Post-traumatic Stress Disorder in children and adolescents: from Sigmund Freud's "trauma" to psychopathology and the (Dys)metabolic syndrome.

Post-traumatic Stress Disorder (PTSD) is an anxiety syndrome that develops after exposure to traumatic life events. Symptoms include re-experience of the initial trauma, avoidance of stimuli associated with the trauma and symptoms of excessive arousal. Neuroendocrine studies in adults with PTSD have demonstrated that basal cerebrospinal fluid (CSF) CRH levels are elevated and urinary cortisol levels are variable--low in the majority of cases--whereas other studies demonstrate no differences in urinary and plasma cortisol concentrations. Urinary catecholamine excretion is higher in PTSD patients than those of control subjects and other psychiatric disorders. Children may differ from adults in their psychologic and physiologic responses to severe stressors. Also, exposure to stress during critical periods of development may have irreversible effects on behavioral maturation and may affect specific vulnerable brain areas, altering CNS development. Similar to findings in adult studies, PTSD in children is characterized by increased sympathetic nervous system (SNS) activity, as indicated by elevated norepinephrine levels in the periphery. High cortisol levels in urine or saliva have been reported in most studies of childhood PTSD, while prospective longitudinal studies concerning the natural history of neuroendocrine changes in pediatric PTSD after an acute stressor are limited. The identification of neurobiologic changes in response to early adverse experiences is of major importance for the prognosis, prevention, management, and treatment of children and adolescents at risk for or suffering from PTSD.     

Maternal Separation Enhances Conditioned Fear and Decreases the mRNA Levels of the Neurotensin Receptor 1 Gene with Hypermethylation of This Gene in the Rat Amygdala

Stress during postnatal development is associated with an increased risk for depression, anxiety disorders, and substance abuse later in life, almost as if mental illness is able to be programed by early life stressors. Recent studies suggest that such “programmed” effects can be caused by epigenetic regulation. With respect to conditioned fear, previous studies have indicated that early life stress influences its development in adulthood, whereas no potential role of epigenetic regulation has been reported. Neurotensin (NTS) is an endogenous neuropeptide that has receptors densely located in the amygdala and hippocampus. Recently, NTS systems have constituted an emerging target for the treatment of anxiety. The aim of the present work is to clarify whether the NTS system is involved in the disturbance of conditioned fear in rats stressed by maternal separation (MS). The results showed that MS enhanced freezing behaviors in fear-conditioned stress and reduced the gene expression of NTS receptor (NTSR) 1 but not of NTS or NTSR2 in the amygdalas of adult rats. The microinjection of a NTSR1 antagonist into the amygdala increased the percentage of freezing in conditioned fear, whereas the microinjection of NTSR1 agonist decreased freezing. These results suggest that NTSR1 in the amygdala may play a role in the effects of MS on conditioned fear stress in adult rats. Moreover, MS increased DNA methylation in the promoter region of NTSR1 in the amygdala. Taken together, MS may leave epigenetic marks in the NTSR1 gene in the amygdala, which may enhance conditioned fear in adulthood. The MS-induced alternations of DNA methylation in the promoter region of NTSR1 in the amygdala may be associated with vulnerability to the development of anxiety disorders and depression in adulthood.     

The role of hormones of hypothalamic-pituitary-adrenocortical system in regulation of pain sensitivity

The review focuses on the role of hypothalamic-pituitary-adrenocortical system (HPAS) in regulation of pain sensitivity and discusses the mechanisms involved in this process. Analgesic effects of exogenous hormones of HPAS (corticotropin-releasing hormone (CRH), ACTH, glucocorticoids) have been shown in rats. It is mediated by both opioid and non-opioid mechanisms. Endogenous glucocorticoids produce development of analgesia mediated by non-opioid mechanisms. Analgesic effect of ACTH is mediated by both non-glucocorticoids mechanisms associated with endogenous glucocorticoids and opioid mechanisms. In contrast to ACTH, analgesic effect of CRH is mediated only by non-opioid mechanisms associated or dissociated with endogenous glucocorticoids. The neurons of midbrain periaqueductal gray matter may be involved in the analgesia induced by glucocorticoids.     

