Post-traumatic Stress Disorder Phenotype Research Articles

Microbiome signature of posttraumatic stress disorder and resilience in youth.

Identifying biomarkers that can distinguish trauma-exposed youth at risk for developing posttraumatic pathology from resilient individuals is essential for targeted interventions. As trauma can alter the microbiome with lasting effects on the host, our longitudinal, multimeasure, cross-species study aimed to identify the microbial signature of posttraumatic stress disorder (PTSD). We followed children exposed to war-related trauma and matched controls from early childhood (Mage = 2.76 years, N = 232) to adolescence (Mage = 16.13 years, N = 84), repeatedly assessing posttraumatic symptomatology and maternal caregiving. In late adolescence, we collected fecal samples from mothers and youth and assessed microbiome composition, diversity, and mother-child microbial synchrony. We then transplanted adolescents' fecal samples into germ-free mice to determine if behavioral changes are observed. Youth with PTSD exhibited a distinct gut microbiome profile and lower diversity compared to resilient individuals, and microbiome diversity mediated the continuity of posttraumatic symptomatology throughout development. Low microbiome diversity correlated with more posttraumatic symptoms in early childhood, more emotional and behavioral problems in adolescence, and poor maternal caregiving. Youth with PTSD demonstrated less mother-child microbial synchrony, suggesting that low microbial concordance between mother and child may indicate susceptibility to posttraumatic illness. Germ-free mice transplanted with microbiomes from individuals with PTSD displayed increased anxious behavior. Our findings provide evidence that the trauma-associated microbiome profile is at least partially responsible for the anxiety component of the PTSD phenotype and highlight microbial underpinnings of resilience. Further, our results suggest that the microbiome may serve as additional biological memory of early life stress and underscore the potential for microbiome-related diagnosis and treatment following trauma. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Early- and late-phase changes of brain activity and early-phase neuromodulation in the posttraumatic stress disorder rat model

Posttraumatic stress disorder (PTSD) is a complex syndrome that may occur after life-threatening events. Fear memory abnormalities may play vital roles in the pathogenesis of PTSD. Previous work has found that fear memories are not rigid; the retrieval of fear memories may change over time. Furthermore, prior studies suggest that theta wave (4 Hz) activity is highly correlated with fear expression in an animal model. However, the relationship between pathological fear memory and potential brain wave features in PTSD remains largely uncharacterized. Here, we hypothesized that after traumatic stress exposure, the longitudinal dynamics of abnormal fears in PTSD animal models could be reflected by the measurement of local field potentials (LFPs). Using a well-established modified single-prolonged stress and footshock (SPS & FS) PTSD rat model, animals were restrained for 2 h and subsequently subjected to 20 min of forced swimming, then exposed to diethyl ether until they lost consciousness and placed in a conditioning chamber for fear conditioning. To characterize the temporal changes, we characterized freezing behavior brain wave features during the conditioning chamber re-exposure in the early (10 and 30 min; 2, 4, and 6 h) and late (day 1, 3, 7, and 14) phases after traumatic stress exposure. Our results indicate that SPS & FS rats showed co-morbid PTSD phenotypes including significantly higher levels of anxiety-, depression-, and anhedonia-like behaviors, and impaired fear extinction. Delta wave (0.5–4 Hz) suppression in the medial prefrontal cortex, amygdala, and ventral hippocampus occurred 10 and 30 min after traumatic stress, followed by continuous delta wave activity from 2 h to day 14, correlating with fear levels. tDCS reduced delta activity and alleviated PTSD-like phenotypes in the SPS & FS group. In this study, profiling abnormal fears with brain wave correlates may improve our understanding of time-dependent pathological fear memory retrieval in PTSD and facilitate the development of effective intervention strategies.

