Salivary inflammatory biomarkers as a predictor of post-traumatic stress disorder and depressive symptom severity in trauma patients: A prospective study.

BACKGROUND: Although post-traumatic stress disorder (PTSD) and depression screening are recommended for traumatic injury patients, routine screening is still uncommon. Salivary inflammatory biomarkers have biological plausibility and potential feasibility and acceptability for screening. This study tested prospective associations between several salivary inflammatory biomarkers (proinflammatory cytokines interleukin-1ß, interleukin-6, tumor necrosis factor-α; and C-reactive protein), collected during hospitalization and PTSD and depressive symptoms at 5-month follow-up. METHODS: Adult traumatic injury patients (N = 696) at a major urban Level 1 trauma center provided salivary samples and completed PTSD and depressive symptom measures during days 0-13 of inpatient hospitalization. At 5-month follow-up, 368 patients (77 % male, 23 % female) completed the Clinician-Administered PTSD Scale for DSM-IV and the Self-rated Inventory of Depressive Symptomatology. Analyses focused on a latent inflammatory cytokine factor and C-reactive protein at baseline predicting 5-month PTSD and depression symptom outcomes and included baseline symptom levels as covariates. RESULTS: A latent factor representing proinflammatory cytokines was not related to 5-month PTSD or depressive symptom severity. Higher salivary CRP was related to greater PTSD symptom severity (ß = .10, p = .03) at 5-month follow-up and more severity in the following depressive symptoms: changes in weight and appetite, bodily complaints, and constipation/diarrhea (ß's from .14 to .16, p's from .004 -.03). CONCLUSION: In a primarily Latine and Black trauma patient sample, salivary CRP measured after traumatic injury was related to greater PTSD symptom severity and severity in several depressive symptom clusters. Our preliminary findings suggest that salivary or systemic CRP may be useful to include in models predicting post-trauma psychopathology.

Relationship closeness buffers the effects of perceived stress on transcriptomic indicators of cellular stress and biological aging marker p16INK4a.

Chronic stress can accelerate biological aging, offering one mechanism through which stress may increase age-related disease risk. Chronic activation of the sympathoadrenal system increases cellular energy production, resulting in cell stress that can initiate cellular senescence, a permanent state of cell growth arrest. Our previous research linked psychosocial stress with increased expression of senescence marker p16INK4a; however, less is known about the role of protective psychosocial factors in biological aging. We examined relationship closeness (perceived interconnectedness with one's spouse) as a protective buffer of the effects of stress on expression of the p16INK4a-encoding gene (CDKN2A) and transcription control pathways activated under cell stress. Seventy parents (Mage=43.2) completed interview-based and questionnaire measures of psychosocial stress and relationship closeness. Blood samples assessed CDKN2A expression and inferred activity of a priori-selected transcription factors Nrf2 and heat shock factors (HSFs) via genome-wide transcriptome profiling. Random intercept models adjusting for age, sex, and ethnicity/race revealed that perceived stress was associated with elevated CDKN2A expression for parents with low but not high closeness. Secondary bioinformatics analyses linked the interaction of perceived stress and relationship closeness to Nrf2 and HSF-1 activity. Findings identify relationship closeness as a protective factor that may buffer the impact of stress on cellular stress and senescence pathways.

Early life stress sensitizes individuals to the psychological correlates of mild fluctuations in inflammation.

BACKGROUND: Early life stress (ELS) has been linked to health disparities across the human lifespan, particularly increased risk for depression and its recurrence. In this study we explore two plausible and competing pathways through which ELS may lead to depression via inflammation. METHODS: Participants (ages 18-22; n = 41) completed the Early Trauma Inventory as a measure of ELS. Participants then completed consecutive daily diaries of mood and other sickness behavior for the 7 days prior to and 7 days after receiving the annual influenza vaccine. Circulating concentrations of plasma interleukin-6 (IL-6) were measured immediately before and 24 hr after vaccination. RESULTS: ELS was not associated with the magnitude of change in IL-6 from pre- to post-vaccine, however, exposure to ELS moderated the association between change in IL-6 from pre- to post-vaccine and changes in both cognitive difficulty and depressed mood. Individuals exposed to greater ELS showed greater psychological sensitivity to increases in IL-6. CONCLUSIONS: Exposure to ELS may increase sensitivity to peripheral inflammation in the central nervous system. Future studies elaborating on the impact of ELS on the sensitivity of specific neural circuits and cells to inflammation are needed.

