Psychosocial predictors of the innate immune response to influenza vaccination.

Experimental activation of the innate immune system has contributed significantly to both our understanding of how psychological factors influence immune function as well as how immune activity influences the brain and behavior. The annual influenza vaccine can be used to interrogate the effects of mild immune stimulation on day-to-day changes in psychological processes in human subjects that range across the lifespan and in both clinical and non-clinical populations. Yet, the immune response to the influenza vaccine in the days immediately following its administration are not well characterized. The present study describes changes in inflammatory and antiviral gene expression within circulating immune cells, plasma cytokines, and C-reactive protein (CRP) following receipt of the flu vaccine, and further reports the association between several common behavioral health factors and the acute immune response. Participants were 65 adults (mean age 18.81 ± 1.03 years; 66.2% female) who provided a blood sample immediately before and then 24 h after receiving the vaccine. A subsample also provided additional blood samples at 48 and 72 h. Plasma was assayed for CRP, IL-6, IL-10, IL-8, TNF-α, and IFN-γ, and peripheral blood mononuclear cell RNA was sequenced for evidence of change in expression of an a priori set of type 1 interferon (IFN) and inflammatory response genes (INFLAM). Plasma cytokines, CRP, and IFN response genes increased 24 h after vaccination, all ps < .001. The increase in IFN gene expression correlated with the observed increase in plasma cytokines and CRP, p < .0001. The immune response to influenza vaccination at 24-hours was moderated by anxiety symptoms, BMI, being female, sleep, and history of influenza vaccination. These factors and their associations with common immune challenges may be useful in studies interrogating the origins of immune dysregulation. The annual influenza vaccine is an accessible and reliable exogenous activator of both circulating and transcriptional markers of innate immune reactivity, with sensitivity to behavioral health factors relevant for psychoneuroimmunology research.

Pitfalls and potential: Translating the two-hit model of early life stress from pre-clinical non-human experiments to human samples.

Exposure to early life stress (ELS) has been linked to at least double the risk of psychopathology as well as higher morbidity and earlier mortality across the lifespan. For this reason, the field of developmental psychopathology has spent decades identifying factors that explain which individuals are at risk for negative health outcomes. Preclinical experiments in this field commonly test the "two-hit hypothesis", which explores how ELS potentiates vulnerability to pathogenic physiological and behavioral outcomes when an individual is exposed to a stressor later in development. Yet, translation of the two-hit hypothesis to humans is conceptually and practically challenging, thus impeding progress in the field. This review summarizes the two-hit hypothesis used in preclinical experiments as it pertains to two putative pathways linking ELS to psychopathology: the innate immune and neuroendocrine systems. This review also identifies important considerations when translating this model to humans and provides several recommendations. Specifically, attention to the "biological salience" of different forms of ELA and the concordance of that salience with later probes of the system are needed. Further, the consequences of ELS may be context-specific rather than ubiquitous, at least among young people. Within this conceptualization, "second hits" may be best operationalized using standardized acute challenges to the innate immune and neuroendocrine systems (e.g., psychosocial stress). Third, more explicit reporting of sex differences in the human literature is needed. Finally, preclinical experimental designs that more accurately reflect the natural occurrence of ELS in community samples will more effectively advance the understanding of developmental mechanisms that occur as a consequence of ELS.

Early life adversity is associated with attenuated testosterone reactivity to acute stress among adolescents.

Understanding how testosterone responds to stress or challenge may be integral to uncovering biological pathways to potentially harmful behaviors like aggression. Yet, studies investigating patterns of testosterone reactivity under stress within adolescent populations are limited. Among those conducted, even fewer have investigated environmental factors which may shape such patterns. Exposure to early life adversity (ELA) has been shown to influence other biological markers of stress reactivity, though how it may be associated with alterations in testosterone reactivity remains underexplored. The current study addresses these gaps by examining salivary testosterone concentrations across the administration of a Trier Social Stress Test for Children in a sample of 87 adolescents (46.4% female, Mage = 13.91 years, SDage = 1.57). The current study tested two central hypotheses: (1) that testosterone would rise in response to a standardized laboratory stressor, and (2) that greater ELA would be associated with higher baseline (or, pre-stress) testosterone scores and a dampened testosterone response to stress. Adolescents in the current sample showed a robust increase in testosterone following administration of the TSST-C, supporting the limited previous findings which indicate testosterone does mount an acute stress response in adolescents. Contrary to hypotheses, ELA was not associated with significant elevations in baseline testosterone scores. However, ELA was associated with dampened testosterone reactivity, even after controlling for important demographic and biological factors. Methodological implications, including considerations for researchers aiming to capture an acute testosterone response, as well as how our understanding of ELA's role in adolescent biological functioning is extended by our findings regarding testosterone, are discussed.