Neuroscientific account of Guilt- and Shame-Driven PTSD phenotypes

ABSTRACT Background: Guilt and Shame, two core self-related emotions, often emerge following trauma and play an important role in the development and maintenance of post-traumatic stress disorder (PTSD). Importantly, Guilt and Shame exhibit specific focal and non-specific global impacts of trauma on self-perception, respectively. Objective and Methods: Integrating psychological theories with neuroscientific knowledge, we suggest a scheme of two diverging clinical phenotypes of PTSD, associated with distinct self-related processes and differential functionality of relevant neural networks. Proposal: The Guilt-driven phenotype is characterized by preoccupation with negative self-attributes of one's actions in the traumatic event. It involves altered functionality of both the salience network (SN) and the default-mode network (DMN), associated with heightened interoceptive signalling and ruminative introspection which may lead to hyperarousal and intrusive symptoms, respectively. On the contrary, the Shame-driven phenotype is characterized by global, identity-related negative self-attributions. It involves altered functionality of both the SN and the DMN, associated with blunted interoceptive signalling and diminished introspection which may result in withdrawal and anhedonia symptoms together with dissociative experiences, respectively. Conclusion: The proposed PTSD phenotypes may inform neuropsychological therapeutic interventions (e.g. self-focused psychotherapy and neuromodulation) aiming to restore the function of large-scale self-related neural processing.

Guilt by Association: Inflammation and Shared Genetic Risk Between Stress-Related and Immune Disorders

Guilt by Association: Inflammation and Shared Genetic Risk Between Stress-Related and Immune Disorders

Distinguishing emotional numbing symptoms of posttraumatic stress disorder from major depressive disorder

Emotional numbing symptoms are a core aspect of posttraumatic stress disorder (PTSD). Since the initial characterization of PTSD in DSM-III, emotional numbing symptoms have been revised and grouped under different symptom clusters (avoidance in DSM-IV, negative alterations in cognitions, and mood in DSM-5). Previous studies have found emotional numbing symptoms to be associated with greater PTSD severity, functional impairment, and worse treatment outcomes. Although considered an important feature, some argue that emotional numbing symptoms may simply reflect the manifestation of major depressive disorder (MDD) symptoms rather than be an inherent part of the PTSD phenotype. Here, we evaluated this question using two different data sets (N1 = 142; CAPS-5, N2 = 163; CAPS-4) of trauma-exposed individuals. First, we evaluated the unique variance of emotional numbing explained by diagnosis as binary variables (i.e., having PTSD, MDD, or both) and the severity of symptoms. Second, we examined the relative importance of each PTSD symptom in relation to emotional numbing symptoms. Results revealed that PTSD had a distinct contribution to the variance explaining emotional numbing symptoms above and beyond MDD. These findings suggest that emotional numbing should not be conceptualized as a simple manifestation of MDD symptoms. Rather, this symptom cluster may be a unique feature of PTSD that should be addressed within the context of trauma.

Differences in genetic correlations between posttraumatic stress disorder and alcohol-related problems phenotypes compared to alcohol consumption-related phenotypes.

Posttraumatic Stress Disorder (PTSD) tends to co-occur with greater alcohol consumption as well as alcohol use disorder (AUD). However, it is unknown whether the same etiologic factors that underlie PTSD-alcohol-related problems comorbidity also contribute to PTSD- alcohol consumption. We used summary statistics from large-scale genome-wide association studies (GWAS) of European-ancestry (EA) and African-ancestry (AA) participants to estimate genetic correlations between PTSD and a range of alcohol consumption-related and alcohol-related problems phenotypes. In EAs, there were positive genetic correlations between PTSD phenotypes and alcohol-related problems phenotypes (e.g. Alcohol Use Disorders Identification Test (AUDIT) problem score) (rGs: 0.132-0.533, all FDR adjusted p < 0.05). However, the genetic correlations between PTSD phenotypes and alcohol consumption -related phenotypes (e.g. drinks per week) were negatively associated or non-significant (rGs: -0.417 to -0.042, FDR adjusted p: <0.05-NS). For AAs, the direction of correlations was sometimes consistent and sometimes inconsistent with that in EAs, and the ranges were larger (rGs for alcohol-related problems: -0.275 to 0.266, FDR adjusted p: NS, alcohol consumption-related: 0.145-0.699, FDR adjusted p: NS). These findings illustrate that the genetic associations between consumption and problem alcohol phenotypes and PTSD differ in both strength and direction. Thus, the genetic factors that may lead someone to develop PTSD and high levels of alcohol consumption are not the same as those that lead someone to develop PTSD and alcohol-related problems. Discussion around needing improved methods to better estimate heritabilities and genetic correlations in diverse and admixed ancestry samples is provided.