Feeling needed: Effects of a randomized generativity intervention on well-being and inflammation in older women.

Generativity, or concern for and contribution to the well-being of younger generations, plays an important role in successful aging. The purpose of this study was to develop a novel, writing-based intervention to increase feelings of generativity and test the effect of this intervention on well-being and inflammation in a sample of older women. Participants in this study (n = 73; mean age = 70.9 years, range 60-86 years) were randomly assigned to a 6-week generativity writing condition (writing about life experiences and sharing advice with others) or a control writing condition (neutral, descriptive writing). Self-reported measures of social well-being, mental health, and physical health, as well as objective measures of systemic and cellular levels of inflammation (plasma pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α; genome-wide RNA transcriptional profiling), were assessed pre- and post-intervention. The generativity intervention led to significant improvements across multiple domains, including increases in participation in social activities, decreases in psychological distress, more positive expectations regarding aging in the physical health domain, and decreases in pro-inflammatory gene expression. Thus, this study provides preliminary evidence for the ability of a novel, low-cost, low-effort intervention to favorably impact inflammation and well-being in older women.

Inflammation and dimensions of reward processing following exposure to the influenza vaccine.

BACKGROUND: Alterations in reward processing are a central feature of depression and may be influenced by inflammation. Indeed, inflammation is associated with deficits in reward-related processes in animal models and with dysregulation in reward-related neural circuitry in humans. However, the downstream behavioral manifestations of such impairments are rarely examined in humans. METHODS: The influenza vaccination was used to elicit a mild inflammatory response in 41 healthy young adults (age range: 18-22, 30 female). Participants provided blood samples and completed behavioral measures of three key aspects of reward-reward motivation, reward learning, and reward sensitivity-before and 1 day after receiving the influenza vaccine. RESULTS: The influenza vaccine led to mild but significant increases in circulating levels of the pro-inflammatory cytokine interleukin-6 (IL-6) (p < .001). Consistent with hypotheses, increases in IL-6 predicted lower reward motivation (p = .029). However, contrary to hypotheses, increases in IL-6 predicted increased performance on a reward learning task (p = .043) and were not associated with changes in reward sensitivity (p's > .288). CONCLUSIONS: These findings contribute to an emerging literature on the nuanced associations between inflammation and reward and demonstrate that even mild alterations in inflammation are associated with multiple facets of reward processing.

Chronic stress exposure and daily stress appraisals relate to biological aging marker p16INK4a.

Previous research has linked exposure to adverse social conditions with DNA damage and accelerated telomere shortening, raising the possibility that chronic stress may impact biological aging pathways, ultimately increasing risk for age-related diseases. Less clear, however, is whether these stress-related effects extend to additional hallmarks of biological aging, including cellular senescence, a stable state of cell cycle arrest. The present study aimed to investigate associations between psychosocial stress and two markers of cellular aging-leukocyte telomere length (LTL) and cellular senescence signal p16INK4a. Seventy-three adults (Mage = 43.0, SD = 7.2; 55% female) with children between 8-13 years of age completed interview-based and questionnaire measures of their exposures to and experiences of stress, as well as daily reports of stress appraisals over an 8-week diary period. Blood samples were used to assess markers of cellular aging: LTL and gene expression of senescent cell signal p16INK4a (CDKN2A). Random effects models covarying for age, sex, ethnicity/race, and BMI revealed that participants with greater chronic stress exposure over the previous 6 months (b = 0.011, p = .04), perceived stress (b = 0.020, p < .001), and accumulated daily stress appraisals over the 8-week period (b = 0.013, p = .02) showed increased p16INK4a. No significant associations with LTL were found. These findings extend previous work on the impact of stress on biological aging by linking chronic stress exposure and daily stressful experiences to an accumulation of senescent cells. Findings also support the hypothesis that chronic stress is associated with accelerated aging by inducing cellular senescence, a common correlate of age-related diseases.

