Early childhood risk exposures and inflammation in early adolescence.

There is now reliable evidence that early psychosocial stress exposures are associated with behavioral health in children; the degree to which these same kinds of stress exposures predict physical health outcomes is not yet clear. We investigated the links between economic adversity, family and caregiving stress in early childhood and several markers of immune function in early adolescence. The sample is derived from the Family Life Project, a prospective longitudinal study of at-risk families. Socio-demographic and psychosocial risks have been assessed at regular intervals since the children were first assessed at 2 months of age. When the children were early adolescents, we conducted an in-depth health assessment of a subsample of families; blood samples were collected from venipuncture for interleukin(IL)-6, Tumor Necrosis Factor (TNF)-alpha, and C-reactive protein (CRP), as well as glucocorticoid resistance. Results indicated limited but reliable evidence of an association between early risk exposure and inflammation in adolescence. Specifically, caregiver depressive symptoms in early childhood predicted elevated CRP almost a decade later, and the prediction was significant after accounting for multiple covariates such as socio-economic adversity, health behaviors and body mass index. Our findings provide strong but limited evidence that early stress exposures may be associated with inflammation, suggesting one mechanism linking early stress exposure to compromised behavioral and somatic health.

Associations of mindfulness with depressive symptoms and well-being in older adults: the moderating role of neuroticism.

OBJECTIVE: To investigate whether observed interactions of mindfulness with the personality trait neuroticism extend to older adults and to aspects of psychological functioning other than depressive symptoms, and whether effects of mindfulness training in this population depend on levels of neuroticism. METHOD: We performed a secondary analysis of data from a randomized controlled trial of Mindfulness-Based Stress Reduction (MBSR) for community-dwelling older adults. We investigated whether neuroticism moderates associations of dispositional mindfulness with various aspects of psychological and physical functioning at baseline, as well as effects of MBSR on these outcomes. RESULTS: Significant two-way interactions showed that greater mindfulness was associated with fewer depressive symptoms and less negative affect at baseline in individuals with average or higher levels of neuroticism. In contrast, mindfulness was associated with greater positive affect and vitality and fewer physical symptoms regardless of the level of neuroticism. There were no effects of MBSR on these outcomes at any level of neuroticism. CONCLUSION: Mindfulness may be more protective against psychological ill-being in older adults with higher levels of neuroticism, but conducive to positive psychological and physical well-being regardless of this personality trait. The potential moderating role of neuroticism should be further evaluated in studies of mindfulness-based interventions in older adults.

Immune and neuroendocrine correlates of temperament in infancy.

There is now a clear focus on incorporating, and integrating, multiple levels of analysis in developmental science. The current study adds to research in this area by including markers of the immune and neuroendocrine systems in a longitudinal study of temperament in infants. Observational and parent-reported ratings of infant temperament, serum markers of the innate immune system, and cortisol reactivity from repeated salivary collections were examined in a sample of 123 infants who were assessed at 6 months and again when they were, on average, 17 months old. Blood from venipuncture was collected for analyses of nine select innate immune cytokines; salivary cortisol collected prior to and 15 min and 30 min following a physical exam including blood draw was used as an index of neuroendocrine functioning. Analyses indicated fairly minimal significant associations between biological markers and temperament at 6 months. However, by 17 months of age, we found reliable and nonoverlapping associations between observed fearful temperament and biological markers of the immune and neuroendocrine systems. The findings provide some of the earliest evidence of robust biological correlates of fear behavior with the immune system, and identify possible immune and neuroendocrine mechanisms for understanding the origins of behavioral development.

Observed parent-child relationship quality predicts antibody response to vaccination in children.

BACKGROUND: Quality of the parent-child relationship is a robust predictor of behavioral and emotional health for children and adolescents; the application to physical health is less clear. METHODS: We investigated the links between observed parent-child relationship quality in an interaction task and antibody response to meningococcal conjugate vaccine in a longitudinal study of 164 ambulatory 10-11 year-old children; additional analyses examine associations with cortisol reactivity, BMI, and somatic illness. RESULTS: Observed Negative/Conflict behavior in the interaction task predicted a less robust antibody response to meningococcal serotype C vaccine in the child over a 6 month-period, after controlling for socio-economic and other covariates. Observer rated interaction conflict also predicted increased cortisol reactivity following the interaction task and higher BMI, but these factors did not account for the link between relationship quality and antibody response. CONCLUSIONS: The results begin to document the degree to which a major source of child stress exposure, parent-child relationship conflict, is associated with altered immune system development in children, and may constitute an important public health consideration.

