Leveraging the Biology of Adversity and Resilience to Transform Pediatric Practice.

Advances in science are fundamentally changing the way we understand how inextricable interactions among genetic predispositions, physical and social environments, and developmental timing influence early childhood development and the foundations of health and how significant early adversity can lead to a lifetime of chronic health impairments. This article and companion article illustrate the extent to which differential outcomes are shaped by ongoing interactive adaptations to context that begin at or even before conception and continue throughout life, with increasing evidence pointing to the importance of the prenatal period and early infancy for the developing brain, the immune system, and metabolic regulation. Although new discoveries in the basic sciences are transforming tertiary medical care and producing breakthrough outcomes in treating disease, this knowledge is not being leveraged effectively to inform new approaches to promoting whole-child development and preventing illness. The opportunity for pediatrics to serve as the leading edge of science-based innovation across the early childhood ecosystem has never been more compelling. In this article, we present a framework for leveraging the frontiers of scientific discovery to inform new strategies in pediatric practice and advocacy to protect all developing biological systems from the disruptive effects of excessive early adversity beyond providing information on child development for parents and enriched learning experiences for young children.

What's Love Got to do with it: Role of oxytocin in trauma, attachment and resilience.

Oxytocin (OT) is a neurohypophysial hormone and neuropeptide produced by the hypothalamus and released by the pituitary gland. It has multiple physiological roles including stimulation of parturition and lactation, and promotion of pro-adaptive social behaviors necessary for mammalian survival. OT interacts with one receptor subtype: the OT receptor (OTR) which, upon stimulation, triggers different intracellular signal transduction cascades to mediate its physiological actions. Preclinical studies show that OT regulates social behaviors such as pair bonding, recognition and social interaction. It also coordinates the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the release of corticotrophin-releasing hormone. Further evidence suggests that OT plays an important role in regulating caloric intake and metabolism, and in maintaining electrolyte and cardiovascular homeostasis. OT is also involved in attenuating the neurophysiological and neurochemical effects of trauma on the brain and body by facilitating both physical attachment such as wound healing, and psychological/social attachment, thereby increasing resilience to subsequent traumatic events. Clinical trials have reported that intranasal administration of OT provides therapeutic benefits for patients diagnosed with traumatic stress-related diseases such as major depressive disorders and post-traumatic stress disorder. OT's therapeutic benefits may result from context-dependent interactions with key neural pathways (social, cognitive, and reward), neurotransmitters (dopamine, norepinephrine, serotonin, and endogenous opioids), and biomarkers (adrenocorticotropic hormone, cortisol, and dehydroepiandrosterone sulfate), that lead to a decrease in stress -associated behaviors, and facilitate post-traumatic growth, ultimately leading to increased resilience, through improved social cohesion and attachment. OT induced-augmentation of physical and cognitive resilience may play a significant role in both the prevention of, and improved clinical outcomes for, traumatic stress-related disorders following either acute or enduring traumatic experiences.

Prenatal traumatic stress and offspring hair cortisol concentration: A nine year follow up to the Red River flood pregnancy study.

INTRODUCTION: Findings concerning the relationship between maternal prenatal and child cortisol concentrations are inconsistent. This study examined whether the influence of an objective traumatic stressor during pregnancy, distance from a natural flood disaster, moderated the association between prenatal maternal diurnal cortisol and 9-year old offspring hair cortisol concentrations. METHODS: Data were collected from 56 of the mothers who took part in a study of flood-related pregnancy outcomes in 2009 and their children. Data included distance of the maternal home from evacuation areas, four maternal saliva cortisol assessments (waking, 30 min after waking, afternoon, and before bed) provided within 3-months of the flood crest and child hair samples to assess cortisol secretion over the past month. RESULTS: There was a significant interaction between proximity to flooding during pregnancy and maternal cortisol AUC predicting child hair cortisol, after controlling for maternal age, gestational age at cortisol sampling, sex of the child, current socioeconomic status and current maternal stress. At greater distance from flooding (lower stress conditions) there was a non-statistically significant positive association between maternal cortisol and child cortisol. In contrast, living closer to flooding (higher stress conditions) produced a significant negative association between maternal and child cortisol. CONCLUSION: Experiencing a traumatic stressor during pregnancy may alter maternal-fetal programming of the hypothalamic-pituitary-adrenal axis. The direct threat of flooding led to offspring cortisol concentrations that resembled cortisol production seen in mothers with symptoms of PTSD and their offspring. This alteration is evident in nine-year-old offspring and may help explain inconsistencies in the previous literature.