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.

Within-subject associations between inflammation and features of depression: Using the flu vaccine as a mild inflammatory stimulus.

BACKGROUND: Inflammation plays a role in mood and behavior that may be relevant to identifying risk factors and treatment for depression and other stress-related illnesses. The purpose of this study was to examine whether fluctuations in inflammation following a mild immune stimulus were associated with changes in daily reported features of depression for up to a week in a healthy sample of young adults. METHODS: Forty-one undergraduate students completed daily diaries of mood, feelings of social disconnection, sleep, and physical symptoms for one week before and after receiving the seasonal influenza vaccine. Circulating plasma interleukin-6 (IL-6) was measured via blood samples taken immediately before and one day after vaccination. RESULTS: There was a significant increase in circulating IL-6 from pre- to post-intervention (p = .008), and there was significant variability in the magnitude of IL-6 change. Greater increases in IL-6 were associated with greater mood disturbance on post-vaccine days, specifically depressed mood and cognitive symptoms. CONCLUSIONS: Minor increases in inflammation were associated with corresponding increases in features of depression, and these associations occurred in the absence of any physical symptoms. The influenza vaccine could be used to probe causal relationships with a high degree of ecological validity, even in high-risk and vulnerable populations, to better understand the role of inflammation in the pathogenesis of depression.

Utility of a salivary biosensor for objective assessment of surgery-related stress.

PURPOSE: To evaluate the clinical utility of a salivary α-amylase (sAA) biosensor for assessing oral surgery-related stress responses and the differential effect of the personality trait of pain catastrophizing. PATIENTS AND METHODS: A prospective cohort study was conducted in 76 healthy subjects who underwent elective removal of their third molars. Along with subjects' self-reports of anxiety and pain, biosensor-facilitated measurements of sAA levels were obtained at multiple time points during the preoperative consult, surgery, and postsurgical follow-up visits. In addition, subjects completed the Pain Catastrophizing Scale at baseline. Mixed-effect regression models examined changes in sAA levels and self-report ratings within and across visits and the contribution of pain catastrophizing. RESULTS: The sAA levels were lower during surgery and postsurgical follow-up compared with the consult visit (P < .01). The sAA levels decreased during the surgery visit (P < .05) and did not change during the consult or follow-up visits. Individuals who reported greater helplessness to pain manifested higher sAA levels during the surgery visit (P < .05). Self-reported anxiety ratings were highest during the surgery visit, and pain ratings were highest during the follow-up visit. CONCLUSIONS: The sAA levels did not show the predicted increases during the surgery visit compared with the consult and postsurgical follow-up visits or increases during the surgery visit. However, individuals who reported responding to pain with helplessness had higher sAA levels in anticipation of surgery, providing proof of concept for the value of point-of-care assessments of surgery-induced stresses and the differential effect of personality traits.

To assess, to control, to exclude: effects of biobehavioral factors on circulating inflammatory markers.

Behavioral scientists have increasingly included inflammatory biology as mechanisms in their investigation of psychosocial dynamics on the pathobiology of disease. However, a lack of standardization of inclusion and exclusion criteria and assessment of relevant control variables impacts the interpretation of these studies. The present paper reviews and discusses human biobehavioral factors that can affect the measurement of circulating markers of inflammation. Keywords relevant to inflammatory biology and biobehavioral factors were searched through PubMed. Age, sex, and hormonal status, socioeconomic status, ethnicity and race, body mass index, exercise, diet, caffeine, smoking, alcohol, sleep disruption, antidepressants, aspirin, and medications for cardiovascular disease are all reviewed. A tiered set of recommendations as to whether each variable should be assessed, controlled for, or used as an exclusion criteria is provided. These recommendations provide a framework for observational and intervention studies investigating linkages between psychosocial and behavioral factors and inflammation.