Annual research review: The neuroinflammation hypothesis for stress and psychopathology in children--developmental psychoneuroimmunology.

Experimental animal and adult human data suggest that stress exposure is associated with alterations in immune system function that may underlie increased susceptibility to disease and behavioral disorders. The implications of these data for child psychology and psychiatry are not yet clear. The current review seeks to distil and translate the relevant animal and adult human work to children to advance a developmental model of psychoneuroimmunology. In addition to reviewing key specific findings, we consider biological/conceptual models and technical aspects of psychoneuroimmunology work in pediatric populations, and outline the rationales and advantages of integrating hypotheses concerning neuroinflammation in developmental studies of psychopathology.

Depressive symptoms and immune response to meningococcal conjugate vaccine in early adolescence.

Research findings in psychoneuroimmunology document reliable, bidirectional linkages among psychological processes, the nervous system, and the immune system. However, available data are based almost entirely on animal and adult human studies; the application to children and adolescents is uncertain. We capitalized on the experimental leverage provided by a routine vaccination to examine the link between mood symptoms and the immune response to a vaccine challenge in early adolescence. One hundred twenty-six 11-year-olds for whom vaccine response data were available were assessed at prevaccination and 4 weeks, 3 months, and 6 months following vaccination; self-report ratings of depression and anxiety as well as measures of psychosocial and somatic risk were assessed prior to vaccine response. Analyses indicated that children's internalizing mood symptoms were associated with elevated and persistently higher antibody responses, with evidence extending to two of the four serogroups. The associations remained after controlling for multiple possible confounders (social class, body mass index, sleep, psychosocial risk, and pubertal status). The observed enhanced vaccine response associated with depressive and anxious symptoms in early adolescence may reflect an important developmental difference in immune system-brain interplay between adults and children, and it underscores the need for further developmental studies of psychoneuroimmunology.

Prenatal maternal anxiety predicts reduced adaptive immunity in infants.

Prenatal anxiety has been linked with altered immune function in offspring in animal studies, but the relevance for human health is unknown. We examined prenatal maternal anxiety as a predictor of adaptive immunity in infants at 2 and 6 months of age as part of a prospective longitudinal study. The humoral immune response to hepatitis B vaccine was assessed at 2 months (n=80) and 6 months (n=76) of age. Prenatal anxiety predicted lower hepatitis B antibody titers at 6 months of age independent of obstetric and socio-demographic covariates; the effects were limited to those infants who had not completed the 3-dose vaccine series (for transformed titer values, r=-.36, p<.05). Cell-mediated immune responses at 2 (n=56) and 6 (n=54) months of age were examined by ELISpot assays for interferon(IFN)-γ, interleukin(IL)-2, and IL-4 responder cell frequencies to three antigens: hepatitis B surface antigen, tetanus toxoid, and phytohaemagglutinin (PHA). Prenatal maternal anxiety was associated with reduced IFN-γ and increased IL-4 responder cell frequencies at 6 months of age, independent of obstetric and socio-demographic covariates. No effect of prenatal anxiety was found on adaptive immunity at 2 months of age. The findings provide the first demonstration in humans that prenatal anxiety alters adaptive immunity in the infant.

Mindfulness-based stress reduction for older adults: effects on executive function, frontal alpha asymmetry and immune function.

