched environments for 30 days before undergoing daily social defeat stress by ICR strain aggressor mice over 10 days. Depressive-like behavior was assessed using the forced swim test (FST) and tail suspension test (TST). Memory and learning functions were evaluated through the Y-maze and novel object recognition (NOR) tests. Brain tissues were subjected to Hematoxylin and Eosin staining to examine histological alterations in the hippocampal region. Environmental enrichment significantly alleviated depressive-like behavior in mice subjected to CSDS. Dysfunctions in spatial working memory and recognition memory as well as hippocampal degeneration induced by CSDS were notably improved in mice exposed to environmental enrichment as compared to those without exposure. This study highlights the significance of environmental enrichment preconditioning in ameliorating memory and learning impairments induced by CSDS.
... Regarding the influence of parental gender, maternal and paternal PTSD had a significant relationship with NR3C1 gene promoter 1F methylation. Having a father with PTSD in the absence of maternal PTSD demonstrates higher methylation of the 1F promoter in offspring, and lower methylation is characteristic of cases where both parents have PTSD [69]. ...
Background: Post-traumatic stress disorder (PTSD) can occur after a traumatic event. PTSD is characterized by nightmares, flashbacks and avoidance of stressors. It currently affects 2–8% of the population, with military personnel particularly susceptible. Studies show that environmental stressors can induce various epigenetic changes that shape the PTSD phenotype. Despite the significant impact of epigenetic factors on PTSD symptoms and susceptibility, they have not been widely discussed in the literature. This review focuses on describing epigenetic mechanisms in PTSD, especially DNA methylation, chromatin regulation, and noncoding RNA. Summary: The article includes relevant studies published from 2013 to 2023, excluding non-English-language studies or studies with insufficient data. This review investigated gene methylation changes in association with PTSD, including those related to the hypothalamic-pituitary-adrenal axis, brain-derived neurotrophic factor, neurotransmitters, and immune system functioning, as well as the role of histones and regulatory noncoding RNAs. Key Messages: Epigenetic alterations play a crucial role in shaping PTSD susceptibility, symptomatology, and long-term outcomes, highlighting their potential as important markers and therapeutic targets. Understanding these alterations can aid in developing clinical strategies to better predict, prevent, and treat PTSD. However, further large-scale longitudinal studies are needed to establish the temporal relationship between epigenetic changes and the onset of PTSD, as well as to classify other potential epigenetic mechanisms.
... However, this explanation may not fully account for the psychological processes involved in internalizing trauma-related beliefs. The role of implicit transmission, as described by Yehuda et al. (2014), suggests that trauma-related behaviors and emotions can be unconsciously communicated through non-verbal cues, emotional responses, and relational patterns. The transition to more implicit transmission mechanisms in the parent generation reflects the changing nature of trauma transmission, where religious values are no longer overtly imposed but continue to exert influence through family dynamics. ...
This study explores the intergenerational transmission of religious trauma across three generations within five families, combining qualitative and quantitative approaches to capture the complexities of trauma manifestation, transmission mechanisms, and coping strategies. The findings reveal significant generational differences in trauma awareness, with the grandparent generation showing lower recognition of trauma impacts compared to heightened awareness in the parent generation. Adult children exhibit residual emotional effects despite reduced religious adherence. The results suggest that trauma transmission shifts from explicit religious control to more implicit family dynamics across generations. Therapeutic implications include tailored approaches for each generational cohort, integrating cognitive, psychodynamic, and mindfulness-based therapies. The study also calls for a broader conceptualization of religious trauma as a form of cultural trauma that encompasses familial and cultural influences. Limitations are acknowledged, with recommendations for future research to include diverse samples and longitudinal studies.
... Furthermore, as a result of the transgenerational transmission, epigenetic modifications that have occurred in the parents in the face of highly impactful events can be inherited by the offspring without having direct experience of them, with consequences also on attachment (Fujiwara et al., 2019). Among the genes implicated in the transmission of epigenetic alterations is the NR3C1 gene for glucocorticoid receptors (Yehuda et al., 2014;Conradt et al., 2018;Sosnowski et al., 2018). The same gene was found to be involved in the attachment process as children who had this highly methylated gene and experienced less supportive maternal care had high levels of attachment anxiety (Bosmans et al., 2018). ...
Attachment is one of the foundational themes in the history of the psychological development of human beings. For this reason, we assume that it must be approached by taking into account multiple scientific perspectives. The present review aims at analyzing the state of the art regarding the genetic, neurobiological and cognitive mechanisms underlying the development of attachment bonding, considering the child as the frame of reference. We hypothesize that attachment may be present in prototypical forms even in the prenatal period, thus our analysis has a temporal origin in the intrauterine period preceding birth. The intrauterine period is assumed to be a period of maximum sensitivity to stimuli and in particular to those coming from a potential primary caregiver: the biological mother. We conclude with a reframing of the state of the art and propose that future research work would benefit from a superordinate model of attachment, capable of containing and regulating all its components and variables.
... Parental trauma exposure has been shown to be associated with trauma in descendants, particularly with childhood emotional abuse (23). Unfortunately, it has been difficult to separate the effects of parental exposure from those potentially conferred by the early-life influences of descendants (24). This is difficult to investigate as parents and children have not been studied at the same time, making it a demanding task to elucidate the origin of changes in parental exposure. ...
... A tempting research avenue might be parallel with the analysis performed for the inter-and transgenerational transmission of stress-induced effects. In this paradigm, the brain glucocorticoid receptor has been reported as a target of epigenetic modifications mediating the outcome of stress intervention and vanishing through generations probably depending on the intensity of the original stimulus (Yehuda et al., 2014(Yehuda et al., , 2016. This model might be used to analyze brain IGF1, BDNF, or VEGF receptors (among other factors) as these have been long reported as targets of exercise interventions mediating the effects on AHN (for a recent review, see Kraemer and Kraemer, 2023). ...
Physical exercise is a robust lifestyle intervention known for its enhancement of cognitive abilities. Nevertheless, the extent to which these benefits can be transmitted across generations (intergenerational inheritance to F1, and transgenerational to F2 and beyond) remains a topic of limited comprehension. We have already shown that cognitive improvements resulting from physical exercise can be inherited from parents to their offspring, proving intergenerational effects. So, we set out to explore whether these enhancements might extend transgenerationally, impacting the F2 generation. In this study, we initially examined the behavioral traits of second generation (F2) male mice, whose grandfathers (F0) had an exercise intervention. Our findings revealed that F2 mice with physically active grandpaternal F0 progenitors displayed significantly improved memory recall, encompassing both spatial and non-spatial information when compared to their counterparts from sedentary F0 progenitors, and proving for the first time the transgenerational inheritance of physical exercise induced cognitive enhancement. Surprisingly, while F2 memory improved (as was the case with F1), adult hippocampal neurogenesis remained unchanged between experimental and control groups (unlike in F1). Additionally, our analysis of small RNA sequences in the hippocampus identified 35 differentially expressed miRNAs linked to important brain function categories. Notably, two of these miRNAs, miRNA-144 and miRNA-298, displayed a robust negative correlation with cognitive performance. These findings highlight the enduring transgenerational transmission of cognitive benefits associated with exercise, even after two generations, suggesting that moderate exercise training can have lasting positive effects, possibly orchestrated by a specific set of miRNAs that exert their influence across multiple generations.
... There are indications, for example, that war-related mental stress can affect descendants' disposition to develop trauma-related vulnerabilities. Children of Vietnam veterans had an increased risk of post-traumatic stress disorder (PTSD) of 5-fold for sons and 3-fold for daughters (O'Toole et al. 2017), the children of Holocaust survivors are more prone to develop PTSD than control groups (Yehuda et al. 2014;Yehuda and Lehrner 2018), and even the short stress of the September 11th attack seems to have led to behavioural changes in the children of the pregnant women who became acutely stressed while witnessing it (Sarapas et al. 2011). A genome-wide study of DNA methylation patterns in the sperm of trauma-exposed Vietnam veterans showed changes in DNA methylation in regions that that have been previously implicated in PTSD, and some of these epigenetically altered sites were significantly associated with a reported history of a diagnosed mental health condition in the children of these veterans. ...
The notion of well-being is relative to the needs of organisms, both non-human and human. I argue that what we have learned about development, animal consciousness and ecological interrelations requires an evolution-informed extension of the way we think about well- and ill-being. Studies of epigenetic inheritance, mostly in animals, but also in humans, show that the effects of both stress and well-being go deeper ‘under the skin’ and extend further into the future than we thought. Studies of animals’ consciousness suggest that welfare considerations should be extended to many more animal species than most of us imagined. Technological innovations and ecological studies show that well-being depends critically, far more than we anticipated, on global social and environmental politics, social justice and the uses of technology.
... Of note, the present study innovatively employed prospective assessment of preconception and prenatal factors, thereby allowing for temporally ordered, rigorous tests of mechanistic pathways linking preconception factors to child outcomes. Although prenatal stress and cortisol did not mediate predictions of child temperament profiles from preconception stress, it is plausible that preconception stress operates through other unmeasured prenatal pathways (e.g., inflammatory processes; Hantsoo et al., 2019;Nazzari & Frigerio, 2020) or pathways that are independent of prenatal factors (e.g., germline epigenetic mechanisms; Bowers & Yehuda, 2016;Chan et al., 2018;Yehuda et al., 2000Yehuda et al., , 2014Yehuda & Lehrner, 2018). Ultimately, these findings underscore the importance of applying life course perspectives to better understand how preconception factors shape offspring development (Keenan et al., 2018). ...