A Protocol for the Induction of Posttraumatic Stress-Disorder (PTSD)-like Behavior in Mice.

Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition that precipitates in ~10% of individuals exposed to a traumatic event (TE). Symptoms include recurrent and intrusive thoughts, sleep disturbance, hypervigilance, exaggerated startle, and reckless or destructive behavior. Given the complex and heterogeneous nature of the disease, animal models for PTSD-like symptomatology are of increasing interest to the field of PTSD research. Because resilience to PTSD-like symptomatology is an important epidemiologic aspect of PTSD, animal models that resolve vulnerable and resilient animals are of particular value. Due to the complex nature of the PTSD phenotype and the potential overlaps between PTSD-like behavior and behaviors associated with other stress-induced psychopathologies such as anxiety or depression, animal models that utilize multiple readouts for PTSD-like behavior are also of increasing value. We utilize a paradigm developed by Lebow et al. 2012 for the induction and identification of PTSD-like symptomatology in mice. This paradigm utilizes inescapable electric foot shock, administered in two decontextualized sessions over two consecutive days. Stressed mice perform four behavioral tests - dark/light transfer, marble burying, acoustic startle, and home cage activity - to generate five behavioral readouts of PTSD-like behavior: % risk assessment (%RA), % marbles buried (%MB), % prepulse inhibition (%PPI), latency to peak startle amplitude (LPSA), and % light phase activity (%LPA). PTSD-like symptomatology is characterized by decreased %RA, increased %MB, decreased %PPI, decreased LPSA, and increased %LPA. The 20% of animals displaying the most PTSD-like behavior in each test are awarded a certain number of points depending on the test, and animals scoring sufficient points are designated as PTSD-like, while animals scoring no points are designated PTSD-resilient. This paradigm identifies PTSD-like behavior in ~15% of animals, a rate comparable to that observed in humans. This protocol represents a robust and reproducible paradigm for the induction of PTSD-like behavior in mice.

Is PTSD an Evolutionary Survival Adaptation Initiated by Unrestrained Cytokine Signaling and Maintained by Epigenetic Change?

Treatment outcomes for PTSD with current psychological therapies are poor, with very few patients achieving sustained symptom remission. A number of authors have identified physiological and immune disturbances in Post Traumatic Stress Disorder (PTSD) patients, but there is no unifying hypothesis that explains the myriad features of the disorder. The medical literature was reviewed over a 6-year period primarily using the medical database PUBMED. The literature contains numerous papers that have identified a range of physiological and immune dysfunction in association with PTSD. This paper proposes that unrestrained cytokine signaling induces epigenetic changes that promote an evolutionary survival adaptation, which maintains a defensive PTSD phenotype. The brain can associate immune signaling with past threat and initiate a defensive behavioral response. The sympathetic nervous system is pro-inflammatory, while the parasympathetic nervous system is anti-inflammatory. Prolonged cholinergic withdrawal will promote a chronic inflammatory state. The innate immune cytokine IL-1β has pleiotropic properties and can regulate autonomic, glucocorticoid, and glutamate receptor functions, sleep, memory, and epigenetic enzymes. Changes in epigenetic enzyme activity can potentially alter phenotype and induce an adaptation. Levels of IL-1β correlate with severity and duration of PTSD and PTSD can be prevented by bolus administration of hydrocortisone in acute sepsis, consistent with unrestrained inflammation being a risk factor for PTSD. The nervous and immune systems engage in crosstalk, governed by common receptors. The benefits of currently used psychiatric medication may arise from immune, as well as synaptic, modulation. The psychedelic drugs (3,4-Methylenedioxymethamphetamine (MDMA), psilocybin, and ketamine) have potent immunosuppressive and anti-inflammatory effects on the adaptive immune system, which may contribute to their reported benefit in PTSD. There may be distinct PTSD phenotypes induced by innate and adaptive cytokine signaling. In order for an organism to survive, it must adapt to its environment. Cytokines signal danger to the brain and can induce epigenetic changes that result in a persistent defensive phenotype. PTSD may be the price individuals pay for the genomic flexibility that promotes adaptation and survival.