The AURORA Study: a longitudinal, multimodal library of brain biology and function after traumatic stress exposure.

Adverse posttraumatic neuropsychiatric sequelae (APNS) are common among civilian trauma survivors and military veterans. These APNS, as traditionally classified, include posttraumatic stress, postconcussion syndrome, depression, and regional or widespread pain. Traditional classifications have come to hamper scientific progress because they artificially fragment APNS into siloed, syndromic diagnoses unmoored to discrete components of brain functioning and studied in isolation. These limitations in classification and ontology slow the discovery of pathophysiologic mechanisms, biobehavioral markers, risk prediction tools, and preventive/treatment interventions. Progress in overcoming these limitations has been challenging because such progress would require studies that both evaluate a broad spectrum of posttraumatic sequelae (to overcome fragmentation) and also perform in-depth biobehavioral evaluation (to index sequelae to domains of brain function). This article summarizes the methods of the Advancing Understanding of RecOvery afteR traumA (AURORA) Study. AURORA conducts a large-scale (n = 5000 target sample) in-depth assessment of APNS development using a state-of-the-art battery of self-report, neurocognitive, physiologic, digital phenotyping, psychophysical, neuroimaging, and genomic assessments, beginning in the early aftermath of trauma and continuing for 1 year. The goals of AURORA are to achieve improved phenotypes, prediction tools, and understanding of molecular mechanisms to inform the future development and testing of preventive and treatment interventions.

Single prolonged stress alters neural activation in the periacqueductal gray and midline thalamic nuclei during emotional learning and memory.

Clinical and preclinical studies that have examined the neurobiology of persistent fear memory in posttraumatic stress disorder (PTSD) have focused on the medial prefrontal cortex, hippocampus, and amygdala. Sensory systems, the periaqueductal gray (PAG), and midline thalamic nuclei have been implicated in fear and extinction memory, but whether neural activity in these substrates is sensitive to traumatic stress (at baseline or during emotional learning and memory) remains unexplored. To address this, we used the single prolonged stress (SPS) model of traumatic stress. SPS and control rats were either subjected to fear conditioning (CS-fear) or presented with CSs alone (CS-only) during fear conditioning. All rats were then subjected to extinction training and testing. A subset of rats were euthanized after each behavioral stage and c-Fos and c-Jun used to measure neural activation in all substrates. SPS lowered c-Jun levels in the dorsomedial and lateral PAG at baseline, but the elevated c-Jun expression in the PAG during emotional learning and memory. SPS also altered c-Fos expression during fear and extinction learning/memory in midline thalamic nuclei. These findings suggest changes in neural function in the PAG and midline thalamic nuclei could contribute to persistent fear memory induced by traumatic stress. Interestingly, SPS effects were also observed in animals that never learned fear or extinction (i.e., CS-only). This raises the possibility that traumatic stress could have broader effects on the psychological function that are dependent on the PAG and midline thalamic nuclei.

Putting Your Trauma Lens On.

Trauma in childhood is now understood to cause long-term effects on the brain and body. The pediatric provider, using a "trauma lens," which constitutes observing a child's attachment, resilience, and stress response, is well poised to identify and support children and families at risk. Fortunately, resilience is a dynamic process that can be learned, enhanced, and supported. Familiarity with the most common symptoms of traumatic stress will help the medical provider quickly recognize which children are impacted or FRAYED (Fits, Frets, and Fear; Regulation disorders; Attachment problems; Yawning and Yelling; Educational and developmental delays; Defeat and Dissociation). Once symptoms are identified, the caregiver can "focus" on attachment and resilience skills, the THREADS (Thinking & learning brain, with opportunity for continued growth; cognitive development; Hope, optimism, faith, belief in a future for one's self; Regulation [self-regulation, self-control]; Efficacy, or knowing one can impact their environment and situation; Attachment, secure; Development, or mastery of age-salient developmental tasks; Social context or the larger network of relationships in which one lives and learns) that can be woven together to promote resilience. Guiding families with empathy and positive regard, the medical provider can help the child and family rebuild resilience skills. Organizing practical guidance around the "3 R's"-Reassuring, Restoring routines, and Regulating-is a roadmap to recovery. [Pediatr Ann. 2019;48(7):e269-e273.].