Although maternal stress during pregnancy and even before conception shapes offspring risk for mental health problems, relatively little is known about the mechanisms through which these associations operate. In theory, preconception and prenatal stress may affect offspring mental health by influencing child responses to postnatal caregiving. To address this knowledge gap, this study had two aims. First, we examined associations between preconception and prenatal stress with child temperament profiles at age four using multilevel assessment of maternal perceived stress and stress physiology. Second, we tested child temperament profiles as moderators of associations between observed parenting behaviors during a parent–child free-play interaction when children were 4 years old and child behavior problems 1 year later. Latent profile analyses yielded four distinct child temperament profiles: inhibited, exuberant, regulated low reactive, and regulated high reactive. Consistent with hypotheses, preconception, and prenatal stress each independently predicted the likelihood of children having temperament profiles characterized by higher negative emotionality and lower regulation. Specifically, preconception perceived stress and prenatal cortisol predicted likelihood of children having an exuberant temperament, whereas prenatal perceived stress predicted likelihood of children having an inhibited temperament. Contrary to hypotheses, temperament profiles did not moderate predictions of child behavior problems from observed parenting behaviors; however, responsive parenting behaviors inversely predicted child behavior problems independently of child temperament. These findings add to growing evidence regarding effects of preconception factors on child outcomes and underscore a central role for responsive parenting behaviors in predicting more favorable child mental health independent of child temperament.
The aftermath of the Holocaust has been long and wide-reaching. Any act of mass murder and genocide leaves powerful traces: the trauma of the survivors, the challenge of punishment for the perpetrators and justice for the victims, and questions of how to properly commemorate and memorialize the loss and how to rebuild and restore. This is all the more true for the Holocaust, which has come to serve as a global cultural touchstone for evaluating mass violence. The legacy of the Holocaust has impacted every area of political and cultural life in many different countries since 1945. What is the state of aftermath studies for the Holocaust? How do we periodize the post-Holocaust landscape? Where are there continuities and where are there changes? How, when, and where has the Holocaust been globalized? In what areas did the Holocaust generate a fundamental rethinking of human relations and state institutions? And where did it not? This volume offers a comprehensive, interdisciplinary account of the impact and legacy of the Holocaust around the world and demonstrates its enduring significance, from the postwar period to the present day.
The repetition of child abuse and neglect over generations has been extensively observed and researched, however the problem remains poorly understood and narrowly conceptualised. This discussion, which is loosely centred on the Australian child protection context, examines the wider research on intergenerational trauma and resilience in other cohorts of survivors and goes on to consider the potential implications of this knowledge for child protection policy and practice. It reveals that an ancestor’s experiences of harm and adversity may result in non-deterministic vulnerabilities toward trauma-related symptomology in descendants which is often activated in times of stress or perceived threat, including parenthood and statutory child protection interventions. The indivisibility of intergenerational trauma and recovery is also evident in the literature, signposting resilience and recovery strategies that may be utilised and further developed to support families when there has been harm to children over generations. Overall, the broader knowledge on intergenerational trauma has the scope to shape more holistic, empathetic, pre-emptive, and strength-focused approaches within contemporary child protection contexts.
Stress is a ubiquitous facet of life. Ranging in form (e.g., psychosocial, physical, nutritional, economic) and longevity (e.g., acute, chronic), stressors affect the biology of those directly in their line of attack. As is becoming increasingly appreciated, the pernicious effects of stress echo across generations (Dias et al. 2015; Yehuda and Lehrner 2018; Jawaid et al. 2021; Dion et al. 2022; Zhou and Ryan 2023; Dias 2024). With a focus on learning and memory, this chapter addresses how stressors derail learning and memory in the generation directly exposed to them andin future generations. To do so, with a specific emphasis on associative fear conditioning in humans and rodents, we touch upon the relevance of extinction training in the aftermath of such conditioning and the recall of such extinction training as windows into normative and disrupted learning. Next, we briefly discuss underlying neuroanatomical substrates mediating these processes. We then draw attention to influences of postnatal, in utero, and pre-conceptional stress on learning and memory across generations. Finally, we briefly outline biological factors that underlie how learning and memory is derailed by these stressors.
This article examines the intergenerational trauma resulting from the 1977 coup d'état in Seychelles, revealing how the psychological impacts experienced by victims continue to affect their descendants. The study highlights that trauma has manifested in the children of victims as anxiety, depression, and a pervasive sense of insecurity, underscoring the complex nature of healing in post-conflict societies. Through analysis of diverse emotional responses to the truth commission, ranging from relief to re-traumatization, the article illustrates the challenges of achieving collective healing. A significant collective call for reparations and justice has emerged, emphasizing the need for acknowledgment, accountability, and comprehensive redress to foster reconciliation. The study advocates for the implementation of holistic support systems, including psychological counselling, legal assistance, and community engagement initiatives tailored to the needs of affected populations. By exploring the transmission of trauma across generations, this research offers practical recommendations for breaking the cycle of suffering and promoting resilience within Seychelles. The findings have broader implications for other post-conflict societies, demonstrating the importance of integrating mental health care, justice mechanisms, and public acknowledgment of historical injustices into post-conflict recovery efforts. This work contributes to a deeper understanding of the enduring impacts of political violence and the critical need for comprehensive approaches to healing that address both individual and collective dimensions of trauma to foster a more just and resilient future.
Objective
The aim of this work is to verify whether a cohort of elderly people with hyper-energy tended to increase depressive symptoms and misaligned social and personal rhythms during the lockdown compared to a cohort of older adults without hyper-energy one year before the lockdown.
Methods
The two cohorts were evaluated in April 2019 (T0) and in April 2020 (T1). Hyper-energy, cognitive performance, depressive symptoms, and social and personal rhythms were evaluated at T0 and T1.
Results
In the measure of the Brief Social Rhythm Scale (BSRS) score, the differences between groups in the two observation times reach statistical significance. The sub-group with previous hyper-energy at T0 but no longer having hyper-energy at T1 increases the score by more than 5 points (a higher score indicates greater rhythm dysregulation, thus having a worse regulation of rhythms at T1), while in those individuals who didn’t have hyper-energy, the score remains substantially unchanged (+0.06). However, if the increase in the score from T0 and T1 is measured, both groups with hyper-energy at T0 presented a greater mean increase compared to people who did not have hyper-energy at T1. In the total of the eleven elderly people with hyper-energy at T0, the mean increase in BSRS score was 1.05±1.19 versus 0.06±0.98 (F=9.407, P=0.003), and in people who no longer had hyper-energy at T1, it was 1.05±1.19 versus 5.50±3.83 (F=105.0, P<0.0001). In people with hyper-energy at T0, the mean increase in the Patient Health Questionnaire-9 (PHQ-9) score was 0.72±0.75 versus 0.01±0.28 (F=37.153, P<0.0001). The gain was even higher in people who no longer had hyper-energy at T1, 1.38±1.03 vs . 0.01±0.28 (F=87.386, P<0.0001). An inverse linear correlation was found between energy perception (measured as the score of Item 10 of SF-12) and the score of PHQ-9 measuring depressive symptoms both at T0 and, more strongly, at T1, as well as with the BSRS scores, but only at T1.
Conclusion
The study, despite the limitations of a small sample, seems to confirm a greater vulnerability to the lockdown situation in people with hyperactivity, even in the absence of psychopathology (i.e., part of the bipolar spectrum).
Stress is a fundamental adaptive response mediated by the amygdala and Hypothalamus-Pituitary-Adrenal (HPA) axis. Extreme or chronic stress, however, can result in a multitude of neuropsychiatric disorders, including anxiety, paranoia, bipolar disorder (BP), major depressive disorder (MDD), and Post-Traumatic Stress Disorder (PTSD). Despite widespread exposure to trauma (70.4%), the incidence of PTSD is relatively low (6.8%), suggesting that either individual susceptibility or adaptability driven by epigenetic and genetic mechanisms are likely at play. PTSD takes hold from exposure to traumatic events, such as death threats or severe abuse, with its severity being impacted by the magnitude of trauma, it's frequency, and the nature. This comprehensive review examines how traumatic experiences and epigenetic modifications in hypothalamic pituitary axis (HPA), such as DNA methylation, histone modifications, non-coding RNAs, and chromatin remodeling, are transmitted across generations, and impact genes like FKBP5, NR3C1, BDNF, and SLC6A4. It also provides a comprehensive overview on trauma reversal, resilience mechanisms, and pro-resilience factors such as HATs/HDACs ratio, DHEA/Cortisol ratio, testosterone levels, and neuropeptide Y, thus highlighting potential therapeutic approaches for trauma-related disorders. The studies highlighted here underscore the narrative, for the first time, that the examination and treatment of PTSD and other depressive disorders must invoke a multitude of approaches to seek out the most effective and personalized strategies. We also hope that the discussion emanating from this review will also inform government policies directed towards intergenerational trauma and PTSD.
המאמר דן במונח הדיסוציאציה, סימפטום פוסט־טראומטי נפוץ, דרך משקפיים ביקורתיים ופמיניסטיים, ומציע המשגה תיאורטית של ניתוק חברתי (דיסוציאציה חברתית) מהיבטים טראומטיים של היות קורבן או מקרבֵּן, ניתוק הנדרש כדי להמשיך ולתפקד כחברה. על בסיס מקרה הבוחן של נשים מזרחיות והמפגש שלהן עם שירותי הרווחה ובריאות הנפש הציבוריים, המאמר עוסק בנראות של דיסוציאציה במופע החברתי שלה ובטראומות החברתיות שגרמו להיווצרותה, ושואל את מי משרתים תהליכים של דיסוציאציה חברתית וכיצד תהליכי טיפול מסייעים לשימור של יחסי כוחות חברתיים. עוד נבדקים האופנים שבהם מזרחיות בחברה הישראלית היא טראומה, שדיסוציאציה היא אחד הסימפטומים הבולטים שלה. המאמר מציג חשיבה ביקורתית על תהליכי בנייה של טיפול ומודעוּת לתהליכי דיסוציאציה חברתיים, ומציע להשתמש בכך כפרקטיקה שעשויה לסייע לחיבור פנימי וחברתי כאחד.