Altered gene expression and PTSD symptom dimensions in World Trade Center responders.

Despite experiencing a significant trauma, only a subset of World Trade Center (WTC) rescue and recovery workers developed posttraumatic stress disorder (PTSD). Identification of biomarkers is critical to the development of targeted interventions for treating disaster responders and potentially preventing the development of PTSD in this population. Analysis of gene expression from these individuals can help in identifying biomarkers of PTSD. We established a well-phenotyped sample of 371 WTC responders, recruited from a longitudinal WTC responder cohort using stratified random sampling, by obtaining blood, self-reported and clinical interview data. Using bulk RNA-sequencing from whole blood, we examined the association between gene expression and WTC-related PTSD symptom severity on (i) highest lifetime Clinician-Administered PTSD Scale (CAPS) score, (ii) past-month CAPS score, and (iii) PTSD symptom dimensions using a 5-factor model of re-experiencing, avoidance, emotional numbing, dysphoric arousal and anxious arousal symptoms. We corrected for sex, age, genotype-derived principal components and surrogate variables. Finally, we performed a meta-analysis with existing PTSD studies (total N = 1016), using case/control status as the predictor and correcting for these variables. We identified 66 genes significantly associated with total highest lifetime CAPS score (FDR-corrected p < 0.05), and 31 genes associated with total past-month CAPS score. Our more granular analyses of PTSD symptom dimensions identified additional genes that did not reach statistical significance in our analyses with total CAPS scores. In particular, we identified 82 genes significantly associated with lifetime anxious arousal symptoms. Several genes significantly associated with multiple PTSD symptom dimensions and total lifetime CAPS score (SERPINA1, RPS6KA1, and STAT3) have been previously associated with PTSD. Geneset enrichment of these findings has identified pathways significant in metabolism, immune signaling, other psychiatric disorders, neurological signaling, and cellular structure. Our meta-analysis revealed 10 genes that reached genome-wide significance, all of which were downregulated in cases compared to controls (CIRBP, TMSB10, FCGRT, CLIC1, RPS6KB2, HNRNPUL1, ALDOA, NACA, ZNF429 and COPE). Additionally, cellular deconvolution highlighted an enrichment in CD4 T cells and eosinophils in responders with PTSD compared to controls. The distinction in significant genes between total lifetime CAPS score and the anxious arousal symptom dimension of PTSD highlights a potential biological difference in the mechanism underlying the heterogeneity of the PTSD phenotype. Future studies should be clear about methods used to analyze PTSD status, as phenotypes based on PTSD symptom dimensions may yield different gene sets than combined CAPS score analysis. Potential biomarkers implicated from our meta-analysis may help improve therapeutic target development for PTSD.

Sex and context differences in the effects of trauma on comorbid alcohol use and post-traumatic stress phenotypes in actively drinking rats.

Alcohol use disorder (AUD) and affective disorders are frequently comorbid and share underlying mechanisms that could be targets for comprehensive treatment. Post-traumatic stress disorder (PTSD) has high comorbidity with AUD, but comprehensive models of this overlap are nascent. We recently characterized a model of comorbid AUD and PTSD-like symptoms, wherein stressed rats receive an inhibitory avoidance (IA)-related footshock on two occasions followed by two-bottle choice (2BC) voluntary alcohol drinking. Stressed rats received the second footshock in a familiar (FAM, same IA box as the first footshock) or novel context (NOV, single-chambered apparatus); the FAM paradigm more effectively increased alcohol drinking in males and the NOV paradigm in females. During abstinence, stressed males displayed avoidance-like PTSD symptoms, and females showed hyperarousal-like PTSD symptoms. Rats in the model had altered spontaneous action potential-independent GABAergic transmission in the central amygdala (CeA), a brain region key in alcohol dependence and stress-related signaling. However, PTSD sufferers may have alcohol experience prior to their trauma. Here, we therefore modified our AUD/PTSD comorbidity model to provide 3weeks of intermittent extended alcohol access before footshock and then studied the effects of NOV and FAM stress on drinking and PTSD phenotypes. NOV stress suppressed the escalation of alcohol intake and preference seen in male controls, but no stress effects were seen on drinking in females. Additionally, NOV males had decreased action potential-independent presynaptic GABA release and delayed postsynaptic GABAA receptor kinetics in the CeA compared to control and FAM males. Despite these changes to alcohol intake and CeA GABA signaling, stressed rats showed broadly similar anxiogenic-like behaviors to our previous comorbid model, suggesting decoupling of the PTSD symptoms from the AUD vulnerability for some of these animals. The collective results show the importance of alcohol history and trauma context in vulnerability to comorbid AUD/PTSD-like symptoms.