BACKGROUND/AIMS: Mindfulness-based stress reduction (MBSR) has enhanced cognition, positive emotion, and immunity in younger and middle-aged samples; its benefits are less well known for older persons. Here we report on a randomized controlled trial of MBSR for older adults and its effects on executive function, left frontal asymmetry of the EEG alpha band, and antibody response. METHODS: Older adults (n = 201) were randomized to MBSR or waiting list control. The outcome measures were: the Trail Making Test part B/A (Trails B/A) ratio, a measure of executive function; changes in left frontal alpha asymmetry, an indicator of positive emotions or approach motivation; depression, mindfulness, and perceived stress scores, and the immunoglobulin G response to a protein antigen, a measure of adaptive immunity. RESULTS: MBSR participants had a lower Trails B/A ratio immediately after intervention (p < 0.05); reduced shift to rightward frontal alpha activation after intervention (p = 0.03); higher baseline antibody levels after intervention (p < 0.01), but lower antibody responses 24 weeks after antigen challenge (p < 0.04), and improved mindfulness after intervention (p = 0.023) and at 21 weeks of follow-up (p = 0.006). CONCLUSIONS: MBSR produced small but significant changes in executive function, mindfulness, and sustained left frontal alpha asymmetry. The antibody findings at follow-up were unexpected. Further study of the effects of MBSR on immune function should assess changes in antibody responses in comparison to T-cell-mediated effector functions, which decline as a function of age.

Depressive symptoms, pain, chronic medical morbidity, and interleukin-6 among primary care patients.

OBJECTIVE: Pain, chronic medical morbidity, and depression are highly prevalent problems that frequently co-occur in primary care. Elevated levels of inflammatory markers are linked with all three of these conditions and may play an important role in patients' comorbidities. The current study aimed to examine if the associations among pain, chronic medical morbidity, and the inflammatory marker interleukin (IL)-6 are dependent on depression status in primary care patients. SETTING, SUBJECTS, AND OUTCOME MEASURES: Primary care patients (N = 106) aged 40 and older were assessed for pain (36-item Medical Outcomes Study Survey Form), chronic medical morbidity (checklist of chronic health conditions), and depressive symptoms (Center for Epidemiologic Studies Depression Scale), and provided a blood sample for the measurement of serum IL-6. RESULTS: Among patients with elevated depressive symptoms, higher IL-6 levels were associated with both greater pain and greater chronic medical comorbidity. IL-6 was unrelated to pain or chronic medical comorbidity among patients without clinically significant depressive symptoms. In mediation analyses, chronic medical morbidity did not mediate the association between IL-6 and pain, and depression severity and pain remained independently associated after adjustment for chronic medical comorbidity. CONCLUSIONS: Depression may increase primary care patients' vulnerability to pain and elevated levels of inflammatory markers such as IL-6.

Emotional benefits of mindfulness-based stress reduction in older adults: the moderating roles of age and depressive symptom severity.

OBJECTIVES: To examine the effects of age and depressive symptom severity on changes in positive affect among older adults randomly assigned to a Mindfulness-Based Stress Reduction (MBSR) program or a Waitlist Control group. Drawing from the Motivational Theory of Life-Span Development, we hypothesized that lower levels of depressive symptom severity and older age would be associated with greater positive affect in response to the MBSR intervention. METHODS: Data were collected from a sample of community-dwelling English-speaking adults (n = 200) aged ≥ 65, randomly assigned to an eight-week MBSR program or a Waitlist Control group. Our main outcome variable was a five-item measure of positive affect, which was measured at study entry as well as eight weeks and six months later. RESULTS: At the six-month follow-up, we observed group by baseline depressive symptom severity (ß = -.17, p = .02) and group by baseline depressive symptom severity by age (ß = -.14, p = .05) interactions. Among MBSR participants, greater baseline depressive symptom severity was also associated with less improvement in positive affect at the six-month follow-up (ß = -.30, p = .003). Findings were qualified by a significant depressive symptom severity by age interaction (ß = -.25, p = .01), such that MBSR participants who were 70 and over with lower baseline depressive symptom severity having the greatest improvement in positive affect at the six-month follow-up. CONCLUSION: MBSR improves positive affect for older adults with lower depressive symptom severity, perhaps because it capitalizes on naturalistic changes in control strategies.

Sleep disturbance and older adults' inflammatory responses to acute stress.