Post-traumatic stress disorder is a mental disorder that is closely associated with dysfunction of the hypothalamic-pituitary-adrenal axis, and for its development is required the experience of a traumatic event that causes negative emotions and memories that persist for quite a long time. The likelihood of development of post-traumatic stress disorder is influenced both environmental factors, and genetic and epigenetic characteristics of the body. In this case epigenetic modifications act as dynamic biomarkers (“nanotags”) of the impact of the environment on the genome (epigenome), which can, under certain conditions, disappear or remain not only in an individual directly exposed to psychogenic trauma, but also transmitted over a number of generations. Review focuses on the possible mechanisms of intergenerational and transgenerational inheritance of the biological effects of post-traumatic and stress-related disorders.
Paternal health and exposure to adverse environments in the period prior to conception have a profound impact on future generations. Adversities such as stress, diet, and toxicants influence offspring health. Emerging evidence indicates that epigenetic mechanisms including noncoding RNA, DNA methylation, and chromatin remodelling mediate these effects. Preclinical studies have contributed to advancing mechanistic understanding in the field; however, human research is limited and primarily observational. Here, we discuss the evidence linking paternal to offspring health and advocate for further research in this area, which may ultimately inform policy and healthcare guidelines to improve paternal preconception health and offspring outcomes.
Cet article offre aux professionnels de santé un aperçu de la recherche sur le contrôle coercitif, concept central pour comprendre la violence conjugale et intrafamiliale, visant majoritairement
femmes et enfants. z Il a pour objectif de favoriser le dialogue interdisciplinaire et l’intégration des avancées scientifiques dans les pratiques professionnelles et la (psycho)éducation. Pour ce faire, il aborde l’évolution conceptuelle du contrôle coercitif et le schéma comportemental des agresseurs, les risques pour les victimes et les professionnels, l’impact dévastateur sur les droits et la santé biopsychosociale des victimes adultes et enfants, ainsi que les défi s posés par la technologie, notamment l’intelligence artificielle générative._______
Coercive control: Health, victims’ rights and the ethics of care. This article provides healthcare professionals with an overview of research on coercive control, a central concept for understanding
domestic violence, primarily targeting women and children. It aims to foster interdisciplinary dialogue and integrate advances into professional practices and (psycho)education. To this end, it addresses the conceptual evolution of coercive control and the behavioral patterns of perpetrators, the risks for victims and professionals, the devastating impact on the rights and biopsychosocial health of adult and child victims, and the challenges posed by technology, particularly generative artificial intelligence.
Background
For more than a century, scientists have tried to find the key to causation of mental ill health in heredity and genetics. The difficulty of finding clear and actionable answers in our genes has not stopped them looking. This history offers important context to understanding mental health science today.
Methods
This article explores the main themes in research on genetics and inheritance in psychiatry from the second half of the nineteenth century to the present day, to address the question: what is the history of genetics as a causative explanation in mental health science? We take a critical historical approach to the literature, interrogating primary and secondary material for the light it brings to the research question, while considering the social and historical context.
Results
We begin with the statistics gathered in asylums and used to ‘prove’ the importance of heredity in mental ill health. We then move through early twentieth century Mendelian models of mental inheritance, the eugenics movement, the influence of social psychiatry, new classifications and techniques of the postwar era, the Human Genome Project and Genome Wide Association Studies (GWAS) and epigenetics. Setting these themes in historical context shows that this research was often popular because of wider social, political and cultural issues, which impacted the views of scientists just as they did those of policymakers, journalists and the general public.
Conclusions
We argue that attempting to unpick this complex history is essential to the modern ethics of mental health and genetics, as well as helping to focus our efforts to better understand causation in mental ill-health.
For a succinct timeline of the history of psychiatric genetics, alongside the history of other proposed causes for mental ill-health, visit: https://historyofcauses.co.uk/
Aim
Parental adverse childhood experiences (ACE) might affect the offspring health through intergenerational inheritance. The aim of this study was to investigate how paternal ACE associate with offspring sensitisation and allergic rhinitis (AR).
Methods
The study included 590 Finnish father‐child dyads from the FinnBrain Birth Cohort Study. Outcomes were offspring sensitisation against allergens and AR at age 5.5 years. Paternal ACE up to 18 years were assessed using the Trauma and Distress Scale (TADS) with the lowest quarter as the reference group.
Results
Of the children, 317 (54%) were males. Sensitisation occurred in 162/533 (30%) and AR in 122/590 (21%). Paternal TADS (median 17 points; interquartile range 11–27) was inversely associated with the risk of sensitisation. Children whose fathers scored the highest quarter had the lowest risk of sensitisation (adjusted odds ratio 0.42; 95% confidence interval 0.24–0.75), followed by those in the second highest quarter (0.58; 0.34–0.99). The association between the highest quarter and reduced risk of AR was similar.
Conclusion
Paternal ACE were associated with a low risk of offspring sensitisation and AR, suggesting paternal childhood stress might influence immune responses in their offspring.
Considering the recent epigenetic studies on the transgenerational transmission of trauma, this article aims to 1) explore its ethical implications for the concept and nature of moral damage, and 2) offer normative suggestions on collective responsibilities both synchronic and diachronic. To do so, I first address recent epigenetic studies’ showing the crystallization of emotional information through generations, and second, defend that a unified approach to the concept of ghost damage may be useful to categorize this phenomenon, facilitate future research on this type of moral damage, and recognize its importance in the identification of hermeneutical injustice. Finally, I suggest that granting a right to transgenerational information may help avoid the perpetuation of inherited damage that jeopardize mental and physical health in the offspring.
Humans have evolved as a species with unique capabilities to destroy this world that we inhabit. Some of this destructiveness is a function of a loss of embodied wisdom and a dissociative
disconnection from the complex systems of life on the planet. Inaction about climate change is a failure to protect our children and can be considered institutional child abuse. Climate disasters,
along with other social injustices, traumatize all life on the planet, and disproportionately impact those already struggling with loss of community support. Fostering posttraumatic wisdom in youth requires recognition that some are vulnerable to maladaptive psychic numbing, while others manifest a resilience born from imagination and creativity.
Early-life adversities, whether prenatal or postnatal exposure, have been linked to adverse mental health outcomes later in life increasing the risk of several psychiatric disorders. Research on its neurobiological consequences demonstrated an association between exposure to adversities and persistent alterations in the structure, function, and connectivity of the brain. Consistent evidence supports the idea that regulation of gene expression through epigenetic mechanisms are involved in embedding the impact of early-life experiences in the genome and mediate between social environments and later behavioral phenotypes. In addition, studies from rodent models and humans suggest that these experiences and the acquired risk factors can be transmitted through epigenetic mechanisms to offspring and the following generations potentially contributing to a cycle of disease or disease risk. However, one of the important aspects of epigenetic mechanisms, unlike genetic sequences that are fixed and unchangeable, is that although the epigenetic markings are long-lasting, they are nevertheless potentially reversible. In this review, we summarize our current understanding of the epigenetic mechanisms involved in the mental health consequences derived from early-life exposure to malnutrition, maltreatment and poverty, adversities with huge and pervasive impact on mental health. We also discuss the evidence about transgenerational epigenetic inheritance in mammals and experimental data suggesting that suitable social and pharmacological interventions could reverse adverse epigenetic modifications induced by early-life negative social experiences. In this regard, these studies must be accompanied by efforts to determine the causes that promote these adversities and that result in health inequity in the population.
Posttraumatic stress disorder (PTSD) is a significant public health concern, with only a third of patients recovering within a year of treatment. While PTSD often disrupts the sense of body ownership and sense of agency (SA), attention to the SA in trauma has been lacking. This perspective paper explores the loss of the SA in PTSD and its relevance in the development of symptoms. Trauma is viewed as a breakdown of the SA, related to a freeze response, with peritraumatic dissociation increasing the risk of PTSD. Drawing from embodied cognition, we propose an enactive perspective of PTSD, suggesting therapies that restore the SA through direct engagement with the body and environment. We discuss the potential of agency-based therapies and innovative technologies such as gesture sonification, which translates body movements into sounds to enhance the SA. Gesture sonification offers a screen-free, noninvasive approach that could complement existing trauma-focused therapies. We emphasize the need for interdisciplinary collaboration and clinical research to further explore these approaches in preventing and treating PTSD.
Background For more than a century, scientists have tried to find the key to causation of mental ill health in heredity and genetics. The difficulty of finding clear and actionable answers in our genes has not stopped them looking. This history offers important context to understanding mental health science today. Methods This article explores the main themes in research on genetics and inheritance in psychiatry from the second half of the nineteenth century to the present day, to address the question: what is the history of genetics as a causative explanation in mental health science? We take a critical historical approach to the literature, interrogating primary and secondary material for the light it brings to the research question, while considering the social and historical context. Results We begin with the statistics gathered in asylums and used to ‘prove’ the importance of heredity in mental ill health. We then move through early twentieth century Mendelian models of mental inheritance, the eugenics movement, the influence of social psychiatry, new classifications and techniques of the postwar era, the Human Genome Project and Genome Wide Association Studies (GWAS) and epigenetics. Setting these themes in historical context shows that this research was often popular because of wider social, political and cultural issues, which impacted the views of scientists just as they did those of policymakers, journalists and the general public. Conclusions We argue that attempting to unpick this complex history is essential to the modern ethics of mental health and genetics, as well as helping to focus our efforts to better understand causation in mental ill-health.
The colonial war that Portugal was involved in between 1961 and 1974 had a significant impact on veterans and their families. However, it is unclear what the consequences of this war are, in particular with regard to levels of childhood maltreatment (CM) in offspring.
Our study aims to analyze the influences of fathers' war exposure and posttraumatic stress disorder (PTSD) on the offspring's CM and simultaneously test the hypothesis of the intergenerational transmission of father-child CM.
Cross-sectional data were collected, using the Childhood Trauma Questionnaire-Short Form, from 203 adult children and 117 fathers. Subjects were distributed according to three conditions based on the father's war exposure status: did not participate in war, or non-war-exposed (NW); participated in war, or war-exposed (W); and war-exposed with PTSD diagnosis (WP). The data were examined using correlations, variance/covariance, and regression analyses.