Pediatrician's Practical Approach to Sleep Disturbances in Children Who Have Experienced Trauma.

Sleep difficulties are a common challenge among children who have experienced trauma. Pediatricians are best positioned to work with families to address sleep challenges after traumatic events and help families return to healthy sleep patterns. In this article, we review the underlying concepts that connect trauma to disturbed sleep, types of sleep difficulties seen in children exposed to trauma, and explore ways in which pediatricians can support families as they help their child return to a normal sleep cycle, including the identification of co-occurring conditions and the use of medications. [Pediatr Ann. 2019;48(7):e280-e285.].

Multiple prenatal stresses increase sexual dimorphism in adult offspring behavior.

INTRODUCTION: Maternal gestational stress and immune activation have independently been associated with affective and neurodevelopmental disorders across the lifespan. We investigated whether rats exposed to prenatal maternal stressors (PNMS) consisting of psychological stress, interleukin (IL)-1ß or both (two-hit stress) during critical developmental windows displayed a behavioral phenotype representative of these conditions. METHODS: Long-Evans dams were exposed to psychological stressors consisting of restraint stress and forced swimming from gestational day (GD)12 to 18 or to no stress (controls). From GD17 until day of delivery, these same animals were injected with saline or IL-1ß as a second hit and immune stressor (5 µg/day, intraperitoneally). The behavior of F1 offspring adults was tested on the open field test, elevated plus maze and affective exploration task on postnatal days (P)90, 100 and 110 respectively. RESULTS: The effects of PNMS differed depending on the specific testing environment and potentially the age at assessment, especially in female offspring. Both locomotion and anxiety-like behavioral measures were susceptible to PNMS effects. In females, psychological stress increased anxiety-like behavior, whereas IL-1ß had an opposite effect, inducing exploration and risk-taking behavior on the open field test and the elevated plus maze. When present, interactions between both stressors limited the anxiogenic effect of psychological stress on its own. In contrast, prenatal psychological stress increased anxiety-like behavior in adult males overall. A similar anxiogenic effect of IL-1ß was only found on the open field test while the Stress*IL-1ß interaction appeared to limit the effect of either alone. Contrarily, the PNMS effects on anxiety-like behavior on the affective exploration task were highly similar between both sexes. Analysis of males and females together revealed an additive effect of Stress and IL-1ß on the number of exits from the refuge, a measure of risk assessment and thus correlated with anxiety. CONCLUSION: PNMS affected offspring adult behavior in a sex-dependent manner. Effects on females were more variable, whereas psychological stress mostly induced anxiety-like behavior in males. These data highlight the sexual dimorphism in vulnerability to prenatal stressors. Maternal or stress-induced programming of the stress response and neuroinflammation may play an important role in mediating stress effects on offspring adult behavior.

Augmentation of Extinction and Inhibitory Learning in Anxiety and Trauma-Related Disorders.

Although the fear response is an adaptive response to threatening situations, a number of psychiatric disorders feature prominent fear-related symptoms caused, in part, by failures of extinction and inhibitory learning. The translational nature of fear conditioning paradigms has enabled us to develop a nuanced understanding of extinction and inhibitory learning based on the molecular substrates to systems neural circuitry and psychological mechanisms. This knowledge has facilitated the development of novel interventions that may augment extinction and inhibitory learning. These interventions include nonpharmacological techniques, such as behavioral methods to implement during psychotherapy, as well as device-based stimulation techniques that enhance or reduce activity in different regions of the brain. There is also emerging support for a number of psychopharmacological interventions that may augment extinction and inhibitory learning specifically if administered in conjunction with exposure-based psychotherapy. This growing body of research may offer promising novel techniques to address debilitating transdiagnostic fear-related symptoms.

Pain perception and modulation in ex-POWs who underwent torture: The role of subjective and objective suffering.