Adolescent-onset depression is associated with altered social functioning into middle adulthood.

Depression during sensitive periods of social development may have consequences that extend well beyond mental health, and far into adulthood. This study compared the social functioning of adults with adolescent-onset depression (ages 10-20) to those with adult-onset depression (ages 21+). Participants were 3,360 adults (67.2% female; ages 42 ± 15) who had experienced major depression. Adult functional outcomes were marital status, divorce, number of children, years of education, employment status, household income, dependency on welfare, and obesity. Participants with depression during adolescence were less likely to get married, have children, and more likely to have lower household incomes. Depression during adolescence may be associated with broader functional outcomes that impact individuals and society, and may be mitigated through intervention and effective policy.

Childhood maltreatment and within-person associations between cortisol and affective experience.

Glucocorticoids exert profound effects on the brain and behavior, but cortisol concentrations are rarely linked to subjectively reported emotional states in humans. This study examined whether the link between cortisol and subjective anxiety varied by childhood maltreatment history. To do this, 97 individuals (60.8% female) participated in a standardized stress task in the laboratory (Trier Social Stress Test, TSST) while providing serial ratings of their feelings of anxiety as well as cortisol samples in blood. These measurements were collected nine times across the laboratory visit, from immediately before the TSST to 65 minutes after stress initiation. We estimated the within-person association between cortisol concentrations and momentary feelings of anxiety for individuals with and without exposure to childhood maltreatment, measured via self-report on the Childhood Trauma Questionnaire (CTQ). Individuals exposed to maltreatment during childhood reported the greatest feelings of anxiety when cortisol concentrations were lowest. This pattern was exaggerated among female participants, those with posttraumatic stress disorder (PTSD), and those exposed to emotional neglect relative to other forms of maltreatment. Early life adversity, such as parental maltreatment, may alter the role of cortisol in affective experiences. This observation may provide preliminary, translational evidence of a novel pathway through which stress may lead to and maintain internalizing symptoms in humans. More studies accounting for the moderating role of childhood maltreatment in biobehavioral pathways are needed.

Aging as a Context for the Role of Inflammation in Depressive Symptoms.

Inflammation has been implicated in the pathogenesis and maintenance of depressive symptoms. The role of inflammation in depressive symptomatology may be complex, varying within endophenotypes and across the lifespan. Aging is associated with myriad changes in the structure and function of the brain. Yet, little attention has been given to the role of inflammation in depressive symptoms within a lifespan developmental framework. In this study, we examined whether the association between inflammation and depressive symptom domains varied by age. Participants were a community sample of individuals (N = 2,077, Range = 30-84) who participated in the Biomarker projects of the MIDUS2, MIDUS Refresher, or the MIDJA study. Inflammation was indexed by two inflammatory markers consistently implicated in depressed individuals, interleukin 6 (IL-6) and C-reactive protein (CRP), measured in blood. Depressive symptom domains, including depressed affect, anhedonia, somatic complaints, and interpersonal problems, were reported via the Center for Epidemiologic Studies-Depression Scale (CES-D). Inflammatory markers were associated with more somatic complaints, more interpersonal problems, and less anhedonia. Age moderated the relationship between inflammatory markers and two depressive symptom subscales. Specifically, the positive association between inflammation and somatic complaints and the negative association between inflammation and anhedonia increased with age. These observations offer preliminary evidence from a large community sample that aging may be an important context for the role of inflammatory signaling in different aspects of psychological and behavioral well-being.

Sleep problems in adolescence are prospectively linked to later depressive symptoms via the cortisol awakening response.

Sleep disturbance is a symptom of and a well-known risk factor for depression. Further, atypical functioning of the HPA axis has been linked to the pathogenesis of depression. The purpose of this study was to examine the role of adolescent HPA axis functioning in the link between adolescent sleep problems and later depressive symptoms. Methods: A sample of 157 17-18 year old adolescents (61.8% female) completed the Pittsburgh Sleep Quality Inventory (PSQI) and provided salivary cortisol samples throughout the day for three consecutive days. Two years later, adolescents reported their depressive symptoms via the Center for Epidemiological Studies Depression Scale (CES-D). Results: Individuals (age 17-18) with greater sleep disturbance reported greater depressive symptoms two years later (age 19-20). This association occurred through the indirect effect of sleep disturbance on the cortisol awakening response (CAR) (indirect effect = 0.14, 95%CI [.02 -.39]). Conclusions: One pathway through which sleep problems may lead to depressive symptoms is by up-regulating components of the body's physiological stress response system that can be measured through the cortisol awakening response. Behavioral interventions that target sleep disturbance in adolescents may mitigate this neurobiological pathway to depression during this high-risk developmental phase.