Children of war veterans with PTSD reported more emotional and physical neglect, while their fathers reported increased emotional and physical abuse exposure during their own childhood. Significant father-child CM correlations were found in the war veteran group but less in the war veteran with PTSD group. Father CM predicted 16% of offspring CM of children of war veterans.
The father's war-related PTSD might be a risk factor for offspring neglect but potentially a protective one for the father-child abuse transmission. War-exposed fathers without PTSD did transmit their own CM experiences more often. Therefore, father's war exposure and father's war PTSD may each be important variables to take into account in the study of intergenerational transmission of CM.
Epigenetic alterations offer promise as diagnostic or prognostic markers, but it is not known whether these measures associate with, or predict, clinical state. These questions were addressed in a pilot study with combat veterans with PTSD to determine whether cytosine methylation in promoter regions of the glucocorticoid related NR3C1 and FKBP51 genes would predict or associate with treatment outcome. Veterans with PTSD received prolonged exposure (PE) psychotherapy, yielding responders (n = 8), defined by no longer meeting diagnostic criteria for PTSD, and non-responders (n = 8). Blood samples were obtained at pre-treatment, after 12 weeks of psychotherapy (post-treatment), and after a 3-month follow-up. Methylation was examined in DNA extracted from lymphocytes. Measures reflecting glucocorticoid receptor (GR) activity were also obtained (i.e., plasma and 24 h-urinary cortisol, plasma ACTH, lymphocyte lysozyme IC50-DEX, and plasma neuropeptide-Y). Methylation of the GR gene (NR3C1) exon 1F promoter assessed at pre-treatment predicted treatment outcome, but was not significantly altered in responders or non-responders at post-treatment or follow-up. In contrast, methylation of the FKBP5 gene (FKBP51) exon 1 promoter region did not predict treatment response, but decreased in association with recovery. In a subset, a corresponding group difference in FKBP5 gene expression was observed, with responders showing higher gene expression at post-treatment than non-responders. Endocrine markers were also associated with the epigenetic markers. These preliminary observations require replication and validation. However, the results support research indicating that some glucocorticoid related genes are subject to environmental regulation throughout life. Moreover, psychotherapy constitutes a form of “environmental regulation” that may alter epigenetic state. Finally, the results further suggest that different genes may be associated with prognosis and symptom state, respectively.
Abstract Developmental plasticity models hypothesize the role of genetic and prenatal environmental influences on the development of the hypothalamic-pituitary-adrenal (HPA) axis and highlight that genes and the prenatal environment may moderate early postnatal environmental influences on HPA functioning. This article examines the interplay of genetic, prenatal, and parenting influences across the first 4.5 years of life on a novel index of children's cortisol variability. Repeated measures data were obtained from 134 adoption-linked families, adopted children and both their adoptive parents and birth mothers, who participated in a longitudinal, prospective US domestic adoption study. Genetic and prenatal influences moderated associations between inconsistency in overreactive parenting from child age 9 months to 4.5 years and children's cortisol variability at 4.5 years differently for mothers and fathers. Among children whose birth mothers had high morning cortisol, adoptive fathers' inconsistent overreactive parenting predicted higher cortisol variability, whereas among children with low birth mother morning cortisol adoptive fathers' inconsistent overreactive parenting predicted lower cortisol variability. Among children who experienced high levels of prenatal risk, adoptive mothers' inconsistent overreactive parenting predicted lower cortisol variability and adoptive fathers' inconsistent overreactive parenting predicted higher cortisol variability, whereas among children who experienced low levels of prenatal risk there were no associations between inconsistent overreactive parenting and children's cortisol variability. Findings supported developmental plasticity models and uncovered novel developmental, gene X environment, and prenatal X environment influences on children's cortisol functioning.
We tested the hypothesis that intergenerational effects of parents' war trauma on offspring's attachment and mental health are mediated by psychological maltreatment. Two hundred and forty children and their parents were sampled from a war-prone area, Gaza, Palestine. The parents reported the number and type of traumatic experiences of war they had had during their lifetime before the child's birth and during a current war when the child was 10-12 years old. The children reported their war traumas, experiences of psychological maltreatment, attachment security, and symptoms of posttraumatic stress (PTSS), depression, and aggression. The direct and indirect intergenerational effects of war trauma were tested in structural equation models. The hypotheses were confirmed for father's past war exposure, and disconfirmed for mother's war exposure. The father's past war trauma had a negative association with attachment security and positive association with the child's mental health problems mediated by increased psychological maltreatment. In contrast, the mother's past war trauma had a negative association with the child's depression via decreased psychological maltreatment. The mother's current war trauma had a negative association with the child's depression and aggression via decreased psychological maltreatment. Among fathers, past war exposure should be considered as a risk factor for psychological maltreatment of children and the associated attachment insecurity and mental health problems. Among mothers, war exposure as such could be given less clinical attention than PTSS in the prevention of psychological maltreatment of children.
Three studies, involving 146 undergraduates and 68 heterosexual couples, assessed the construct validity of the self- and other-model dimensions underlying the 4-category model of adult attachment. Five methods were used to assess the hypothesized dimensions: self-reports, friend-reports, romantic partner reports, trained judges' ratings of peer attachment, and trained judges' ratings of family attachment. Study 2 related the latent attachment dimensions to theoretically relevant outcome latent variables. As predicted, Ss' self models converged with direct measures of the positivity of their self-concepts, and Ss' other models converged with direct measures of the positivity of their interpersonal orientations. Study 3 related the latent attachment dimensions to 3 alternate self-report measures of adult attachment and showed that the 2 dimensions served as an organizing framework for the different measurement approaches. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Prenatal exposure to maternal stress can have lifelong implications for psychological function, such as behavioral problems and even the development of mental illness. Previous research suggests that this is due to transgenerational epigenetic programming of genes operating in the hypothalamic-pituitary-adrenal axis, such as the glucocorticoid receptor (GR). However, it is not known whether intrauterine exposure to maternal stress affects the epigenetic state of these genes beyond infancy. Here, we analyze the methylation status of the GR gene in mothers and their children, at 10-19 years after birth. We combine these data with a retrospective evaluation of maternal exposure to intimate partner violence (IPV). Methylation of the mother's GR gene was not affected by IPV. For the first time, we show that methylation status of the GR gene of adolescent children is influenced by their mother's experience of IPV during pregnancy. As these sustained epigenetic modifications are established in utero, we consider this to be a plausible mechanism by which prenatal stress may program adult psychosocial function.
Childhood maltreatment, through epigenetic modification of the glucocorticoid receptor gene (NR3C1), influences the hypothalamic–pituitary–adrenal axis (HPA axis). We investigated whether childhood maltreatment and its severity were associated with increased methylation of the exon 1F
NR3C1 promoter, in 101 borderline personality disorder (BPD) and 99 major depressive disorder (MDD) subjects with, respectively, a high and low rate of childhood maltreatment, and 15 MDD subjects with comorbid post-traumatic stress disorder (PTSD). Childhood sexual abuse, its severity and the number of type of maltreatments positively correlated with NR3C1 methylation (P=6.16 × 10−8, 5.18 × 10−7 and 1.25 × 10−9, respectively). In BPD, repetition of abuses and sexual abuse with penetration correlated with a higher methylation percentage. Peripheral blood might therefore serve as a proxy for environmental effects on epigenetic processes. These findings suggest that early life events may permanently impact on the HPA axis though epigenetic modifications of the NR3C1. This is a mechanism by which childhood maltreatment may lead to adulthood psychopathology.
A history of early adverse experiences is an important risk factor for adult psychopathology. Changes in stress sensitivity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the association between stress and risk for psychiatric disorders. Preclinical work in rodents has linked low levels of maternal care to increased methylation of the promoter region of the glucocorticoid receptor (GR) gene, as well as to exaggerated hormonal and behavioral responses to stress. Recent studies have begun to examine whether early-life stress leads to epigenetic modifications of the GR gene in humans.
We examined the degree of methylation of a region of the promoter of the human GR gene (NR3C1) in leukocyte DNA from 99 healthy adults. Participants reported on their childhood experiences of parental behavior, parental death or desertion, and childhood maltreatment. On a separate day, participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, a standardized neuroendocrine challenge test.
Disruption or lack of adequate nurturing, as measured by parental loss, childhood maltreatment, and parental care, was associated with increased NR3C1 promoter methylation (p<.05). In addition, NR3C1 promoter methylation was linked to attenuated cortisol responses to the Dex/CRH test (p<.05).
These findings suggest that childhood maltreatment or adversity may lead to epigenetic modifications of the human GR gene. Alterations in methylation of this gene could underlie the associations between childhood adversity, alterations in stress reactivity, and risk for psychopathology.
Maternal licking and grooming (LG) in infancy influences stress responsiveness and cognitive performance in the offspring. We examined the effects of variation in the frequency of pup LG on morphological, electrophysiological, and behavioral aspects of hippocampal synaptic plasticity under basal and stress-like conditions. We found shorter dendritic branch length and lower spine density in CA1 cells from the adult offspring of low compared with high LG offspring. We also observed dramatic effects on long-term potentiation (LTP) depending on corticosterone treatment. Low LG offspring, in contrast to those of high LG mothers, displayed significantly impaired LTP under basal conditions but surprisingly a significantly enhanced LTP in response to high corticosterone in vitro. This enhanced plasticity under conditions that mimic those of a stressful event was apparent in vivo. Adult low LG offspring displayed enhanced memory relative to high LG offspring when tested in a hippocampal-dependent, contextual fear-conditioning paradigm. Hippocampal levels of glucocorticoid and mineralocorticoid receptors were reduced in low compared with high LG offspring. Such effects, as well as the differences in dendritic morphology, likely contribute to LTP differences under resting conditions, as well as to the maternal effects on synaptic plasticity and behavior in response to elevated corticosterone levels. These results suggest that maternal effects may modulate optimal cognitive functioning in environments varying in demand in later life, with offspring of high and low LG mothers showing enhanced learning under contexts of low and high stress, respectively.