Type and Timing of Childhood Maltreatment and Severity of Shutdown Dissociation in Patients with Schizophrenia Spectrum Disorder

Dissociation, particularly the shutting down of sensory, motor and speech systems, has been proposed to emerge in susceptible individuals as a defensive response to traumatic stress. In contrast, other individuals show signs of hyperarousal to acute threat. A key question is whether exposure to particular types of stressful events during specific stages of development can program an individual to have a strong dissociative response to subsequent stressors. Vulnerability to ongoing shutdown dissociation was assessed in 75 inpatients (46M/29F, M = 31±10 years old) with schizophrenia spectrum disorder and related to number of traumatic events experienced or witnessed during childhood or adulthood. The Maltreatment and Abuse Chronology of Exposure (MACE) scale was used to collect retrospective recall of exposure to ten types of maltreatment during each year of childhood. Severity of shutdown dissociation was related to number of childhood but not adult traumatic events. Random forest regression with conditional trees indicated that type and timing of childhood maltreatment could predictably account for 31% of the variance (p < 0.003) in shutdown dissociation, with peak vulnerability occurring at 13-14 years of age and with exposure to emotional neglect followed by various forms of emotional abuse. These findings suggest that there may be windows of vulnerability to the development of shutdown dissociation. Results support the hypothesis that experienced events are more important than witnessed events, but challenge the hypothesis that “life-threatening” events are a critical determinant.     

The physiological roles of placental corticotropin releasing hormone in pregnancy and childbirth

In response to stress, the hypothalamus releases cortiticotropin releasing hormone (CRH) that travels to the anterior pituitary, where it stimulates the release of adrenocorticotropic hormone (ACTH). ACTH travels to the adrenal cortex, where it stimulates the release of cortisol and other steroids that liberate energy stores to cope with the stress. During pregnancy, the placenta synthesises CRH and releases it into the bloodstream at increasing levels to reach concentrations 1,000 to 10, 000 times of that found in the non-pregnant individual. Urocortins, which are CRH analogues are also secreted by the placenta. Desensitisation of the maternal pituitary to CRH and resetting after birth may be a factor in post-partum depression. Recently, CRH has been found to modulate glucose transporter (GLUT) proteins in placental tissue, and therefore there may be a link between CRH levels and foetal growth. Evidence suggests CRH is involved in the timing of birth by modulating signalling systems that control the contractile properties of the myometrium. In the placenta, cortisol stimulates CRH synthesis via activation of nuclear factor kappa B (NF-κB), a component in a cellular messenger system that may also be triggered by stressors such as hypoxia and infection, indicating that intrauterine stress could bring forward childbirth and cause low birth weight infants. Such infants could suffer health issues into their adult life as a result of foetal programming. Future treatment of these problems with CRH antagonists is an exciting possibility.     

Childhood adversity during the post-apartheid transition and COVID-19 stress independently predict adult PTSD risk in urban South Africa: A biocultural analysis of the stress sensitization hypothesis

Objectives

The COVID-19 pandemic in South Africa introduced new societal adversities and mental health threats in a country where one in three individuals are expected to develop a psychiatric condition sometime in their life. Scientists have suggested that psychosocial stress and trauma during childhood may increase one's vulnerability to the mental health consequences of future stressors—a process known as stress sensitization. This prospective analysis assessed whether childhood adversity experienced among South African children across the first 18 years of life, coinciding with the post-apartheid transition, exacerbates the mental health impacts of psychosocial stress experienced during the 2019 coronavirus (COVID-19) pandemic (ca. 2020–2021).

Materials and Methods

Data came from 88 adults who participated in a follow-up study of a longitudinal birth cohort study in Soweto, South Africa. Childhood adversity and COVID-19 psychosocial stress were assessed as primary predictors of adult PTSD risk, and an interaction term between childhood adversity and COVID-19 stress was calculated to evaluate the potential effect of stress sensitization.

Results

Fifty-six percent of adults exhibited moderate-to-severe PTSD symptoms. Greater childhood adversity and higher COVID-19 psychosocial stress independently predicted worse post-traumatic stress disorder symptoms in adults. Adults who reported greater childhood adversity exhibited non-significantly worse PTSD symptoms from COVID-19 psychosocial stress.

Discussion

These results highlight the deleterious mental health effects of both childhood trauma and COVID-19 psychosocial stress in our sample and emphasize the need for greater and more accessible mental health support as the pandemic progresses in South Africa.     