Potential causal effect of posttraumatic stress disorder on alcohol use disorder and alcohol consumption in individuals of European descent: A Mendelian Randomization Study.

Posttraumatic stress disorder (PTSD) often co-occurs with alcohol consumption (AC) and alcohol use disorder (AUD). However, it is unknown whether the same etiologic influences that underlie PTSD co-occurring with AUD are those that underlie PTSD and AC individually. This study used large-scale genome-wide association study (GWAS) data to test whether PTSD and drinks per week [DPW]/AUD are causally related to one another, and, if so, whether PTSD precedes DPW/AUD and/or vice versa. We used Mendelian Randomization methods to analyze European ancestry GWAS summary statistics from the Psychiatric Genomics Consortium (PGC; PTSD), GWAS & Sequencing Consortium of Alcohol and Nicotine Use (GSCAN; DPW), and the Million Veteran Program (MVP; AUD). PTSD exerted a potentially causal effect on AUD (β=0.039, SE=0.014, p=0.005), but not on DPW (β=0.002, SE=0.003, p=0.414). Additionally, neither DPW (β=0.019, SE=0.041, p=0.637) nor AUD (β=8.87×10-4 , SE=0.001, p=0.441) exerted a causal effect on PTSD. These findings are consistent with the self-medication model, in which individuals misuse alcohol to cope with aversive trauma-related symptoms. These findings extend latent analysis and molecular findings of shared and correlated risk between PTSD and alcohol phenotypes. Given the health behaviors associated with these phenotypes, these findings are important in that they suggest groups to prioritize for prevention efforts. Further, they provide a rationale for future preclinical and clinical studies examining the biological mechanisms by which PTSD may impact AUD.

Predicting susceptibility and resilience in an animal model of post-traumatic stress disorder (PTSD)

Post-traumatic stress disorder (PTSD) is a psychiatric disorder whose pathogenesis relies on a maladaptive expression of the memory for a life-threatening experience, characterized by over-consolidation, generalization, and impaired extinction, which are responsible of dramatic changes in arousal, mood, anxiety, and social behavior. Even if subjects experiencing a traumatic event during lifetime all show an acute response to the trauma, only a subset of them (susceptible) ultimately develops PTSD, meanwhile the others (resilient) fully recover after the first acute response. However, the dynamic relationships between the interacting brain circuits that might potentially link trauma-related experiences to the emergence of susceptible and resilient PTSD phenotypes in individuals is not well understood. Toward the first step to reach this goal, we have implemented our experimental PTSD model previously developed, making it suitable to differentiate between susceptible (high responders, HR) and resilient (low responders, LR) rats in terms of over-consolidation, impaired extinction, and social impairment long after trauma. Rats were exposed to five footshocks paired with social isolation. One week after trauma but before extinction, animals were tested in the Open Field and Social Interaction tasks for the identification of a predictive variable to identify susceptible and resilient animals before the possible appearance of a PTSD-like phenotype. Our findings show that exploratory activity after trauma in a novel environment is a very robust variable to predict susceptibility towards a PTSD-like phenotype. This experimental model is thus able to screen and differentiate, before extinction learning and potential therapeutic intervention, susceptible and resilient PTSD-like rats.