Although the link between chronic stress and the development of cardiovascular and metabolic diseases of adulthood has been known for some time, there is growing recognition that early environmental influences may result in developmental programming via epigenetic mechanisms, thereby affecting the developmental trajectory of disease progression. Previous studies support the idea that offspring of Holocaust survivors may have been subjected to early developmental programming. We evaluated the relationship between parental exposure to the Holocaust and self-reported health ratings and disorders made by their adult offspring (i.e., second generation Holocaust survivors). A total of 137 subjects were evaluated. Regression analyses demonstrated that maternal but not paternal exposure to the Holocaust was related to poorer subjective impressions of emotional and physical health. This relationship was diminished when the offspring's own level of trait anxiety was considered. Offspring with maternal, but not paternal, Holocaust exposure also reported greater use of psychotropic and other medications, including medications for the treatment of hypertension and lipid disorders. The mechanism linking these health outcomes and maternal exposure deserves further investigation, including the possibility that fetal or early developmental programming is involved.
The development of posttraumatic stress disorder (PTSD) is influenced by preexisting vulnerability factors. The authors aimed at identifying a preexisting biomarker representing a vulnerability factor for the development of PTSD. To that end, they determined whether the dexamethasone binding capacity of leukocytes, as a measure of glucocorticoid receptor (GR) number, before exposure to trauma was a predictor of development of PTSD symptoms. In addition, the authors analyzed mRNA expression for GR subtypes and GR target genes.
Participants were selected from a large prospective study on deployment-related disorders, in which peripheral blood mononuclear cells (PBMCs) were obtained prior to and 1 and 6 months after military deployment. Participants included armed forces personnel with high levels of PTSD symptoms 6 months after deployment (N=34) and comparison subjects without high levels of PTSD or depressive symptoms (N=34) matched for age, rank, previous deployments, educational level, and function during deployment.
Before military deployment, the GR number in PBMCs was significantly higher in participants who developed high levels of PTSD symptoms after deployment relative to matched comparison subjects. Logistic regression analysis showed that the risk for inclusion in the PTSD group after deployment increased 7.5-fold with each GR increase of 1,000. No group differences were observed in mRNA expression of GR-α, GR-P, GR-β, glucocorticoid-induced leucine zipper (GILZ), serum and glucocorticoid-inducible kinase-1 (SGK-1), and FKBP5. The higher GR number in the PTSD group was maintained at 1 and 6 months after deployment.
These results demonstrate that a preexisting high GR number in PBMCs is a vulnerability factor for subsequent development of PTSD symptoms.
Traumatic experiences in early life are risk factors for the development of behavioral and emotional disorders. Such disorders can persist through adulthood and have often been reported to be transmitted across generations.
To investigate the transgenerational effect of early stress, mice were exposed to chronic and unpredictable maternal separation from postnatal day 1 to 14.
We show that chronic and unpredictable maternal separation induces depressive-like behaviors and alters the behavioral response to aversive environments in the separated animals when adult. Most of the behavioral alterations are further expressed by the offspring of males subjected to maternal separation, despite the fact that these males are reared normally. Chronic and unpredictable maternal separation also alters the profile of DNA methylation in the promoter of several candidate genes in the germline of the separated males. Comparable changes in DNA methylation are also present in the brain of the offspring and are associated with altered gene expression.
These findings highlight the negative impact of early stress on behavioral responses across generations and on the regulation of DNA methylation in the germline.
Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A-inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.
Dissociation is a lack of the normal integration of thoughts, feelings, and experiences into the stream of consciousness and memory. Dissociation occurs to some degree in normal individuals and is thought to be more prevalent in persons with major mental illnesses. The Dissociative Experiences Scale (DES) has been developed to offer a means of reliably measuring dissociation in normal and clinical populations. Scale items were developed using clinical data and interviews, scales involving memory loss, and consultations with experts in dissociation. Pilot testing was performed to refine the wording and format of the scale. The scale is a 28-item self-report questionnaire. Subjects were asked to make slashes on 100-mm lines to indicate where they fall on a continuum for each question. In addition, demographic information (age, sex, occupation, and level of education) was collected so that the connection between these variables and scale scores could be examined. The mean of all item scores ranges from 0 to 100 and is called the DES score. The scale was administered to between 10 and 39 subjects in each of the following populations: normal adults, late adolescent college students, and persons suffering from alcoholism, agoraphobia, phobic-anxious disorders, posttraumatic stress disorder, schizophrenia, and multiple personality disorder. Reliability testing of the scale showed that the scale had good test-retest and good split-half reliability. Item-scale score correlations were all significant, indicating good internal consistency and construct validity. A Kruskal-Wallis test and post hoc comparisons of the scores of the eight populations provided evidence of the scale's criterion-referenced validity.(ABSTRACT TRUNCATED AT 250 WORDS)
Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.
Monozygous twins share a common genotype. However, most monozygotic twin pairs are not identical; several types of phenotypic discordance may be observed, such as differences in susceptibilities to disease and a wide range of anthropomorphic features. There are several possible explanations for these observations, but one is the existence of epigenetic differences. To address this issue, we examined the global and locus-specific differences in DNA methylation and histone acetylation of a large cohort of monozygotic twins. We found that, although twins are epigenetically indistinguishable during the early years of life, older monozygous twins exhibited remarkable differences in their overall content and genomic distribution of 5-methylcytosine DNA and histone acetylation, affecting their gene-expression portrait. These findings indicate how an appreciation of epigenetics is missing from our understanding of how different phenotypes can be originated from the same genotype.
• DNA methylation
• epigenetics
• histones
In animal models, variations in early maternal care are associated with differences in hypothalamic-pituitary-adrenal(HPA) stress response in the offspring, mediated via changes in the epigenetic regulation of glucocorticoid receptor (GR) gene (Nr3c1) expression.
To study this in humans, relationships between prenatal exposure to maternal mood and the methylation status of a CpG-rich region in the promoter and exon 1F of the human GR gene (NR3C1) in newborns and HPA stress reactivity at age three months were examined.
Prenatal exposure to increased third trimester maternal depressed/anxious mood was associated with increased methylation of NR3C1 at a predicted NGFI-A binding site. Increased NR3C1 methylation at this site was also associated with increased salivary cortisol stress responses at 3 months, controlling for prenatal SRI exposure, postnatal age and pre and postnatal maternal mood.
The methylation status of a CpG-rich region of the NR3C1 gene, including exon 1F, in genomic DNA from cord blood mononuclear cells was quantified by bisulfite pyrosequencing in infants of depressed mothers treated with a serotonin reuptake inhibitor antidepressant (SRI) (n = 33), infants of depressed nontreated mothers (n = 13) and infants of non depressed/non treated mothers (n = 36). To study the functional implications of the newborn methylation status of NR3C1 in newborns, HPA function was assessed at three months using salivary cortisol obtained before and following a non noxious stressor and at a late afternoon basal time.
Methylation status of the human NR3C1 gene in newborns is sensitive to prenatal maternal mood and may offer a potential epigenetic process that links antenatal maternal mood and altered HPA stress reactivity during infancy.
Although most people will gradually recover from the psychological effects of a traumatic event, PTSD will develop in a substantial proportion. PTSD appears to represent a failure to recover from a nearly universal set of emotions and reactions and is typically manifested as distressing memories or nightmares related to the traumatic event, attempts to avoid reminders of the trauma, and a heightened state of physiological arousal. Studies of the biologic mechanisms of PTSD have delineated circumscribed alterations in brain regions, such as the amygdala and hippocampus, that are associated with fear and memory, as well as changes in hormonal, neurochemical, and physiological systems involved in coordinating the body's response to stress. The treatment of PTSD involves educating the patient about the nature of the disorder, providing a safe and supportive environment for discussing traumatic events and their impact, and relieving the distress associated with memories and reminders of the event. A variety of approaches, such as exposure therapy, cognitive therapy, and pharmacotherapy, have been found to be effective in the treatment of PTSD.
Three studies assessed the construct validity of the self- and other-model dimensions underlying the 4-category model of adult attachment (Bartholomew, 1990). Five methods were used to assess the hypothesized dimensions: self-reports, friend-reports, romantic partner reports, trained judges' ratings of peer attachment, and trained judges' ratings of family attachment. In each study, the convergent and discriminant validity of the dimensions were assessed by multitrait-multimethod matrices and by confirmatory factor analysis. Study 2 related the latent attachment dimensions to theoretically relevant outcome latent variables. As predicted, individuals' self models converged with direct measures of the positivity of their self-concepts, and individuals' other models converged with direct measures of the positivity of their interpersonal orientations. Study 3 related the latent attachment dimensions to 3 alternate self-report measures of adult attachment and showed that the 2 dimensions serve as an organizing framework for the different measurement approaches.
• A test-retest reliability study of the Structured Clinical Interview for DSM-III-R was conducted on 592 subjects in four patient and two nonpatient sites in this country as well as one patient site in Germany. For most of the major categories, ks for current and lifetime diagnoses in the patient samples were above.60, with an overall weighted k of.61 for current and.68 for lifetime diagnoses. For the nonpatients, however, agreement was considerably lower, with a mean k of.37 for current and.51 for lifetime diagnoses. These values for the patient and nonpatient samples are roughly comparable to those obtained with other structured diagnostic instruments. Sources of diagnostic disagreement, such as inadequate training of interviewers, information variance, and low base rates for many disorders, are discussed.
Background
Enhanced glucocorticoid receptor (GR) sensitivity is present in people with PTSD, but the molecular mechanisms of GR sensitivity are not understood. Epigenetic factors have emerged as one potential mechanism that account for how trauma exposure leads to sustained PTSD symptomatology given that PTSD develops in only a subset of trauma survivors.
Methods
Cytosine methylation of a relevant promoter of the GR gene (NR3C1-1F promoter), and three functional neuroendocrine markers of hypothalamic-pituitary-adrenal (HPA) axis function, were examined in a sample of 122 combat veterans.