OBJECTIVES: Poor sleep diminishes mental and physical health. The objective of this study was to examine associations between sleep disturbance and interleukin-6 (IL-6) responses to acute mental stress in older adults. DESIGN: Observational study of community-dwelling, healthy older adults. SETTING: Participants completed the study in a clinical research laboratory of a mid-sized university. PARTICIPANTS: Generally healthy, community-dwelling men and women age 50 and older. MEASUREMENTS: IL-6 and negative affect at rest and following a series of challenging cognitive tests; sleep quality; depressive symptoms; perceived stress; loneliness. RESULTS: Participants categorized as poor sleepers on the basis of Pittsburgh Sleep Quality Index scores had significantly larger IL-6 responses to the cognitive stressors than good sleepers. The association between poor sleep and heightened IL-6 response to acute stress was not explained by other psychosocial factors previously linked to immune dysregulation, including depressive symptoms, perceived stress, and loneliness. CONCLUSIONS: Findings add to the growing evidence for poor sleep as an independent risk factor for poor mental and physical health. Older adults may be particularly vulnerable to effects of sleep disturbance due to significant age-related changes in both sleep and inflammatory regulation.

Psychiatric symptoms and proinflammatory cytokines in pregnancy.

OBJECTIVE: Clinical studies suggest that psychiatric symptoms, particularly depression, anxiety, and trauma, may be associated with inflammation, as indexed by proinflammatory cytokines. Such a link may be especially significant in pregnancy and may shed additional light on the etiology of perinatal mood disorders. METHODS: We prospectively observed 145 women selected from a community obstetric clinic serving a primarily low-income, high-psychosocial risk population. Women without evidence of medical high-risk pregnancies were screened (including psychiatric and trauma histories) and then assessed in detail (e.g., mood symptoms) at approximately 18 and 32 weeks' gestation. Blood was drawn to measure key proinflammatory markers, interleukin 6 and tumor necrosis factor α (TNF-α). Data on pregnancy and obstetric outcome were derived from medical records. RESULTS: There was considerable stability of cytokine levels within individuals and a significant mean increase across pregnancy observed for interleukin 6 (p < .001) and TNF-α (p < .001). History of trauma was associated with significantly elevated TNF-α levels (F(1,135) = 4.43, p < .05), controlling for psychosocial and obstetric covariates. In contrast, elevated measures of depression and anxiety were unrelated to proinflammatory cytokines (p > .1). Exploratory analyses indicated that neither psychiatric symptoms nor proinflammatory cytokines predicted birth weight, gestational age, or obstetric complications. CONCLUSIONS: These findings suggest that antecedent trauma may be associated with persistently elevated TNF-α levels during pregnancy. The evidence that a generalized proinflammatory state was associated with symptoms of depression or anxiety in pregnant women was not found.

Social Relationships and Inflammatory Markers in the MIDUS Cohort: The Role of Age and Gender Differences.

OBJECTIVE: To better understand age and gender differences in associations of social relationships with chronic inflammation. METHOD: Using a sample of middle-aged and older adults ( N = 963) from the Midlife Development in the United States (MIDUS) biomarker project, we examined interactions of age and gender with structural and functional social network measures in predicting interleukin-6 (IL-6) and C-reactive protein (CRP). RESULTS: Significant interactions involving age and gender showed that social support was associated with lower IL-6 in older women, whereas perceived positive relationships and social integration were related to lower IL-6 in both men and women of advanced age. Functional measures were associated with higher CRP in both men and women after adjustment for health conditions and behaviors, with some further variation by age. DISCUSSION: Greater social support may be related to lower IL-6 in older women. Further research is needed to understand observed associations of social support with higher CRP.

Associations between inflammatory markers and cognitive function in breast cancer patients receiving chemotherapy.