Hostility and pain are related to inflammation in older adults.

Chronically elevated systemic inflammation has a dramatic impact on health for older individuals. As stress-related responses, both hostility and pain perception may contribute to inflammation which in turn may maintain negative emotion and pain over time. We used structural equation modeling to examine the degree to which trait hostility and pain were uniquely associated with C-reactive protein (CRP) and serum IL-6 levels over a 6-year span in a sample of older adults. The sample included 113 present or former caregivers of a spouse with dementia and 101 non-caregivers. After accounting for depression, health behaviours, and other risk factors, which were also assessed longitudinally, pain and, to a lesser extent, hostility were uniquely associated with plasma levels of CRP but not IL-6. When examined separately, the association between pain and CRP was significant only for caregivers, while the association between hostility and CRP was comparable for the two groups. These findings suggest that hostility may play a role in a cycle of inflammation among older adults, and that pain may be particularly problematic for those under chronic stress. Our results also shed light on inflammation as a mechanism underlying the effects of hostility on cardiovascular disease morbidity and mortality.

Mild depressive symptoms are associated with amplified and prolonged inflammatory responses after influenza virus vaccination in older adults.

BACKGROUND: Depression is associated with enhanced production of proinflammatory cytokines that influence a spectrum of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes mellitus, certain cancers, periodontal disease, frailty, and functional decline. In this prospective community study, we assessed the relationship between depressive symptoms and changes in inflammatory response after an influenza virus vaccination. METHODS: To study the dynamics of interleukin (IL) 6 levels in plasma in response to an immunological challenge, we obtained blood samples in 119 older adults (mean age, 71.21 +/- 8.68 years [SD]) immediately before an annual influenza vaccination and again 2 weeks later. The short form of the Beck Depression Inventory, completed at these same times, provided information on depressive symptoms. RESULTS: The number of depressive symptoms in this sample was low on average before vaccination (mean +/- SD number of symptoms, 3.07 +/- 3.09) and did not change significantly after vaccination. Participants with more depressive symptoms had higher levels of IL-6 before and after vaccination than did those who reported fewer symptoms; moreover, individuals reporting more depressive symptoms also showed an increase in plasma IL-6 levels 2 weeks later, while there was little change in IL-6 levels among those reporting few or no symptoms. CONCLUSIONS: Even a modest number of depressive symptoms may sensitize the inflammatory response system in older adults and produce amplified and prolonged inflammatory responses after infection and other immunological challenges. Sustained and/or amplified inflammatory responses could accelerate a range of age-related diseases.

Psychoneuroimmunology: psychological influences on immune function and health.

This review focuses on human psychoneuroimmunology studies published in the past decade. Issues discussed include the routes through which psychological factors influence immune function, how a stressor's duration may influence the changes observed, individual difference variables, the ability of interventions to modulate immune function, and the health consequences of psychosocially mediated immune dysregulation. The importance of negative affect and supportive personal relationships are highlighted. Recent data suggest that immune dysregulation may be one core mechanism for a spectrum of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, Type 2 diabetes, certain cancers, and frailty and functional decline; production of proinflammatory cytokines that influence these and other conditions can be stimulated directly by negative emotions and indirectly by prolonged infection.

Emotions, morbidity, and mortality: new perspectives from psychoneuroimmunology.

Negative emotions can intensify a variety of health threats. We provide a broad framework relating negative emotions to a range of diseases whose onset and course may be influenced by the immune system; inflammation has been linked to a spectrum of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes, certain cancers, Alzheimer's disease, frailty and functional decline, and periodontal disease. Production of proinflammatory cytokines that influence these and other conditions can be directly stimulated by negative emotions and stressful experiences. Additionally, negative emotions also contribute to prolonged infection and delayed wound healing, processes that fuel sustained proinflammatory cytokine production. Accordingly, we argue that distress-related immune dysregulation may be one core mechanism behind a large and diverse set of health risks associated with negative emotions. Resources such as close personal relationships that diminish negative emotions enhance health in part through their positive impact on immune and endocrine regulation.