Results
Lower NR3C1-1F promoter methylation in peripheral blood mononuclear cells (PBMCs) was observed in combat veterans with PTSD compared to combat-exposed veterans who did not develop PTSD. Importantly, NR3C1-1F promoter methylation was also associated with three functional measures of glucocorticoid activity that have been associated with PTSD in combat veterans: PBMC lysozyme inhibition on the lysozyme suppression test, plasma cortisol decline on the low-dose (0.50 mg) dexamethasone suppression test (DST), and 24-hour urinary cortisol excretion. Finally, NR3C1-1F promoter methylation was inversely correlated with clinical markers and symptoms associated with PTSD.
Conclusions
Alterations in NR3C1-1F promoter methylation may reflect enduring changes resulting from combat exposure that lead to functional neuroendocrine alterations. As epigenetic measures are thought to reflect enduring effects of environmental exposures, they may be useful in distinguishing combat-exposed veterans who do or do not develop without PTSD.
Intergenerational effects of trauma have been observed clinically in a wide range of populations, and parental PTSD has been associated with an increased risk for psychopathology in offspring. In studies of Holocaust survivor offspring, parental PTSD, and particularly maternal PTSD, has been associated with increased risk for PTSD, low basal urinary cortisol excretion and enhanced cortisol suppression in response to dexamethasone. Such findings implicate maternally derived glucocorticoid programming in the intergenerational transmission of trauma-related consequences, potentially resulting from in utero influences or early life experiences. This study investigated the relative influence of Holocaust exposure and PTSD in mothers and fathers on glucocorticoid sensitivity in offspring. Eighty Holocaust offspring and 15 offspring of non-exposed Jewish parents completed evaluations and provided blood and urine samples. Glucocorticoid sensitivity was evaluated using the lysozyme suppression test (LST), an in vitro measure of glucocorticoid receptor sensitivity in a peripheral tissue, the dexamethasone suppression test (DST), and 24-h urinary cortisol excretion. Maternal PTSD was associated with greater glucocorticoid sensitivity in offspring across all three measures of glucocorticoid function. An interaction of maternal and paternal PTSD on the DST and 24-h urinary cortisol showed an effect of decreased glucocorticoid sensitivity in offspring with paternal, but not maternal, PTSD. Although indirect, these findings are consistent with the hypothesis that epigenetic programming may be involved in the intergenerational transmission of trauma-related effects on glucocorticoid regulation.
Context
Evidence suggests that early adverse experiences play a preeminent role
in development of mood and anxiety disorders and that corticotropin-releasing
factor (CRF) systems may mediate this association.Objective
To determine whether early-life stress results in a persistent sensitization
of the hypothalamic-pituitary-adrenal axis to mild stress in adulthood, thereby
contributing to vulnerability to psychopathological conditions.Design and Setting
Prospective controlled study conducted from May 1997 to July 1999 at
the General Clinical Research Center of Emory University Hospital, Atlanta,
Ga.Participants
Forty-nine healthy women aged 18 to 45 years with regular menses, with
no history of mania or psychosis, with no active substance abuse or eating
disorder within 6 months, and who were free of hormonal and psychotropic medications
were recruited into 4 study groups (n = 12 with no history of childhood abuse
or psychiatric disorder [controls]; n = 13 with diagnosis of current major
depression who were sexually or physically abused as children; n = 14 without
current major depression who were sexually or physically abused as children;
and n = 10 with diagnosis of current major depression and no history of childhood
abuse).Main Outcome Measures
Adrenocorticotropic hormone (ACTH) and cortisol levels and heart rate
responses to a standardized psychosocial laboratory stressor compared among
the 4 study groups.Results
Women with a history of childhood abuse exhibited increased pituitary-adrenal
and autonomic responses to stress compared with controls. This effect was
particularly robust in women with current symptoms of depression and anxiety.
Women with a history of childhood abuse and a current major depression diagnosis
exhibited a more than 6-fold greater ACTH response to stress than age-matched
controls (net peak of 9.0 pmol/L [41.0 pg/mL]; 95% confidence interval [CI],
4.7-13.3 pmol/L [21.6-60.4 pg/mL]; vs net peak of 1.4 pmol/L [6.19 pg/mL];
95% CI, 0.2-2.5 pmol/L [1.0-11.4 pg/mL]; difference, 8.6 pmol/L [38.9 pg/mL];
95% CI, 4.6-12.6 pmol/L [20.8-57.1 pg/mL]; P<.001).Conclusions
Our findings suggest that hypothalamic-pituitary-adrenal axis and autonomic
nervous system hyperreactivity, presumably due to CRF hypersecretion, is a
persistent consequence of childhood abuse that may contribute to the diathesis
for adulthood psychopathological conditions. Furthermore, these results imply
a role for CRF receptor antagonists in the prevention and treatment of psychopathological
conditions related to early-life stress.
Figures in this Article
The relative contribution of genetic and environmental factors in the
etiology of psychiatric disorders has long been a hotly debated area of investigation.
Considerable evidence from a variety of studies suggests a preeminent role
of early adverse experiences in the development of mood and anxiety disorders.
One study1 composed of almost 2000 women revealed
that those with a history of childhood sexual or physical abuse exhibited
more symptoms of depression and anxiety and had more frequently attempted
suicide than women without a history of childhood abuse. Women who have been
abused in childhood are 4 times more likely to develop syndromal major depression
in adulthood than women who have not been abused, and the magnitude of the
abuse is correlated with the severity of depression.2
Early parental loss predominantly due to parental separation has also
been found to increase the risk for major depression in case-control and epidemiological
studies.3- 8
Twin studies9- 10 have provided
concordant findings. Childhood abuse also predisposes to the development of
anxiety disorders in adulthood, including panic disorder and generalized anxiety
disorder.11- 12 In addition, posttraumatic
stress disorder (PTSD) may be a direct consequence of childhood abuse, and,
moreover, such trauma early in life also appears to increase an individual's
risk of developing PTSD in response to other traumas in adulthood.13 Depression and anxiety disorders, including PTSD,
are often comorbid in individuals with a history of diverse early adversities.14
There is evidence that central nervous system (CNS) corticotropin-releasing
factor (CRF) systems are likely to mediate the association between early-life
stress and the development of mood and anxiety disorders in adulthood. Corticotropin-releasing
factor neurons are found not only in the hypothalamus, but also in the neocortex
and the central nucleus of the amygdala, which are believed to be involved
in cognitive and emotional processing and in brainstem nuclei that contain
the bulk of the noradrenergic and serotonergic perikarya that project to the
forebrain.
These CNS CRF systems have also been strongly implicated in the pathophysiology
of both depression and anxiety disorders.15
Thus, when administered directly into the CNS of laboratory animals, CRF produces
many physiological and behavioral changes that closely parallel symptoms of
depression and anxiety, such as elevations of peripheral adrenocorticotropic
hormone (ACTH), corticosterone, and catecholamine concentrations, increases
in heart rate and mean arterial pressure, changes in gastrointestinal activity,
decreased reproductive behavior, decreased appetite, disruption of sleep,
increased grooming behavior, increased locomotor activity in a familiar environment,
suppression of exploratory behavior in a novel environment, potentiation of
acoustic startle responses, facilitation of fear conditioning, and enhancement
of shock-induced freezing and fighting behavior.16- 20
Enhanced release of CRF from 1 or more CNS circuits may, thus, account
for many of the symptoms of depression and anxiety and for the frequent comorbidity
between these disorders.21- 22
Indeed, our group and others have repeatedly measured increased CRF-like immunoreactivity
in cerebrospinal fluid (CSF) of untreated depressed patients compared with
healthy controls and patients with other psychiatric disorders.23- 26
Moreover, increased numbers of CRF-positive neurons and increased CRF messenger
RNA (mRNA) expression have recently been measured in the paraventricular nucleus
(PVN) in postmortem hypothalamic tissue of untreated depressed patients.27- 28 Similar to findings in depression,
increased CSF CRF concentrations have been reported in patients with PTSD
and obsessive-compulsive disorder.29- 31
Of particular relevance to the current study is evidence from preclinical
studies that suggests that increased activity of CRF circuits may be the persisting
neurobiological consequence of stress early in development. Adult rats repeatedly
separated from their dams for 180 min/d on postnatal days 2 to 14 demonstrate
increased CRF concentrations in the median eminence, hypothalamohypophysial
portal blood, and CSF and increased CRF mRNA expression in the hypothalamic
PVN under resting conditions. In response to a variety of stressors, these
maternally separated rats exhibit increased CRF mRNA expression in the hypothalamic
PVN and increased ACTH and corticosterone responses.32- 33
Similarly, nonhuman primates reared as neonates with their mothers in a variable
foraging demand condition for 12 weeks demonstrate significantly elevated
CSF CRF concentrations along with stable traits of anxiety as adults.34- 35 We hypothesize that stress early
in life results in a persistent sensitization or hyperactivity of CNS CRF
systems to even mild stress in adulthood, contributing to the development
of mood and anxiety disorders. This study sought to test this hypothesis in
human subjects.
Epigenetics is emerging as an attractive mechanism to explain the persistent genomic embedding of early-life experiences. Tightly linked to chromatin, which packages DNA into chromosomes, epigenetic marks primarily serve to regulate the activity of genes. DNA methylation is the most accessible and characterized component of the many chromatin marks that constitute the epigenome, making it an ideal target for epigenetic studies in human populations. Here, using peripheral blood mononuclear cells collected from a community-based cohort stratified for early-life socioeconomic status, we measured DNA methylation in the promoter regions of more than 14,000 human genes. Using this approach, we broadly assessed and characterized epigenetic variation, identified some of the factors that sculpt the epigenome, and determined its functional relation to gene expression. We found that the leukocyte composition of peripheral blood covaried with patterns of DNA methylation at many sites, as did demographic factors, such as sex, age, and ethnicity. Furthermore, psychosocial factors, such as perceived stress, and cortisol output were associated with DNA methylation, as was early-life socioeconomic status. Interestingly, we determined that DNA methylation was strongly correlated to the ex vivo inflammatory response of peripheral blood mononuclear cells to stimulation with microbial products that engage Toll-like receptors. In contrast, our work found limited effects of DNA methylation marks on the expression of associated genes across individuals, suggesting a more complex relationship than anticipated.