BACKGROUND: Cancer-related cognitive impairment (CRCI) is often related to chemotherapy. Increased chronic inflammation is believed to play a key role in the development of CRCI related to chemotherapy but studies assessing this hypothesis specifically in patients receiving chemotherapy are rare. METHODS: We assessed several cognitive domains using the Cambridge Neuropsychological Test Automated Battery (CANTAB) in twenty-two breast cancer patients currently receiving chemotherapy. We also measured inflammatory cytokine and receptor (MCP-1, TNF-α, sTNFRI, sTNFRII) concentrations in patient sera using Luminex assays. These concentrations were log-transformed to obtain a normal distribution. Associations between log-transformed cytokines and cognition were evaluated using Pearson correlations and linear regression, taking into account relevant covariates. RESULTS: Increased concentrations of sTNFRI and sTNFRII were associated with poorer performance on the CANTAB Delayed Matching to Sample (DMS, tests visual memory). Increasing sTNFRI levels were negatively correlated with DMS percent correct (r=-0.47, p=0.029) and DMS percent correct after a 12 second (s) delay (r=-0.65, p=0.001). Increasing levels of sTNFRII negatively correlated with DMS percent correct after 12s delay (r=-0.57, p=0.006). After controlling for relevant demographic (i.e. age, education) and clinical variables (i.e. disease stage, regimen type), we found that increased sTNFRI remained significantly related to decline on the DMS at the 12s delay (p=0.018). CONCLUSION: This preliminary study shows a significant association between higher sTNFRI and lower scores on the short-term visual memory delayed match to sample test in breast cancer patients receiving chemotherapy, supporting the hypothesis that sTNFRI is involved in CRCI.

Chronic foot shock induces hyperactive behaviors and accompanying pro- and anti-inflammatory responses in mice.

Behavioral and accompanying physiological and immunological changes were investigated at various times during chronic irregular mild foot shock (CMFS) in adult male BALB/c mice. CMFS induced a significant hyperlocomotor activity in a familiar environment as well as increased consumption of chocolate milk (a favored drink) throughout the 5-week stress period. Unlike other chronic stress models, CMFS did not induce depressive-like behaviors. Hyperactivity was associated with transient elevations of pro-inflammatory cytokines (TNFalpha and IL-1beta) and IL-2 and more sustained (IL-10) or later (arginase activity) elevations in anti-inflammatory mediators in the spleen (serum levels below levels of detection) suggesting a transition from a pro-inflammatory state to an anti-inflammatory state during CMFS. Similar increases in brain levels of IL-2 and arginase activity were also detected and may contribute to CMFS-induced hyperactivity as both of these mediators have been shown to induce hyperactivity. To our knowledge, this is the first time that increased arginase activity has been documented during a stress paradigm. Altogether, the data indicate that CMFS induces behavioral changes distinct from other chronic stress models. CMFS is associated with multiple dynamic immunological changes, suggesting involvement of multiple factors in chronic stress-induced behavioral changes.

Acute morphine exposure potentiates the development of HSV-1-induced encephalitis.

A devastating consequence of HSV-1 infection is development of HSV-1-induced encephalitis (HSVE). While only a minority of individuals infected with HSV-1 experiences HSVE, clearly defined variables that consistently predict development of the disease remain to be elucidated. The current study examined the effects of a single dose of morphine prior to infection with HSV-1 on the development of HSVE in BALB/cByJ mice. Acute morphine exposure was observed to potentiate the development of HSVE in HSV-1 infected mice. The present data implicate a potential role for the blood-brain barrier in the development of HSVE in morphine-treated mice.

Lifetime Exposure to Intimate Partner Violence and Proinflammatory Cytokine Levels Across the Perinatal Period.

BACKGROUND: Intimate partner violence (IPV) is a public health concern, affecting one-third of US women. Prior research suggests an association between exposure to IPV and poor maternal perinatal health, but the underlying biological correlates are not well understood. This study examined the relationship between exposure to IPV and proinflammatory cytokine levels, a candidate mechanism accounting for poor psychiatric and obstetric outcomes, across the perinatal period. MATERIALS AND METHODS: Data were obtained from a prospective, longitudinal cohort study of 171 women receiving obstetrical care from a hospital-based practice serving a predominantly low-income minority population. Participants completed questionnaires on IPV exposure, psychiatric symptoms, and psychosocial and obstetric factors and provided blood samples at 18 and 32 weeks of gestation and 6 weeks and 6 months postpartum. Serum levels of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) were assayed via enzyme-linked immunosorbent assay. RESULTS: Thirty-five (20.5%) women reported lifetime exposure to IPV and 7 (4.1%) reported being physically hurt in the preceding 12 months (4 while pregnant). Lifetime exposure to IPV was associated with increased likelihood of experiencing perinatal depression and smoking during pregnancy. Women with a history of IPV had significantly higher levels of TNF-α at 18 weeks (z = -2.29, p < 0.05), but significantly smaller changes in levels of IL-6 (ß = -0.36, p = 0.04) across time. CONCLUSION: Lifetime exposure to IPV was associated with a range of adverse mental health outcomes and may affect proinflammatory cytokine levels in pregnancy.