OBJECTIVE: Previous findings have demonstrated that torture survivors exhibit chronic pain and alterations in pain perception. However, not much is known regarding the characteristics of the torture experience and its contribution to these long-term ramifications. The current study examined the unique role of objective severity and subjective suffering in torture in predicting chronic pain and acute pain perception and pain modulation. METHOD: Eighteen years after war, 59 former prisoners of war who were subjected to severe torture in captivity were assessed for subjective suffering in torture and estimated weight loss during captivity (an indication of torture severity) using self-administered questionnaires. Thirty-five years after captivity, systemic quantitative somatosensory testing was conducted, which included the measurement of pain threshold, pain tolerance, conditioned pain modulation, and perceived suprathreshold stimuli. Self-administered questionnaires were also used to evaluate chronic pain and posttraumatic stress disorder. RESULTS: The findings indicated that subjective suffering was associated with pain threshold, conditioned pain modulation, perceived suprathreshold stimuli, and chronic pain while controlling for posttraumatic stress symptoms. Estimated weight loss was associated only with pain threshold. CONCLUSION: The findings demonstrate that the experience of chronic and acute pain is rooted in the subjective perception of traumatic experiences. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Harnessing Electroceuticals to Treat Disorders Arising From Traumatic Stress: Theoretical Considerations Using A Psychosensory Model.

Traumatically encoded memories can last a lifetime. These memories, either by purposeful or inadvertent re-activation, cause the release of stress hormones and generate a persistent and inescapable allostatic load on the body, brain and mind. This leads to a maladaptive response, as the ability to return to pre-event homeostasis is no longer possible. The consequence of this response is that it increases risk for further traumatization and other disorders. Remarkably, recent research has shown that these memories become labile and subject to disruption upon recall. In this paper we outline conditions needed for an event to be encoded as a trauma and describe a method that abrogates the release stress hormones when cued by these memories of the event. Critical to this process is the AMPA receptor (so named for its specific agonist, AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, a compound that acts as glutamate, its natural substrate). It is hypothesized that traumatic encoding requires increasing the number and permanence of AMPA receptors on the lateral nucleus of the amygdala by a process called synaptic potentiation. Depotentiation, that is removal of these AMPA receptors, is required for de-encoding. We speculate that the generation of oscillatory intracellular calcium waves is necessary for this to occur. Electromagnetic fields, acting as electroceuticals, interact with voltage-gated calcium channels on depolarized post-synaptic membranes to produce these intracellular calcium oscillations of varying frequency. These oscillatory calcium waves are decoded by intracellular calmodulin which, depending on the frequency, either act to potentiate or depotentiate AMPA receptors. This article describes the theory and practical application of a psychosensory approach called Event Havening that generates an electromagnetic field to synaptically depotentiate these encoded AMPA receptors and eliminate the effects of traumatic encoding.

[Evaluation of verbal inhibitory control with the Stroop Test in early episodes of psychosis with the experience of traumatic events in infancy]. / Evaluacion del control inhibitorio verbal con el test de Stroop en primeros episodios de psicosis con experiencia de trauma en la infancia.

INTRODUCTION: Data from clinical experience highlight the high prevalence of traumatic experiences in subjects with schizophrenia spectrum disorder. However, much is left to examine about the effect of traumatic experiences in the development and severity of psychosis. The Stroop Test assess the verbal response inhibition, an executive function which allows to stop an automatic response and makes possible the inhibition of new behaviours, depending on the situation. AIM: To examine the relationship between subjective experience of trauma, verbal response inhibition in the Stroop Test, and severity of the diagnosis at six months from the onset of the disease, in patients with first episode psychosis. PATIENTS AND METHODS: Data were obtained from a longitudinal intervention program of first-episode of psychosis (PAFIP) conducted at the University Hospital Marques de Valdecilla, Spain. The variables of interest in the present study were the Stroop Test and the Childhood Trauma Questionnaire as part of the neuropsychological assessment of PAFIP. RESULTS: Statistically significant differences were obtained in verbal response inhibition, being more subjects with high response inhibition when the said trauma was of low intensity. CONCLUSIONS: These data support the relationship between intensity of the traumatic experience in childhood and response inhibition dysfunction in people with first episode psychosis, although we cannot conclude a more severe diagnosis at six months from the onset of psychosis in people with traumatic experiences more intense.