Persistent Low Positive Affect and Sleep Disturbance across Adolescence Moderate Link between Stress and Depressive Symptoms in Early Adulthood.

The purpose of this study was to characterize the association between recent major life events and depressive symptoms during early adulthood, and to determine whether adolescents with chronically low positive affect or persistent sleep disturbance were more vulnerable to the link between stress and depressive symptoms. Adolescents (n = 147; 63.9% female; 33.7% non-Hispanic white) were recruited in 10th-11th grade and re-assessed 2 and 4 years later. At each assessment, adolescents completed measures of positive affect and sleep disturbances. At the final assessment, participants reported on their exposure to major life events in the past 12 months. Exposure to more major life events in the past year was associated with greater depressive symptoms in early adulthood. Chronically low positive affect and persistent sleep disturbances throughout adolescence each independently moderated this relationship. Specifically, only participants reporting low positive affect across the three assessments showed a positive and significant association between major life events and depressive symptoms. Further, only participants reporting sleep disturbances at all three assessments showed a positive and significant association between major life events and depressive symptoms. Chronically low positive affect and persistent sleep disturbances during adolescence may be useful indicators of risk for depression during early adulthood. Further, interventions targeting adolescent sleep disturbances and improving positive affect may be useful in reducing the risk for depression following life stress during this high risk developmental phase.

Testing plausible biopsychosocial models in diverse community samples: Common pitfalls and strategies.

It is imperative that research interrogating the biological pathways linking stress processes to health continue to translate the results of basic, preclinical experimental research to diverse and under-represented populations, particularly those at elevated risk for morbidity and mortality. Conducting research within these populations and in community settings involves a number of challenges that ultimately contribute to their rarity and uneven quality in the scientific literature. In this review, we summarize the experiences and insights of members of an expert panel on this topic held at the 2018 meeting of the International Society of Psychoneuroendocrinology in Newport Beach, CA. The goals of the session were to identify challenges and share strategies for testing plausible biopsychosocial models within diverse community samples in order to encourage others and improve future research. The present paper is organized into three themes: 1) Recruitment and retention, 2) Collecting biological samples outside of the laboratory, 3) Data analysis, interpretation, and dissemination. Our goal in composing this overview of the conference session was to share within the field of psychoneuroendocrinology the challenges inherent in translating basic research to community populations.

Stability of diurnal cortisol measures across days, weeks, and years across middle childhood and early adolescence: Exploring the role of age, pubertal development, and sex.

Effective regulation of the hypothalamic-pituitary-adrenal axis (HPA-axis) has been linked to numerous health outcomes. Within-person variation in diurnal measures of HPA-axis regulation assessed over days, months, and years can range between 50-73% of total variation. In this study of 59 youth (ages 8-13), we quantified the stability of the cortisol awakening response (CAR), the diurnal slope, and tonic cortisol concentrations at waking and bedtime across 8 days (2 sets of 4 consecutive days separated by 3 weeks), 3 weeks, and 3 years. We then compared the stability of these indices across three key developmental factors: age, pubertal status, and sex. Youth provided 4 saliva samples per day (waking, 30 min post-waking, before dinner, and before bedtime) for 4 consecutive days during the 3rd week of an ongoing 8-week daily diary study. Youth repeated this same sampling procedure 3 weeks and 3 years later. Using multi-level modeling, we computed the amount of variance in diurnal HPA-axis regulation that was accounted for by nesting an individual's diurnal cortisol indices within days, weeks, or years. Across days, diurnal slope was the most stable index, whereas waking cortisol and CAR were the least stable. All indices except bedtime cortisol were similarly stable when measured across weeks, and all indices were uniformly stable when measured across 3 years. Boys, younger participants, and youth earlier in their pubertal development at study enrollment exhibited greater HPA-axis stability overall compared with females and older, more physically mature participants. We conclude that important within- and between-subjects questions can be answered about health and human development by studying HPA-axis regulation, and selection of the index of interest should be determined in part by its psychometric characteristics. To this end, we propose a decision tree to guide study design for research in pediatric samples by longitudinal timeframe and sample characteristics.

Interparental conflict and child HPA-axis responses to acute stress: Insights using intensive repeated measures.