Regulation of Hypothalamo-Pituitary-Adrenocortical Responses to Stressors by the Nucleus of the Solitary Tract/Dorsal Vagal Complex

Hindbrain neurons in the nucleus of the solitary tract (NTS) are critical for regulation of hypothalamo-pituitary-adrenocortical (HPA) responses to stress. It is well known that noradrenergic (as well as adrenergic) neurons in the NTS send direct projections to hypophysiotropic corticotropin-releasing hormone (CRH) neurons and control activation of HPA axis responses to acute systemic (but not psychogenic) stressors. Norepinephrine (NE) signaling via alpha1 receptors is primarily excitatory, working either directly on CRH neurons or through presynaptic activation of glutamate release. However, there is also evidence for NE inhibition of CRH neurons (possibly via beta receptors), an effect that may occur at higher levels of stimulation, suggesting that NE effects on the HPA axis may be context-dependent. Lesions of ascending NE inputs to the paraventricular nucleus attenuate stress-induced ACTH but not corticosterone release after chronic stress, indicating reduction in central HPA drive and increased adrenal sensitivity. Non-catecholaminergic NTS glucagon-like peptide 1/glutamate neurons play a broader role in stress regulation, being important in HPA activation to both systemic and psychogenic stressors as well as HPA axis sensitization under conditions of chronic stress. Overall, the data highlight the importance of the NTS as a key regulatory node for coordination of acute and chronic stress.     

The role of CRH in behavioral responses to stress

Corticotropin-releasing hormone (CRH) and urocortin in the central nervous system affect behavior and can enhance behavioral responses to stressors. The action of CRH-related peptides is mediated through multiple receptors that differ markedly in their pharmacological profiles and anatomical distribution. Comparative pharmacology of CRH receptor agonists suggests that CRH, urocortin, sauvagine and urotensin consistently mimic, and CRH receptor antagonists consistently lessen, functional consequences of stressor exposure. Recently, important advances have been made in understanding the CRH system and its role in behavioral responses to stress by the development of specific CRH receptor antagonists, application of antisense oligonucleotides and development of transgenic mice lacking peptides and functional receptors. This review summarizes recent findings with respect to components of the CRH system and their role in stress-induced behavioral responses.     

The balance between stress resilience and vulnerability is regulated by corticotropin‐releasing hormone during the critical postnatal period for sensory development

Determining whether a stressful event will lead to stress‐resilience or vulnerability depends probably on an adjustable stress response set point, which is most likely effective during postnatal sensory development and involves the regulation of corticotrophin‐releasing hormone (CRH) expression. During the critical period of thermal‐control establishment in 3‐day‐old chicks, heat stress was found to render resilient or sensitized response, depending on the ambient temperature. These two different responses were correlated with the amount of activation of the hypothalamic–pituitary–adrenal (HPA) axis. The expression of CRH mRNA in the hypothalamic paraventricular nucleus was augmented during heat challenge a week after heat conditioning in chicks which were trained to be vulnerable to heat, while it declined in chicks that were trained to be resilient. To study the role of CRH in HPA‐axis plasticity, CRH or Crh‐antisense were intracranially injected into the third ventricle. CRH caused an elevation of both body temperature and plasma corticosterone level, while Crh‐antisense caused an opposite response. Moreover, these effects had long term implications by reversing a week later, heat resilience into vulnerability and vice versa. Chicks that had been injected with CRH followed by exposure to mild heat stress, normally inducing resilience, demonstrated, a week later, an elevation in body temperature, and Crh mRNA level similar to heat vulnerability, while Crh‐antisense injected chicks, which were exposed to harsh temperature, responded in heat resilience. These results demonstrate a potential role for CRH in determining the stress resilience/vulnerability balance. © 2014 Wiley Periodicals, Inc. Develop Neurobiol 75: 842–853, 2015     

Gene-environment interactions in addictive disorders: epidemiological and methodological aspects

The gene-environment interactions' approach could explain some epidemiological and clinical factors associated with addictive behaviours. Twin studies first help to disentangle the respective roles of environment and genetic effects, finding convincing evidence for common genetic vulnerability in several addictive behaviours, and helping to delimit what syndrome could belong to the addictive disorder spectrum. Assessing gene x environment interaction (G x E) needs specifically designed studies, using multiplicative or additive approaches. Focusing on this G x E interaction already showed its relevancy in many recent studies, using both epidemiological and molecular approaches. For example, in a non-human primate model of alcohol dependence assessing the respective role of genetic vulnerability (having the short allele located in the promoter region of the gene coding for the serotonin transporter) and severe fostering conditions (as locked up in a cage with other inmates for the first six months of life), the only group of monkeys that has a significant risk of using spontaneously alcohol is the one that gathers both risk factors, i.e. being peer-raised and having the short allele. Such approach could help to more accurately select specific candidate genes, to identify more homogenous subgroups of patients (as sharing the same genetic vulnerability), to understand how genetic factors mediate the risk of associated psychiatric disorders, and ultimately, may lead to more focused, i.e. more efficient, prevention strategies.     