A series of related studies were designed to test the general hypothesis that depressed patients have a persistent need to suffer. In order to identify the depressed group, a Depression Inventory was developed and found to have a high degree of reliability and a reasonably high degree of correlation with clinicians' ratings of the depth of depression.The concept of the need to suffer, or masochism, was operationally defined by a variety of measures designed to reflect the manifestations of masochistic tendencies in the ideational productions of patients. It was found that the depressed group reported significantly more masochistic dreams and early memories than the non-depressed group, and that the masochism scores on the Focused Fantasy Test and the Masochism Inventory were also significantly higher in the depressed group. The results of these studies support the hypothesis
The social environment plays a considerable role in determining major psychiatric disorders. Emerging evidence suggests that features of the social environment modify gene expression independently of the primary DNA sequence through epigenetic processes. Accordingly, dysfunction of epigenetic mechanisms offers a plausible mechanism by which an adverse social environment gets "into the mind" and results in poor mental health. The purpose of this review is to provide an overview of the studies suggesting that epigenetic changes introduced by the social environment then manifest as psychological consequences. Our goal is to build a platform to discuss the ways in which future epidemiologic studies may benefit from including epigenetic measures. We focus on schizophrenia, major depressive disorder, post-traumatic stress disorder, anorexia nervosa, and substance dependence as examples that highlight the ways in which social environmental exposures, mediated through epigenetic processes, affect mental health.
This study examined the impact of parental styles on second generation effects of trauma among adolescent offspring of survivors of the Khmer Rouge (KR) genocide in Cambodia. Two hundred high school students completed measures addressing their parents' trauma stemming from the KR regime, parental styles (role reversing, overprotective), depression and anxiety. Parents' role reversing parental style and mothers' overprotective parenting were shown to mediate the impact of their trauma symptoms on the child's depression and anxiety. The implications of the findings are discussed.
Several stress-associated neuropsychiatric disorders, notably posttraumatic stress disorder and chronic pain and fatigue syndromes, paradoxically exhibit somewhat low plasma levels of the stress hormone cortisol. The effects appear greatest in those initially traumatized in early life, implying a degree of developmental programming, perhaps of both lower cortisol and vulnerability to psychopathology. In these conditions, lowered cortisol is not due to any adrenal or pituitary insufficiency. Instead, two processes appear involved. First, there is increased target cell sensitivity to glucocorticoid action, notably negative feedback upon the hypothalamic-pituitary-adrenal (stress) axis. Altered density of the glucocorticoid receptor is inferred, squaring with much preclinical data showing early life challenges can permanently program glucocorticoid receptors in a tissue-specific manner. These effects involve epigenetic mechanisms. Second, early life trauma/starvation induces long-lasting lowering of glucocorticoid catabolism, specifically by 5α-reductase type 1 (predominantly a liver enzyme) and 11β-hydroxysteroid dehydrogenase type 2 (in kidney), an effect also seen in model systems. These changes reflect a plausible early-life adaptation to increase the persistence of active cortisol in liver (to maximize fuel output) and kidney (to increase salt retention) without elevation of circulating levels, thus avoiding their deleterious effects on brain and muscle. Modestly lowered circulating cortisol and increased vulnerability to stress-associated disorders may be the outcome. This notion implies a vulnerable early-life phenotype may be discernable and indicates potential therapy by modest glucocorticoid replacement. Indeed, early clinical trials with cortisol have shown a modicum of promise.
Though there are multiple routes through which parents can influence their offspring, recent studies of environmentally induced epigenetic variation have highlighted the role of non-genomic pathways. In addition to the experience-dependent modification of DNA methylation that can be achieved via mother-infant interactions, there has been increasing interest in the epigenetic mechanisms through which paternal influences on offspring development can be achieved. Epidemiological and laboratory studies suggest that paternal nutritional and toxicological exposures as well as paternal age and phenotypic variation can lead to variations in offspring and, in some cases, grand-offspring development. These findings suggest a potential epigenetic germline inheritance of paternal effects. However, it may be important to consider the interplay between maternal and paternal influences as well as the experimental dissociation between experience-dependent and germline transmission when exploring the role of epigenetic variation within the germline as a mediator of these effects. In this review, we will explore these issues, with a particular focus on the potential role of paternally induced maternal investment, highlight the literature illustrating the transgenerational impact of paternal experiences, and discuss the evidence supporting the role of epigenetic mechanisms in maintaining paternal effects both within and across generations.
There has been considerable controversy regarding the impact of the Holocaust on the second generation, but few empirical data are available that systematically document trauma exposure and psychiatric disorder in these individuals. To obtain such data, the authors examined the prevalence of stress and exposure to trauma, current and lifetime posttraumatic stress disorder (PTSD), and other psychiatric diagnoses in a group of adult offspring of Holocaust survivors (N=100) and a demographically similar comparison group (N=44).
Subjects were recruited from both community and clinical populations and were evaluated with the use of structured clinical instruments. Stress and trauma history were evaluated with the Antonovsky Life Crises Scale and the Trauma History Questionnaire, PTSD was diagnosed with the Clinician Administered PTSD Scale, and other psychiatric disorders were evaluated according to the Structured Clinical Interview for DSM-IV.
The data show that although adult offspring of Holocaust survivors did not experience more traumatic events, they had a greater prevalence of current and lifetime PTSD and other psychiatric diagnoses than the demographically similar comparison subjects. This was true in both community and clinical subjects.
The findings demonstrate an increased vulnerability to PTSD and other psychiatric disorders among offspring of Holocaust survivors, thus identifying adult offspring as a possible high-risk group within which to explore the individual differences that constitute risk factors for PTSD.
Evidence suggests that early adverse experiences play a preeminent role in development of mood and anxiety disorders and that corticotropin-releasing factor (CRF) systems may mediate this association.
To determine whether early-life stress results in a persistent sensitization of the hypothalamic-pituitary-adrenal axis to mild stress in adulthood, thereby contributing to vulnerability to psychopathological conditions.
Prospective controlled study conducted from May 1997 to July 1999 at the General Clinical Research Center of Emory University Hospital, Atlanta, Ga.
Forty-nine healthy women aged 18 to 45 years with regular menses, with no history of mania or psychosis, with no active substance abuse or eating disorder within 6 months, and who were free of hormonal and psychotropic medications were recruited into 4 study groups (n = 12 with no history of childhood abuse or psychiatric disorder [controls]; n = 13 with diagnosis of current major depression who were sexually or physically abused as children; n = 14 without current major depression who were sexually or physically abused as children; and n = 10 with diagnosis of current major depression and no history of childhood abuse).
Adrenocorticotropic hormone (ACTH) and cortisol levels and heart rate responses to a standardized psychosocial laboratory stressor compared among the 4 study groups.
Women with a history of childhood abuse exhibited increased pituitary-adrenal and autonomic responses to stress compared with controls. This effect was particularly robust in women with current symptoms of depression and anxiety. Women with a history of childhood abuse and a current major depression diagnosis exhibited a more than 6-fold greater ACTH response to stress than age-matched controls (net peak of 9.0 pmol/L [41.0 pg/mL]; 95% confidence interval [CI], 4.7-13.3 pmol/L [21.6-60. 4 pg/mL]; vs net peak of 1.4 pmol/L [6.19 pg/mL]; 95% CI, 0.2-2.5 pmol/L [1.0-11.4 pg/mL]; difference, 8.6 pmol/L [38.9 pg/mL]; 95% CI, 4.6-12.6 pmol/L [20.8-57.1 pg/mL]; P<.001).
Our findings suggest that hypothalamic-pituitary-adrenal axis and autonomic nervous system hyperreactivity, presumably due to CRF hypersecretion, is a persistent consequence of childhood abuse that may contribute to the diathesis for adulthood psychopathological conditions. Furthermore, these results imply a role for CRF receptor antagonists in the prevention and treatment of psychopathological conditions related to early-life stress. JAMA. 2000;284:592-597
Hyperactivity of the hypothalamic--pituitary--adrenal (HPA) axis has been reliably observed in patients with major depression. One of the primary features of this HPA axis hyperactivity is reduced sensitivity to the inhibitory effects of the glucocorticoid dexamethasone on the production of adrenocorticotropic hormone and cortisol during the dexamethasone suppression test and, more recently, the dexamethasone--corticotropin-releasing hormone test. Because the effects of glucocorticoids are mediated by intracellular receptors including, most notably, the glucocorticoid receptor (GR), a number of studies have considered the possibility that the number and/or function of GRs are reduced in depressed patients. Moreover, whether antidepressants act by reversing these putative GR changes has been examined. The extant literature on GR receptors in major depression was reviewed along with studies examining the impact of antidepressants on the GR. The data support the hypothesis that the function of the GR is reduced in major depression in the absence of clear evidence of decreased GR expression. The data also indicate that some antidepressants have direct effects on the GR, leading to enhanced GR function and increased GR expression. Hypotheses regarding the mechanism of these receptor changes involve relevant second messenger pathways that regulate GR function. The findings indicate that the GR is an important molecular target in major depression. Further elucidation of the biochemical and molecular mechanisms involved in GR changes in major depression is an exciting frontier that will no doubt lead to new insights into the pathophysiology and treatment of affective disorders.
The goal of this study was to develop and validate a short form of the Childhood Trauma Questionnaire (the CTQ-SF) as a screening measure for maltreatment histories in both clinical and nonreferred groups.
Exploratory and confirmatory factor analyses of the 70 original CTQ items were used to create a 28-item version of the scale (25 clinical items and three validity items) and test the measurement invariance of the 25 clinical items across four samples: 378 adult substance abusing patients from New York City, 396 adolescent psychiatric inpatients, 625 substance abusing individuals from southwest Texas, and 579 individuals from a normative community sample (combined N=1978).
Results showed that the CTQ-SF's items held essentially the same meaning across all four samples (i.e., measurement invariance). Moreover, the scale demonstrated good criterion-related validity in a subsample of adolescents on whom corroborative data were available.