TITLE: Evaluacion del control inhibitorio verbal con el test de Stroop en primeros episodios de psicosis con experiencia de trauma en la infancia.Introduccion. Los datos aportados por la experiencia clinica evidencian la elevada prevalencia de experiencias traumaticas en sujetos que desarrollan psicosis. No obstante, queda mucho por examinar sobre el efecto de las experiencias traumaticas en su desarrollo y gravedad. El test de Stroop mide la inhibicion cognitiva verbal, una funcion ejecutiva que permite frenar una respuesta automatizada y posibilita la inhibicion de comportamientos alternativos a los ya aprendidos, en funcion de las demandas. Objetivo. Examinar la relacion entre la experiencia subjetiva de trauma, el control inhibitorio verbal medido con el test de Stroop y la gravedad del diagnostico a los seis meses desde el inicio de la enfermedad en sujetos con un primer episodio psicotico. Pacientes y metodos. La muestra estuvo formada por 119 pacientes del «Programa Asistencial para Fases Iniciales de Psicosis¼ del Hospital Universitario Marques de Valdecilla. Las variables de interes fueron el test de Stroop y el Childhood Trauma Questionnaire como parte del protocolo de evaluacion neuropsicologica de dicho programa. Resultados. Se obtuvieron diferencias estadisticamente significativas en control inhibitorio verbal y se encontro un mayor numero de sujetos con alto control inhibitorio cuando el trauma referido fue de baja intensidad. Conclusiones. Estos datos confirman la relacion entre intensidad de la experiencia traumatica en la infancia y alteracion del control inhibitorio verbal en personas con primer episodio psicotico, aunque no permiten concluir una mayor gravedad del diagnostico a los seis meses del inicio de la psicosis en personas con experiencias traumaticas de mayor intensidad.

Secondary traumatic stress increases expression of proteins implicated in peripheral and central sensitization of trigeminal neurons.

The pathology of migraine, a common neurological disease, involves sensitization and activation of trigeminal nociceptive neurons to promote hyperalgesia and allodynia during an attack. Migraineurs often exhibit characteristics of a hyperexcitable or hypervigilant nervous system. One of the primary reported risk factors for development of a hyperexcitable trigeminal system is chronic, unmanaged stress and anxiety. While primary traumatic stress is a commonly cited risk factor for many pain conditions, exposure to secondary traumatic stress early in life is also thought to be a contributing risk factor. The goal of this study was to investigate cellular changes within the spinal trigeminal nucleus and trigeminal ganglion mediated by secondary traumatic stress. Male Sprague Dawley rats (sender) were subjected to forced swim testing (primary traumatic stress) and were then housed in close visual, olfactory, and auditory proximity to the breeding male and female rats, pregnant female rats, or female rats and their nursing offspring (all receivers). In response to secondary stress, levels of calcitonin gene-related peptide, active forms of the mitogen activated protein kinases ERK, JNK, and p38, and astrocyte expression of glial fibrillary acidic protein were significantly elevated in the spinal trigeminal nucleus in day 45 offspring when compared to naïve offspring. In addition, increased nuclear expression of ERK and p38 was observed in trigeminal ganglion neurons. Our results demonstrate that secondary traumatic stress promotes cellular events associated with prolonged trigeminal sensitization in the offspring, and provides a mechanism of how early life stress may function as a risk factor for migraine.

The impact of traumatic stress on Pavlovian biases.