Personality Predicts Utilization of Mindfulness-Based Stress Reduction During and Post-Intervention in a Community Sample of Older Adults.

OBJECTIVES: Mindfulness-based stress reduction (MBSR) is a promising intervention for older adults seeking to improve quality of life. More research is needed, however, to determine who is most willing to use the four techniques taught in the program (yoga, sitting meditation, informal meditation, and body scanning). This study evaluated the relationship between the Big Five personality dimensions (neuroticism, extraversion, openness to experience, conscientiousness, and agreeableness) and use of MBSR techniques both during the intervention and at a 6-month follow-up. The hypothesis was that those with higher levels of openness and agreeableness would be more likely to use the techniques. METHODS: Participants were a community sample of 100 older adults who received an 8-week manualized MBSR intervention. Personality was assessed at baseline by using the 60-item NEO Five-Factor Inventory. Use of MBSR techniques was assessed through weekly practice logs during the intervention and a 6-month follow-up survey. Regression analyses were used to examine the association between each personality dimension and each indicator of MBSR use both during and after the intervention. RESULTS: As hypothesized, openness and agreeableness predicted greater use of MBSR both during and after the intervention, while controlling for demographic differences in age, educational level, and sex. Openness was related to use of a variety of MBSR techniques during and after the intervention, while agreeableness was related to use of meditation techniques during the intervention. Mediation analysis suggested that personality explained postintervention MBSR use, both directly and by fostering initial uptake of MBSR during treatment. CONCLUSIONS: Personality dimensions accounted for individual differences in the use of MBSR techniques during and 6 months after the intervention. Future studies should consider how mental health practitioners would use these findings to target and tailor MBSR interventions to appeal to broader segments of the population.

Modulation of the innate immune response to HSV-1 following acute administration of morphine: role of hypothalamo-pituitary-adrenal axis.

A single injection of morphine significantly increased interferon (IFN)-beta and IFN-alpha mRNA in spleens from herpes simplex virus (HSV)-1 infected male Balb/cByJ mice. However, significant suppression of IFN-gamma and interleukin (IL)-12 production was observed in spleens from morphine-treated mice. Pretreatment with RU486 blocked morphine-induced increases in IFN-beta, and reversed the suppression of IFN-gamma. However, RU486 did not restore IFN-alpha or IL-12. The results suggest that a single exposure to morphine 4 h prior to infection can significantly alter innate immune responses to a viral pathogen, and that these effects are partially mediated by glucocorticoids.

Mindfulness-based stress reduction to enhance psychological functioning and improve inflammatory biomarkers in trauma-exposed women: A pilot study.

This study examined the effects of a mindfulness-based stress reduction (MBSR) program on psychological functioning and inflammatory biomarkers in women with histories of interpersonal trauma. The 8-week MBSR program was conducted at a community-based health center and participants (N = 50) completed several measures of psychological functioning at study entry as well as 4 weeks, 8 weeks, and 12 weeks later. Inflammatory biomarkers were assayed from blood collected at each assessment. A series of linear mixed-model analyses were conducted to measure the effect of attendance and time on the dependent variables. Time was associated with significant decreases in perceived stress, depression, trait and state anxiety, emotion dysregulation, and posttraumatic stress symptoms, as well as increases in mindfulness. Session attendance was associated with significant decreases in interleukin (IL)-6 levels. This pilot study demonstrated the potential beneficial effects of MBSR on psychological functioning and the inflammatory biomarker IL-6 among trauma-exposed and primarily low-income women. Decreases in inflammation have implications for this population, as interpersonal trauma can instigate chronic physiological dysregulation, heightened morbidity, and premature death. This study's preliminary results support efforts to investigate biological remediation with behavioral interventions in vulnerable populations.