These findings support the viability of the CTQ-SF across diverse clinical and nonreferred populations.
Reduced cortisol levels have been linked with vulnerability to posttraumatic stress disorder (PTSD) and the risk factor of parental PTSD in adult offspring of Holocaust survivors.
The purpose of this study was to report on the relationship between maternal PTSD symptoms and salivary cortisol levels in infants of mothers directly exposed to the World Trade Center collapse on September 11, 2001 during pregnancy.
Mothers (n = 38) collected salivary cortisol samples from themselves and their 1-yr-old babies at awakening and at bedtime.
Lower cortisol levels were observed in both mothers (F = 5.15, df = 1, 34; P = 0.030) and babies of mothers (F = 8.0, df = 1, 29; P = 0.008) who developed PTSD in response to September 11 compared with mothers who did not develop PTSD and their babies. Lower cortisol levels were most apparent in babies born to mothers with PTSD exposed in their third trimesters.
The data suggest that effects of maternal PTSD related to cortisol can be observed very early in the life of the offspring and underscore the relevance of in utero contributors to putative biological risk for PTSD.
Epidemiological studies suggest that environmental adversity can alter parental care and thus influence child development. We addressed the question of whether stressors can directly affect parental behavior using a rodent model of stable, individual differences in maternal behavior.
Lactating rat mothers were characterized as high or low in pup-directed licking/grooming (LG) behavior, rebred, and subjected to 7 days of intermittent stress or control conditions during gestation. Female rats were mated a third time without any subsequent intervention. Maternal behavior, oxytocin receptor (OTR) binding, and offspring behavior were examined.
Stress reduced OTR levels and pup LG of high LG mothers to levels comparable with those of low LG mothers. The adult offspring of the gestational stress/high LG mothers resembled those of low LG mothers on behavioral measures of anxiety and maternal behavior, as well as OTR levels. The results of the third mating revealed an enduring effect of gestational stress on both mother and offspring maternal LG.
These findings suggest that stress can directly alter maternal care through the neuroendocrine systems that normally regulate this behavior. Thus, the effects of environmental adversity can be transmitted across generations through a nongenomic mechanism involving maternal care.
We developed a short questionnaire--Parental PTSD Questionnaire--(PPQ), designed to assess the presence of posttraumatic stress disorder (PTSD) symptoms in parents. Fifty-eight adult offspring of Holocaust survivors (23 men and 35 women) completed the questionnaire about a parent who was independently evaluated by a trained clinician using the Clinician Administered PTSD Scale (CAPS). Only 5.2% of the offspring reported, "not knowing" if their parent had experienced 10 or fewer symptoms, while 56.9% provided estimates for all 17 items. There were no significant differences between lifetime frequencies of the individual symptoms as endorsed on the PPQ compared to the CAPS when subjects with completed PPQs were compared with CAPS. Interrater reliability between offspring and clinician was highly significant for each of the items when evaluated separately so as to include data for subjects who endorsed not knowing if a certain symptom had been present. Further studies are warranted to examine the psychometric properties of this measure.
The authors used a low-dose dexamethasone suppression test to examine the effect of a PTSD risk factor, parental PTSD, on cortisol negative feedback inhibition in adult offspring of Holocaust survivors with PTSD (N=13) versus without PTSD (N=12) as well as a comparison group of offspring whose parents had no Holocaust exposure (N=16).
Blood samples were obtained at 8:00 a.m. for the determination of baseline cortisol. Participants ingested 0.5 mg of dexamethasone at 11:00 p.m., and blood samples were obtained again at 8:00 a.m. the following day.
Enhanced cortisol suppression in response to dexamethasone was associated primarily with parental PTSD status, with minimal contribution of subjects' own trauma-related symptoms.
Enhanced cortisol negative feedback inhibition may be associated with PTSD because it is related to the PTSD risk factor of parental PTSD.
Lower cortisol levels in posttraumatic stress disorder (PTSD) may reflect a preexisting vulnerability associated with developing the disorder after trauma exposure. Because offspring of trauma survivors with PTSD have a greater prevalence of PTSD after their own life events than offspring of trauma survivors without PTSD and offspring of nonexposed persons, examination of patterns of basal cortisol secretion in such offspring provides an opportunity to test this hypothesis.
To characterize the patterns of basal cortisol secretion in offspring of Holocaust survivors with and without parental PTSD and children of nonexposed parents.
Cortisol secretion was measured every 30 minutes for 24 hours. The raw hormonal data were subjected to a chronobiological analysis by applying single-oscillator and multioscillator cosinor analyses, a nonlinear least squares curve-fitting program, to determine circadian and ultradian regulatory dynamics.
The study was conducted under controlled conditions at the General Clinical Research Center at the Mount Sinai School of Medicine.
Twenty-three Holocaust offspring with parental PTSD and 10 without parental PTSD were compared with 16 children of nonexposed parents. No participant had PTSD.
Mean cortisol levels during the 24-hour cycle and other chronobiological parameters (amplitude, acrophase, circadian quotient, and goodness-of-fit coefficient) derived from single-oscillator and multioscillator models.
Offspring with parental PTSD displayed lower mean cortisol levels, reflected by the circadian mesor and reduced cortisol amplitude, compared with offspring without parental PTSD and children of nonexposed parents. This effect seemed to be specifically related to the presence of maternal PTSD.
Low cortisol levels and other chronobiological alterations in offspring are associated with the risk factor of maternal PTSD, raising the possibility that these alterations are acquired via glucocorticoid programming either from in utero exposures or in response to maternal behaviors early in life.
Parental posttraumatic stress disorder (PTSD) appears to be a relevant risk factor for the development of PTSD, as evidenced by a greater prevalence of PTSD, but not trauma exposure, in adult offspring of Holocaust survivors with PTSD, compared to children of Holocaust-exposed parents without PTSD. This paper summarizes recent neuroendocrine studies in offspring of parents with PTSD. Offspring of trauma survivors with PTSD show significantly lower 24-h mean urinary cortisol excretion and salivary cortisol levels as well as enhanced plasma cortisol suppression in response to low dose dexamethasone administration than offspring of survivors without PTSD. In all cases, neuroendocrine measures were negatively correlated with severity of parental PTSD symptoms, even after controlling for PTSD and even other symptoms in offspring. Though the majority of our work has focused on adult offspring of Holocaust survivors, recent observations in infants born to mothers who were pregnant on 9/11 demonstrate that low cortisol in relation to parental PTSD appears to be present early in the course of development and may be influenced by in utero factors such as glucocorticoid programming. Since low cortisol levels are particularly associated with the presence of maternal PTSD the findings suggest the involvement of epigenetic mechanisms.
A significant association between parental PTSD and the occurrence of PTSD in offspring has been noted, consistent with the idea that risk for the development of PTSD is transmitted from parent to child. Two recent reports linking maternal PTSD and low offspring cortisol prompted us to examine the relative contributions of maternal vs. paternal PTSD in the prediction of PTSD and other psychiatric diagnoses in offspring.
One hundred seventeen men and 167 women, recruited from the community, were evaluated using a comprehensive psychiatric battery designed to identify traumatic life experiences and lifetime psychiatric diagnoses. 211 of these subjects were the adult offspring of Holocaust survivors and 73 were demographically comparable Jewish controls. Participants were further subdivided based on whether their mother, father, neither, or both parents met diagnostic criteria for lifetime PTSD.
A higher prevalence of lifetime PTSD, mood, anxiety disorders, and to a lesser extent, substance abuse disorders, was observed in offspring of Holocaust survivors than controls. The presence of maternal PTSD was specifically associated with PTSD in adult offspring of Holocaust survivors. However, other psychiatric diagnoses did not show specific effects associated with maternal PTSD.
The tendency for maternal PTSD to make a greater contribution than paternal PTSD to PTSD risk suggests that classic genetic mechanisms are not the sole model of transmission, and paves way for the speculation that epigenetic factors may be involved. In contrast, PTSD in any parent contributes to risk for depression, and parental traumatization is associated with increased anxiety disorders in offspring.
Early-life emotional stress may be associated with affective and cognitive disorders later in life, yet satisfactory animal models for studying the underlying mechanisms are limited. Because maternal presence and behavior critically influence molecular and behavioral stress responses in offspring, we sought to create a model of dysfunctional, fragmented maternal nurturing behavior that would, in turn, provoke chronic early-life stress in the offspring.
Sprague-Dawley rat dams' nursing and nurturing behaviors were altered by limiting their ability to create satisfactory nests during postpartum days 2-9. Maternal behavior was observed throughout the diurnal cycle, and the frequency and duration of nurturing behaviors were scored. In addition, potential stress and anxiety of the dams were assessed using behavioral, molecular and hormonal measures.
Both the quantity and the quality of dams' care of their pups were profoundly influenced by restriction of nesting materials in their cages: licking/grooming activities decreased and the frequency of leaving the pups increased, resulting in fragmented interactions between the dams and pups. The abnormal activity patterns of the dams were accompanied by increased anxiety-like behavior in the open field, but not in the elevated plus maze tests. Additionally, dams' plasma corticosterone levels and adrenal weights were augmented, suggesting chronic stress of these dams. By the end of the limited-nesting, stress-inducing period, hypothalamic corticotropin releasing hormone (CRH) mRNA expression was reduced in the limited-nesting dams, while arginine-vasopressin (AVP) mRNA levels were not significantly affected.
Limiting dams' ability to construct a nest for their pups leads to an abnormal repertoire of nurturing behaviors, possibly as a result of chronic stress and mild anxiety of the dams. Because the fragmented and aberrant maternal behavior provoked chronic stress in the pups, the limited-nesting paradigm provides a useful tool for studying the mechanisms and consequences of such early-life stress experience in the offspring.
- R L Spitzer
- Jbw Williams
- M Gibbon
Spitzer RL, Williams JBW, Gibbon M: Structured Clinical Interview for DSM-IV (SCID). New York, New York State Psychiatric
Institute, Biometrics Research, 1995