Altered response to neuroendocrine challenge linked to indices of the metabolic syndrome in healthy adults

Metabolic syndrome (MetS) is characterized by central obesity, hypertension, insulin resistance, and hypercholesterolemia. Hypothalamic-pituitary-adrenal (HPA) axis activity is frequently abnormal in MetS, and excessive cortisol exposure may be implicated in metabolic derangements. We investigated the hypothesis that cortisol and adrenocorticotropic hormone (ACTH) responses to a standardized neuroendocrine challenge test would be associated with indices of MetS in a community sample of healthy adults. Healthy adults, 125 men and 170 women, without significant medical problems or chronic medications were recruited from the community. Participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, and anthropometric measurements, blood pressure, glycosylated hemoglobin (HbA1c), and cholesterol were measured. Participants reported on their history of early life stress and recent stress, as well as mood and anxiety symptoms. Cortisol and ACTH responses to the Dex/CRH test were negatively associated with measures of central adiposity (p<0.001) and blood pressure (p<0.01), and positively associated with HDL cholesterol (p<0.01). These findings remained significant after controlling for body mass index (BMI). Measures of stress and anxiety and depressive symptoms were negatively correlated with cortisol and ACTH responses in the Dex/CRH test but were not related to MetS indices. That altered HPA axis function is linked to MetS components even in a healthy community sample suggests that these processes may be involved in the pathogenesis of MetS. Identification of premorbid risk processes might allow for detection and intervention prior to the development of disease.     

Psychophysiological markers of vulnerability to psychopathology in men with an extra X chromosome (XXY)

Studying genetically defined syndromes associated with increased risk for psychopathology may help in understanding neurodevelopmental mechanisms related to risk for psychopathology. Klinefelter syndrome (47,XXY) is one of the most common sex chromosomal aneuploidies (1 in 650 male births) and associated with increased vulnerability for psychopathology, including psychotic symptoms. Yet, it remains unknown whether this increased risk is associated with underlying psychophysiological mechanisms that are typically deficient in individuals with psychotic disorders. The present study assessed three "classic" psychophysiological markers of psychosis in Klinefelter syndrome (KS): smooth pursuit eye movements (SPEM), prepulse inhibition (PPI) and P50 suppression. Fourteen adults with KS and 15 non-clinical adults participated in the study. Data on SPEM (reflecting visuo-motor control) as well as PPI and P50 suppression (reflecting sensory gating) were collected. Dysfunctions in SPEM were observed in individuals with KS, with less smooth pursuit as expressed in lower position gain. Also, reduced sensory gating in individuals with KS was suggested by significantly reduced prepulse inhibition of the startle response (PPI) (effect size 1.6). No abnormalities were found in suppression of the P50 (effect size 0.6). We speculate that impairments in these psychophysiological mechanisms may reflect core brain dysfunctions that may also mediate the described increased vulnerability for psychotic symptoms in KS. Although speculative, such deficit specific, rather than disorder specific, psychophysiological dysfunctions in KS might convey vulnerability to other types of psychopathology as well. As KS already can be diagnosed prenatally, the predictive value of childhood impairments in prepulse inhibition and smooth pursuit for development of psychopathology later in life could be assessed. In sum, studying individuals with KS may prove to be an avenue of research leading to new hypotheses and insights into "at risk" pathways to psychopathology.     

Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress

Intestinal dysfunction is related to stress and early life events, but the mechanisms are largely unknown. Our aim was to determine whether early trauma predisposes adult rats to intestinal mucosal dysfunction in response to stress. Neonatal Sprague-Dawley rats were individually separated from their mothers for 3 h/day at 4-21 days of age. Between days 80 and 90, separated and control rats were subjected to mild acute stress (30-min water avoidance) or sham stress. Mucosal barrier function and ion transport were assessed in colonic tissues mounted in Ussing chambers. Mild stress increased short-circuit current, conductance, and transepithelial transport of macromolecules in separated rats, while having minimal effects in controls. Pretreatment of the separated rats with a corticotropin-releasing hormone (CRH) antagonist, the peptide alpha-helical CRH(9-41) injected intraperitoneally 20 min before stress, abolished the stress-induced mucosal changes. Our results indicate that neonatal trauma can induce phenotypic changes in adulthood, including enhanced vulnerability of the gut mucosa to stress via mechanisms involving peripherally located CRH receptors.     