Interparental conflict is a common source of psychosocial stress in the lives of children. The purpose of this study was to examine the association between recent interparental conflict and one component of the physiological stress response system, the hypothalamic-pituitary-adrenal (HPA)-axis. Parents of 42 children (ages 8-13 years) completed daily diaries of interparental conflict for 8 weeks. At the end of the 8 weeks, youth participated in the Trier Social Stress Test for Children (TSST-C) while providing 2 pre- and 4 poststress salivary cortisol samples. Youth whose fathers reported a pattern of increasing interparental conflict over the past 8 weeks demonstrated an exaggerated HPA-axis response to acute stress. Mother-reported interparental conflict was not associated with children's HPA-axis responses without accounting for fathers' reports. When accounting for fathers' reports, the offspring of mothers reporting higher average daily interparental conflict demonstrated an attenuated HPA-axis response to the stressor. By estimating both average exposure and recent patterns of change in exposure to conflict, we address the circumstances that may prompt attenuation versus sensitization of the HPA-axis in the context of interparental conflict. We conclude that the HPA-axis is sensitive to proximal increases in interparental conflict which may be one pathway through which stress affects health across development, and that incorporating father's reports is important to understanding the role of the family environment in stress responses. This study further demonstrates the value of using intensive repeated measures and multiple reporters to characterize children's psychosocial environment. (PsycINFO Database Record

Screening for childhood adversity: the what and when of identifying individuals at risk for lifespan health disparities.

Existing research on childhood adversity and health risk across the lifespan lacks specificity regarding which types of exposures to assess and when. The purpose of this study was to contribute to an empirically-supported framework to guide practitioners interested in identifying youth who may be at greatest risk for a lifelong trajectory of health disparities. We also sought to identify the point in childhood at which screening for adversity exposure would capture the largest group of at risk individuals for triage to prevention and intervention services. Participants (n = 4036) collected as part of the Midlife in the United States study reported their medical status and history including physical (cardiovascular disease, hypertension, obesity, diabetes, cancer) and mental health (depression, substance use problems, sleep problems). Participants indicated whether they were exposed to 7 adversities at any point in childhood and their age of exposure to 19 additional lifetime adversities before the age of 18. Parent drug abuse, dropping out or failing out of school, being fired from a job, and sexual assault during childhood exhibited the largest effect sizes on health in adulthood, which were comparable to the effects of childhood maltreatment. Childhood adversity screening in early adolescence may identify the largest proportion of youth at risk for negative health trajectories. The results of this descriptive analysis provide an empirical framework to guide screening for childhood adversity in pediatric populations. We discuss the implications of these observations in the context of prevention science and practice.

Childhood maltreatment, psychological resources, and depressive symptoms in women with breast cancer.

Childhood maltreatment is associated with elevated risk for depression across the human lifespan. Identifying the pathways through which childhood maltreatment relates to depressive symptoms may elucidate intervention targets that have the potential to reduce the lifelong negative health sequelae of maltreatment exposure. In this cross-sectional study, 271 women with early-stage breast cancer were assessed after their diagnosis but before the start of adjuvant treatment (chemotherapy, radiation, endocrine therapy). Participants completed measures of childhood maltreatment exposure, psychological resources (optimism, mastery, self-esteem, mindfulness), and depressive symptoms. Using multiple mediation analyses, we examined which psychological resources uniquely mediated the relationship between childhood maltreatment and depressive symptoms. Exposure to maltreatment during childhood was robustly associated with lower psychological resources and elevated depressive symptoms. Further, lower optimism and mindfulness mediated the association between childhood maltreatment and elevated depressive symptoms. These results support existing theory that childhood maltreatment is associated with lower psychological resources, which partially explains elevated depressive symptoms in a sample of women facing breast cancer diagnosis and treatment. These findings warrant replication in populations facing other major life events and highlight the need for additional studies examining childhood maltreatment as a moderator of treatment outcomes.

Cortisol Awakening Response as a Prospective Risk Factor for Depressive Symptoms in Women After Treatment for Breast Cancer.