BACKGROUND: Disturbances in Pavlovian valuation systems are reported to follow traumatic stress exposure. However, motivated decisions are also guided by instrumental mechanisms, but to date the effect of traumatic stress on these instrumental systems remain poorly investigated. Here, we examine whether a single episode of severe traumatic stress influences flexible instrumental decisions through an impact on a Pavlovian system. METHODS: Twenty-six survivors of the 2011 Norwegian terror attack and 30 matched control subjects performed an instrumental learning task in which Pavlovian and instrumental associations promoted congruent or conflicting responses. We used reinforcement learning models to infer how traumatic stress affected learning and decision-making. Based on the importance of dorsal anterior cingulate cortex (dACC) for cognitive control, we also investigated if individual concentrations of Glx (=glutamate + glutamine) in dACC predicted the Pavlovian bias of choice. RESULTS: Survivors of traumatic stress expressed a greater Pavlovian interference with instrumental action selection and had significantly lower levels of Glx in the dACC. Across subjects, the degree of Pavlovian interference was negatively associated with dACC Glx concentrations. CONCLUSIONS: Experiencing traumatic stress appears to render instrumental decisions less flexible by increasing the susceptibility to Pavlovian influences. An observed association between prefrontal glutamatergic levels and this Pavlovian bias provides novel insight into the neurochemical basis of decision-making, and suggests a mechanism by which traumatic stress can impair flexible instrumental behaviours.

Traumatic Stress and Accelerated Cellular Aging: From Epigenetics to Cardiometabolic Disease.

PURPOSE OF REVIEW: The aim of this paper is to review the recent literature on traumatic stress-related accelerated aging, including a focus on cellular mechanisms and biomarkers of cellular aging and on the clinical manifestations of accelerated biological aging. RECENT FINDINGS: Multiple lines of research converge to suggest that PTSD is associated with accelerated aging in the epigenome, and the immune and inflammation systems, and this may be reflected in premature onset of cardiometabolic and cardiovascular disease. The current state of research paves the way for future work focused on identifying the peripheral and central biological mechanisms linking traumatic stress to accelerated biological aging and medical morbidity, with an emphasis on processes involved in inflammation, immune functioning, oxidative stress, autonomic arousal, and stress response. Ultimately, such work could help reduce the pace of biological aging and improve health and wellness.

Traumatic stress, neural self and the spiritual mind.

According to recent findings stressful experiences may influence various physiological disturbances and also neuroanatomical changes and some studies also show that psychotherapy and meditation may influence brain functions. Traumatic stress is frequently related to a dissociative response that disintegrates conscious experience. In this context, self-reflection is an essential principle in the process of posttraumatic growth related to spiritual experiences and meditation states that enable mental integration and create the novel integrated self. According to recent findings there is no widely accepted evidence about specific neural mechanisms of processes related to mental integration linked to the spiritual experiences and meditation. Nevertheless there is growing evidence that these integrative experiences are related to various alterations in the brain's physiology and morphology. These findings provide a new paradigm for understanding of mental disorders and emphasize the fundamental role of mental integration and integrated self in the therapy of psychiatric disorders.

The Emerging Role of Metabotropic Glutamate Receptors in the Pathophysiology of Chronic Stress-Related Disorders.

Chronic stress-related psychiatric conditions such as anxiety, depression, and alcohol abuse are an enormous public health concern. The etiology of these pathologies is complex, with psychosocial stressors being among the most frequently discussed risk factors. The brain glutamatergic neurotransmitter system has often been found involved in behaviors and pathophysiologies resulting from acute stress and fear. Despite this, relatively little is known about the role of glutamatergic system components in chronic psychosocial stress, neither in rodents nor in humans. Recently, drug discovery efforts at the metabotropic receptor subtypes of the glutamatergic system (mGlu1-8 receptors) led to the identification of pharmacological tools with emerging potential in psychiatric conditions. But again, the contribution of individual mGlu subtypes to the manifestation of physiological, molecular, and behavioral consequences of chronic psychosocial stress remains still largely unaddressed. The current review will describe animal models typically used to analyze acute and particularly chronic stress conditions, including models of psychosocial stress, and there we will discuss the emerging roles for mGlu receptor subtypes. Indeed, accumulating evidence indicates relevance and potential therapeutic usefulness of mGlu2/3 ligands and mGlu5 receptor antagonists in chronic stress-related disorders. In addition, a role for further mechanisms, e.g. mGlu7-selective compounds, is beginning to emerge. These mechanisms are important to be analyzed in chronic psychosocial stress paradigms, e.g. in the chronic subordinate colony housing (CSC) model. We summarize the early results and discuss necessary future investigations, especially for mGlu5 and mGlu7 receptor blockers, which might serve to suggest improved therapeutic strategies to treat stress-related disorders.