Do smart birds stress less? An interspecific relationship between brain size and corticosterone levels

Vertebrates respond to unpredictable noxious environmental stimuli by increasing secretion of glucocorticoids (CORT). Although this hormonal stress response is adaptive, high levels of CORT may induce significant costs if stressful situations are frequent. Thus, alternative coping mechanisms that help buffer individuals against environmental stressors may be selected for when the costs of CORT levels are elevated. By allowing individuals to identify, anticipate and cope with the stressful circumstances, cognition may enable stress-specific behavioural coping. Although there is evidence that behavioural responses allow animals to cope with stressful situations, it is unclear whether or not cognition reduces investment in the neuroendocrine stress response. Here, we report that in birds, species with larger brains relative to their body size show lower baseline and peak CORT levels than species with smaller brains. This relationship is consistent across life-history stages, and cannot be accounted for by differences in life history and geographical latitude. Because a large brain is a major feature of birds that base their lifetime in learning new things, our results support the hypothesis that enhanced cognition represents a general alternative to the neuroendocrine stress response.     

Resilience and vulnerability are dose-dependently related to neonatal stressors in mice

Early life experiences have been shown to adjust cognitive abilities, stress reactivity, fear responses and immune activity in adult mammals of many species. However, whereas severe stressors have been generally associated with the emergence of hypothalamic pituitary adreno-cortical (HPA)-mediated pathology, mild neonatal stressful experiences have been traditionally associated with ‘positive’ effects or resilience. External stressors stimulate the HPA axis to induce a corticosterone secretion in mouse dams, which, in turn is directly transmitted to the progeny through lactation. Such corticosteroid transfer may offer a unitary mechanism whereby early low corticosterone exposure may favor resilience in the offspring and high corticosterone increase vulnerability to pathology. In this study we further investigated this hypothesis by evaluating the long-term effects of a neonatal exposure to low (33 mg/l) and high (100 mg/l) doses of corticosterone during the first 10 days of life in outbred CD-1 mice through supplementation in the maternal drinking water. Offspring attentional set-shifting abilities, central neurotrophic regulation and levels of natural auto-antibodies (na-Abs) directed to serotonin (SERT) and dopamine (DAT) transporters were assessed in adulthood. While low levels of neonatal corticosterone improved adult cognitive abilities and increased na-Abs levels directed to SERT, high doses of neonatal corticosterone reduced hippocampal BDNF levels and na-Abs directed to DAT. These findings confirm and extend our previous findings, supporting the view that both adaptive plasticity and pathological outcomes in adulthood may depend on circulating neonatal corticosterone levels and that these effects follow a U-shaped profile.     

The lasting impact of early‐life adversity on individuals and their descendants: potential mechanisms and hope for intervention

The adverse effects of early‐life stress are pervasive, with well‐established mental and physical health consequences for exposed individuals. The impact of early adverse experiences is also highly persistent, with documented increases in risk for mental illness across the life span that are accompanied by stable alterations in neural function and hormonal responses to stress. Here, we review some of these ‘stress phenotypes’, with a focus on intermediary factors that may signal risk for long‐term mental health outcomes, such as altered development of the fear regulation system. Intriguingly, recent research suggests that such stress phenotypes may persist even beyond the life span of the individuals, with consequences for their offspring and grand‐offspring. Phenotypic characteristics may be transmitted to future generations via either the matriline or the patriline, a phenomenon that has been demonstrated in both human and animal studies. In this review, we highlight behavioral and epigenetic factors that may contribute to this multigenerational transmission and discuss the potential of various treatment approaches that may halt the cycle of stress phenotypes.     

Epigenetics and memory: causes,consequences and treatments for post‐traumatic stress disorder and addiction

Understanding the interaction between fear and reward at the circuit and molecular levels has implications for basic scientific approaches to memory and for understanding the etiology of psychiatric disorders. Both stress and exposure to drugs of abuse induce epigenetic changes that result in persistent behavioral changes, some of which may contribute to the formation of a drug addiction or a stress‐related psychiatric disorder. Converging evidence suggests that similar behavioral, neurobiological and molecular mechanisms control the extinction of learned fear and drug‐seeking responses. This may, in part, account for the fact that individuals with post‐traumatic stress disorder have a significantly elevated risk of developing a substance use disorder and have high rates of relapse to drugs of abuse, even after long periods of abstinence. At the behavioral level, a major challenge in treatments is that extinguished behavior is often not persistent, returning with changes in context, the passage of time or exposure to mild stressors. A common goal of treatments is therefore to weaken the ability of stressors to induce relapse. With the discovery of epigenetic mechanisms that create persistent molecular signals, recent work on extinction has focused on how modulating these epigenetic targets can create lasting extinction of fear or drug‐seeking behavior. Here, we review recent evidence pointing to common behavioral, systems and epigenetic mechanisms in the regulation of fear and drug seeking. We suggest that targeting these mechanisms in combination with behavioral therapy may promote treatment and weaken stress‐induced relapse.