OBJECTIVE: The aim of the study was to investigate hypothalamic-pituitary-adrenal axis (HPA axis) functioning as a neurobiological risk factor for depressive symptoms in an ongoing longitudinal, observational study of women undergoing treatment and recovery from breast cancer. Many women with breast cancer experience depressive symptoms that interfere with their treatment, recovery, and quality of life. Psychosocial risk factors for depression among patients with cancer and survivors have been identified, yet neurobiological risk factors in this population remain largely unexamined. METHODS: Women recently diagnosed with early-stage breast cancer (N = 135) were enrolled before starting neoadjuvant/adjuvant treatment (radiation, chemotherapy, endocrine therapy). At baseline, participants collected saliva samples to measure diurnal HPA axis functioning for 3 days: at waking, 30 minutes after waking, 8 hours after waking, and bedtime. Participants also completed a standardized measure of depressive symptoms (Center for Epidemiological Studies-Depression Scale) at baseline and 6 months after completion of primary treatment. Multivariate regression was used to predict continuous depressive symptoms at 6-month posttreatment from continuous depressive symptoms at baseline, cortisol awakening response (CAR), and other measures of diurnal HPA axis functioning. RESULTS: The magnitude of CAR predicted changes in depressive symptoms over time, such that women with a higher CAR showed a greater increase from baseline to 6-month posttreatment (b = 5.67, p = .023). Diurnal slope and total cortisol output were not associated with concurrent depressive symptoms or their change over time. CONCLUSIONS: Elevated CAR may be a neurobiological risk factor for increases in depressive symptoms in the months after breast cancer treatment and warrants further investigation.

Developmental psychoneuroendocrine and psychoneuroimmune pathways from childhood adversity to disease.

Childhood adversity has been repeatedly and robustly linked to physical and mental illness across the lifespan. Yet, the biological pathways through which this occurs remain unclear. Functioning of the inflammatory arm of the immune system and the hypothalamic-pituitary-adrenal (HPA)-axis are both hypothesized pathways through which childhood adversity leads to disease. This review provides a novel developmental framework for examining the role of adversity type and timing in inflammatory and HPA-axis functioning. In particular, we identify elements of childhood adversity that are salient to the developing organism: physical threat, disrupted caregiving, and unpredictable environmental conditions. We propose that existing, well-characterized animal models may be useful in differentiating the effects of these adversity elements and review both the animal and human literature that supports these ideas. To support these hypotheses, we also provide a detailed description of the development and structure of both the HPA-axis and the inflammatory arm of the immune system, as well as recent methodological advances in their measurement. Recommendations for future basic, developmental, translational, and clinical research are discussed.

Age of Trauma Onset and HPA Axis Dysregulation Among Trauma-Exposed Youth.

The hypothalamic-pituitary-adrenal axis (HPA axis) is a pathway through which childhood trauma may increase risk for negative health outcomes. The HPA axis is sensitive to stress throughout development; however, few studies have examined whether timing of exposure to childhood trauma is related to differences in later HPA axis functioning. Therefore, we examined the association between age of first trauma and HPA axis functioning among adolescents, and whether these associations varied by sex. Parents of 97 youth (aged 9-16 years) completed the Early Trauma Inventory (ETI), and youth completed the Socially-Evaluated Cold-Pressor Task (SECPT). We measured salivary cortisol response to the SECPT, the cortisol awakening response, and diurnal regulation at home across 2 consecutive weekdays. Exposure to trauma during infancy related to delayed cortisol recovery from peak responses to acute stress, d = 0.23 to 0.42. Timing of trauma exposure related to diverging patterns of diurnal cortisol regulation for males, d = 0.55, and females, d = 0.57. Therefore, the HPA axis may be susceptible to developing acute stress dysregulation when exposed to trauma during infancy, whereas the consequences within circadian cortisol regulation may occur in the context of later trauma exposure and vary by sex. Further investigations are warranted to characterize HPA axis sensitivity to exposure to childhood trauma across child development.

Developmental and contextual factors in the role of severe childhood trauma in geriatric depression: the sample case of former indentured child laborers.

The purpose of this study was to quantify the association between childhood traumatic experiences and geriatric depression (GDS) in a population of elderly who were exposed to severe childhood trauma. We aimed to identify the role of childhood maltreatment exposure in geriatric depression and the developmental and contextual factors that exacerbate this relationship. We interviewed 141 former indentured child laborers (58 females) about their experiences as children and their current depressive symptoms (Mage=77, SD=6.8). Participants provided their age, the year they were first indentured, duration indentured, current physical health, completed the Childhood Trauma Questionnaire (CTQ) and the Geriatric Depression Scale (GDS). Child maltreatment, specifically emotional abuse, was strongly associated with geriatric depression symptoms. These effects were specific to individuals who were removed from their biological families between the ages of 3 and 9 years, and for children who were indentured for 6-12 years. Finally, depression partially mediated the association between medical conditions and daily health impairment, but not for individuals "at risk" for depression by virtue of their maltreatment experiences. This study was conducted with a specific subpopulation of elderly and therefore may not generalize to all geriatric depression, nor to all generations or populations with exposure to childhood adversity. This study demonstrates the importance of using a developmental framework to understand how childhood maltreatment facilitates increased risk for the development of depression in late life.