Associations between PTSD symptoms and suicide risk: A comparison of 4-factor and 7-factor models

BackgroundWhile posttraumatic stress disorder (PTSD) symptoms in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) are categorized into four clusters, emerging studies suggest the disorder is best characterized by seven symptom clusters: re-experiencing, avoidance, negative affect, anhedonia, externalizing behaviors, and anxious and dysphoric arousal symptoms. However, data are sparse regarding the relation between this novel model of DSM-5 PTSD symptoms and suicide risk. MethodsUsing data from the National Survey for Stress and Health, a sample of 6180 Japanese individuals, we evaluated the relationship between suicide ideation and PTSD symptoms using 4- and 7-factor models. ResultsDifferent association patterns were observed between each model and suicidal ideation. In the 4-factor model, we found re-experiencing feelings (odds ratio [OR] = 1.03, 95% confidence interval [CI] = 1.01–1.06, p = 0.002), negative alterations in cognition and mood symptoms (OR = 1.08, 95%CI = 1.06–1.09, p < 0.001), and hyperarousal (OR = 1.03, 95% CI = 1.01–1.05, p = 0.014) were associated with increased suicide ideation. In the 7-factor model, we found re-experiencing feelings (OR = 1.04, 95%CI = 1.02–1.06, p = 0.001), negative affect (OR = 1.04, 95%CI = 1.01–1.07, p = 0.012), anhedonia (OR = 1.08–1.16, 95%CI, p < 0.001), and externalizing behavior (OR = 1.12, 95%CI = 1.07–1.17, p < 0.001) were associated with increased suicide risk. ConclusionsA more refined 7-factor model of DSM-5 PTSD symptoms may help us understand their associations with comorbid psychopathology and suicide. Prevention and treatment efforts that target distinct aspects of the PTSD phenotype may be more effective in mitigating key clinical and functional outcomes in this population.

Classifying post-traumatic stress disorder using the magnetoencephalographic connectome and machine learning

Given the subjective nature of conventional diagnostic methods for post-traumatic stress disorder (PTSD), an objectively measurable biomarker is highly desirable; especially to clinicians and researchers. Macroscopic neural circuits measured using magnetoencephalography (MEG) has previously been shown to be indicative of the PTSD phenotype and severity. In the present study, we employed a machine learning-based classification framework using MEG neural synchrony to distinguish combat-related PTSD from trauma-exposed controls. Support vector machine (SVM) was used as the core classification algorithm. A recursive random forest feature selection step was directly incorporated in the nested SVM cross validation process (CV-SVM-rRF-FS) for identifying the most important features for PTSD classification. For the five frequency bands tested, the CV-SVM-rRF-FS analysis selected the minimum numbers of edges per frequency that could serve as a PTSD signature and be used as the basis for SVM modelling. Many of the selected edges have been reported previously to be core in PTSD pathophysiology, with frequency-specific patterns also observed. Furthermore, the independent partial least squares discriminant analysis suggested low bias in the machine learning process. The final SVM models built with selected features showed excellent PTSD classification performance (area-under-curve value up to 0.9). Testament to its robustness when distinguishing individuals from a heavily traumatised control group, these developments for a classification model for PTSD also provide a comprehensive machine learning-based computational framework for classifying other mental health challenges using MEG connectome profiles.

Examination of the effects of impulsivity and risk-taking propensity on alcohol use in OEF/OIF/OND Veterans.

A strong association between posttraumatic stress disorder (PTSD) and problematic alcohol use has been demonstrated among Veteran populations exposed to combat trauma. Several traits, such as higher levels of risk-taking propensity (RTP) and impulsivity (e.g., negative urgency [NU]), are associated with both increased PTSD symptom-atology and greater alcohol use problems. The present study examined the effects of NU and RTP on alcohol use (measured by average weekly alcohol consumption and number of binge drinking days in 1 month), as well as their potential moderating effects on the association between PTSD symptom severity and alcohol use in a sample of Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) US Veterans. We hypothesized that NU and RTP would both significantly predict alcohol use and moderate the relation between PTSD symptom severity and alcohol use, such that the association between PTSD symptoms and alcohol use would be greater among individuals high compared to low in NU and RTP. As hypothesized, the main effects of RTP and NU were significantly positively associated with average weekly alcohol consumption and the number of binge drinking days in the past month. However, neither NU nor RTP moderated the relation between PTSD and either alcohol variable. NU and RTP may represent transdiagnostic risk markers for PTSD and alcohol use problems; however, the current study did not support an exploratory role of NU or RTP in the association between PTSD and alcohol use phenotypes.

A Review of Epigenetics of PTSD in Comorbid Psychiatric Conditions.

Post-traumatic stress disorder (PTSD) is an acquired psychiatric disorder with functionally impairing physiological and psychological symptoms following a traumatic exposure. Genetic, epigenetic, and environmental factors act together to determine both an individual’s susceptibility to PTSD and its clinical phenotype. In this literature review, we briefly review the candidate genes that have been implicated in the development and severity of the PTSD phenotype. We discuss the importance of the epigenetic regulation of these candidate genes. We review the general epigenetic mechanisms that are currently understood, with examples of each in the PTSD phenotype. Our focus then turns to studies that have examined PTSD in the context of comorbid psychiatric disorders or associated social and behavioral stressors. We examine the epigenetic variation in cases or models of PTSD with comorbid depressive disorders, anxiety disorders, psychotic disorders, and substance use disorders. We reviewed the literature that has explored epigenetic regulation in PTSD in adverse childhood experiences and suicide phenotypes. Finally, we review some of the information available from studies of the transgenerational transmission of epigenetic variation in maternal cases of PTSD. We discuss areas pertinent for future study to further elucidate the complex interactions between epigenetic modifications and this complex psychiatric disorder.

Differentiating PTSD from anxiety and depression: Lessons from the ICD-11 PTSD diagnostic criteria.

Posttraumatic stress disorder (PTSD) is frequently associated with depression and anxiety, but the nature of the relationship is unclear. By removing mood and anxiety diagnostic criteria, the 11th edition of the International Classification of Diseases (ICD-11) aims to delineate a distinct PTSD phenotype. We examined the effect of implementing ICD-11 criteria on rates of codiagnosed depression and anxiety in survivors with recent PTSD. Participants were 1,061 survivors of traumatic injury admitted to acute care centers in Israel. ICD-10 and ICD-11 diagnostic rules were applied to the Clinician-Administered PTSD Scale for DSM-IV. Co-occurring disorders were identified using the Structured Clinical Interview for DSM-IV (SCID). Depression severity was measured by the Beck Depression Inventory-II (BDI-II). Assessments were performed 0-60 ("wave 1") and 90-240 ("wave 2") days after trauma exposure. Participants identified by ICD-11 PTSD criteria were equally or more likely than those identified by the ICD-10 alone to meet depression or anxiety disorder diagnostic criteria (for wave 1: depressive disorders, OR[odds ratio]=1.98, 95% CI[confidence interval] =[1.36, 2.87]; anxiety disorders, OR=1.04, 95% CI=[0.67, 1.64]; for wave 2: depressive disorders, OR=1.70, 95% CI=[1.00, 2.91]; anxiety disorders, OR=1.04, 95% CI=[0.54, 2.01]). ICD-11 PTSD was associated with higher BDI scores (M=23.15vs. 17.93, P<0.001 for wave 1; M=23.93vs. 17.94, P<0.001 for wave 2). PTSD symptom severity accounted for the higher levels of depression in ICD-11 PTSD. Despite excluding depression and anxiety symptom criteria, the ICD-11 identified equal or higher proportion of depression and anxiety disorders, suggesting that those are inherently associated with PTSD.

Role of Endogenous and Exogenous Corticosterone on Behavioral and Cognitive Responses to Low-Pressure Blast Wave Exposure.

The complex interactions and overlapping symptoms of comorbid post-traumatic stress disorder (PTSD) and mild traumatic brain injury (mTBI) induced by an explosive blast wave have become a focus of attention in recent years, making clinical distinction and effective intervention difficult. Because dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is thought to underlie trauma-related (psycho)pathology, we evaluated both the endogenous corticosterone response and the efficacy of exogenous hydrocortisone treatment provided shortly after blast exposure. We employed a controlled experimental blast-wave paradigm in which unanesthetized animals were exposed to visual, auditory, olfactory, and tactile effects of an explosive blast wave produced by exploding a thin copper wire. Endogenous corticosterone concentrations were evaluated at different time points (before, and 3 h, 5 h and 17 days) after blast exposure. Subsequently, the efficacy of exogenous hydrocortisone (25 mg/kg-1 or 125 mg/kg-1) injected intraperitoneally 1 h after exposure was compared with that of a similarly timed saline injection. Validated cognitive and behavioral tests were used to assess both PTSD and mTBI phenotypes on days 7-14 following the blast. Retrospective analysis revealed that animals demonstrating the PTSD phenotype exhibited a significantly blunted endogenous corticosterone response to the blast compared with all other groups. Moreover, a single 125 mg/kg-1 dose of hydrocortisone administered 1 h after exposure significantly reduced the occurrence of the PTSD phenotype. Hydrocortisone treatment did not have a similar effect on the mTBI phenotype. Results of this study indicate that an inadequate corticosteroid response following blast exposure increases risk for PTSD phenotype, and corticosteroid treatment is a potential clinical intervention for attenuating PTSD. The differences in patterns of physiological and therapeutic response between PTSD and mTBI phenotypes lend credence to the retrospective behavioral and cognitive classification criteria we designed, and is in keeping with the assumption that mTBI and PTSD phenotypes may reflect distinct underlying biological and clinical profiles.

Neurotransmitter, Peptide, and Steroid Hormone Abnormalities in PTSD: Biological Endophenotypes Relevant to Treatment.

This review summarizes neurotransmitter, peptide, and other neurohormone abnormalities associated with posttraumatic stress disorder (PTSD) and relevant to development of precision medicine therapeutics for PTSD. As the number of molecular abnormalities associated with PTSD across a variety of subpopulations continues to grow, it becomes clear that no single abnormality characterizes all individuals with PTSD. Instead, individually variable points of molecular dysfunction occur within several different stress-responsive systems that interact to produce the clinical PTSD phenotype. Future work should focus on critical interactions among the systems that influence PTSD risk, severity, chronicity, comorbidity, and response to treatment. Effort also should be directed toward development of clinical procedures by which points of molecular dysfunction within these systems can be identified in individual patients. Some molecular abnormalities are more common than others and may serve as subpopulation biological endophenotypes for targeting of currently available and novel treatments.

Blunted basal corticosterone pulsatility predicts post-exposure susceptibility to PTSD phenotype in rats

The basal activity of the hypothalamic–pituitary–adrenal axis is highly dynamic and is characterized by both circadian and ultradian (pulsatile) patterns of hormone secretion. Pulsatility of glucocorticoids has been determined to be critical for optimal transcriptional, neuroendocrine, and behavioral responses. We used an animal model of post-traumatic stress disorder (PTSD) to assess whether stress-induced impairment of behavioral responses is correlated with aberrant secretion of corticosterone. Serial blood samples were collected manually via the jugular vein cannula during the light-(inactive)-phase in conscious male rats at 20-min intervals for a period of 5 h before and 6.5 h after exposure to predator scent stress. The outcome measures included behavior in an elevated plus-maze and acoustic startle response 7 days after exposure. Individual animals were retrospectively classified as having “extreme”, “partial”, or “minimal” behavioral responses according to pre-set cut-off criteria for behavioral response patterns. Corticosterone secretion patterns were analyzed retrospectively. Under basal conditions, the amplitude of ultradian oscillations of corticosterone levels, rather than the mean corticosterone level or the frequency of corticosterone pulsatility, was significantly reduced in individuals who displayed PTSD-phenotype 8 days later. In addition, extreme disruption of behavior on day 8 post-exposure was also characterized by a blunting of corticosterone response to the stressor. Animals with behavior that was only partially affected or unaffected displayed none of the above changes.Blunted basal corticosterone pulse amplitude is a pre-existing susceptibility or risk factor for PTSD, which originates from prior (life) experiences and may therefore predict post-exposure PTSD-phenotype in rats.