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Author(s): Kuhlman, Kate R; Robles, Theodore F; Haydon, Marcie D; Dooley, Larissa; Boyle, Chloe C; Bower, Julienne E | Abstract: BackgroundEarly 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.MethodsParticipants (ages 18-22; nn=n41) completed the Early Trauma Inventory as a measure of ELS. Participants then completed consecutive daily diaries of mood and other sickness behavior for the 7ndays prior to and 7ndays after receiving the annual influenza vaccine. Circulating concentrations of plasma interleukin-6 (IL-6) were measured immediately before and 24nhr after vaccination.ResultsELS 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.ConclusionsExposure 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.

Background The conserved transcriptional response to adversity (CTRA), characterized by increased expression of proinflammatory genes and decreased expression of antiviral and antibody-related genes, is upregulated in the context of chronic adversity and distress and has been linked to cancer progression. Several studies suggest that the CTRA may also be down-regulated in association with some positive psychological states, particularly eudaimonic well-being. However, it is not clear if the link between inter-individual differences in the CTRA and eudaimonic well-being can be extended to intra-individual change. Using a standardized mindfulness-based intervention, the current study tested whether mindfulness-related increases in eudaimonic well-being related to intra-individual reduction in the CTRA in a sample of younger breast cancer survivors. Methods Participants were 22 women who had been diagnosed and treated for early-stage breast cancer at or before age 50 (Mage = 46.6 years) and had no evidence of active disease. Women completed self-report questionnaires and provided peripheral blood samples before and after a 6-week mindfulness meditation intervention. Regression analyses were used to quantify associations between the magnitude of change in eudaimonic well-being and the magnitude of change in the global CTRA score. Results Women reported significant increases in eudaimonic well–being and showed decreased expression of the pro-inflammatory subcomponent of the CTRA from pre- to post-intervention. The magnitude of increase in eudaimonic well-being was associated with the magnitude of decrease in the composite CTRA score, and this relationship was driven primarily by increased expression of the antiviral/antibody-related CTRA subcomponent. While the intervention was also associated with reduced depressive symptoms, there was no association between change in depressive symptoms and change in the overall CTRA composite score or either of its subcomponents. Conclusions Results are consistent with the hypothesis that eudaimonic well-being may be an important mechanism in interventions aimed at enhancing health in vulnerable groups, and contribute to our understanding of how psychological well-being may influence physical health in cancer patients.

Mindfulness meditation has been shown to reduce distress and increase well-being among individuals with chronic disease, including breast cancer survivors. However, the neural correlates of these changes and their links with inflammatory biology are not yet known. The present study examined whether a mindfulness meditation intervention was associated with changes in neural responses to threat and reward from pre- to post-intervention, and whether those neural changes were associated with changes in markers of inflammation in breast cancer survivors.This was a single-arm trial of a standardized, validated 6-week mindfulness meditation intervention. Participants were 20 women who had been diagnosed and treated for early-stage breast cancer. Participants provided peripheral blood samples and underwent a 90-minute neuroimaging scan before and after the intervention, with a focus on tasks known to elicit activity in threat- and reward-related neural regions.There were significant changes in neural responses to the two tasks of interest from pre to post-intervention (ps 0.042). Participants showed significant reductions in amygdala activity in response to threatening images and significant increases in ventral striatum activity to rewarding images from pre- to post-intervention. Although changes in amygdala activity were not correlated with inflammatory markers, increases in ventral striatum activity were correlated with decreases in circulating concentrations of the proinflammatory cytokine IL-6 and the inflammatory marker CRP.These results, while preliminary, suggest that while a mindfulness meditation intervention can alter neural responses to both threat and nonsocial reward-related stimuli, changes in neural reward activity may be more closely linked to changes in circulating levels of inflammation.

Facial emotion perception (FEP) is pivotal for discriminating salient emotional information. Accumulating data indicate that FEP responses, particularly to sad emotional stimuli, are impaired in depression. This study tests whether sleep disturbance and inflammation, two risk factors for depression, contribute to impaired FEP to sad emotional stimuli.In older adults (n = 40, 71.7 ± 6.8y, 56.4% female), disturbance of sleep maintenance (i.e., wake time after sleep onset [WASO]) was evaluated by polysomnography. In the morning, plasma concentrations of two markers of systemic inflammation were evaluated (i.e., interleukin [IL]-6, tumor necrosis factor [TNF]-α), followed by two FEP tasks, which assessed delays in emotion recognition (ER) and ratings of perceived emotion intensity (EI) in response to sad facial emotional stimuli, with exploration of FEP responses to happiness and anger. Linear regression models tested whether WASO, IL-6, and TNF-α would be associated with impaired FEP to sad emotional stimuli. In addition, moderation tests examined whether inflammation would moderate the link between sleep disturbance and impaired FEP to sad emotional stimuli.Longer WASO predicted longer ER delays (p 0.05) and lower EI ratings in response to sad faces (p 0.01). Further, higher TNF-α (p 0.05) but not IL-6 predicted longer ER delays for sad faces, whereas higher IL-6 (p 0.01) but not TNF-α predicted lower EI ratings for sad faces. Finally, TNF-α moderated the relationship between longer WASO and longer ER delays to sad faces (p 0.001), while IL-6 moderated the relationship between longer WASO and lower EI ratings to sad faces (p 0.01). Neither sleep nor inflammatory measures were associated with FEP responses to happiness or anger.In older adults, disturbance of sleep maintenance is associated with impaired FEP to sad emotion, a relationship that appears to be moderated by inflammation. These data indicate that sleep disturbance and inflammation converge and contribute to impaired FEP with implications for risk for late-life depression.

Background Anhedonia, or loss of interest or pleasure, is a feature of depression and transdiagnostic construct in psychopathology. Theory and compelling evidence from preclinical models implicates stress-induced inflammation as a psychobiological pathway to anhedonic behavior; however, this pathway has not been tested in human models. Further, although anhedonia may reflect dysregulation in multiple dimensions of reward, the extent to which stress-induced inflammation alters these dimensions is unclear. Thus, the current experimental study used a standardized laboratory stressor task to elicit an inflammatory response and evaluate effects of stress-induced inflammation on multiple behavioral indices of reward processing. Methods Healthy young women (age 18–25) completed behavioral reward tasks assessing reward learning, motivation, and sensitivity and were randomized to undergo an acute psychosocial stressor (n = 37) or a no-stress active control (n = 17). Tasks were re-administered 90–120 min post-stress to coincide with the peak of the stress-induced inflammatory response. Blood samples were collected for assessment of the pro-inflammatory cytokine interleukin-6 (IL-6) at baseline and 90 and 120 min post stressor. Results Stress-induced IL-6 was associated with increased response bias during reward learning and increased motivation when probability of receiving a reward was low. Sensitivity to reward in the context of a motivation task was not altered in association with stress-induced IL-6. Conclusions Contrary to hypotheses, mild increases in IL-6 following acute stress were associated with increased reward responsiveness during reward learning and selective increases in motivation. Results contribute to an emerging and nuanced literature linking inflammation to reward processing, and demonstrate that behavioral effects of stress-induced inflammation may be detected in the laboratory setting. Clinical trial registration: NCT03828604.

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.

The goal of this review is to provide an overview of current findings on mindfulness interventions (MIs) for use with breast cancer survivors. We highlight new research and identify several theoretical and conceptual issues worthy of further consideration. To date, randomized controlled trials have shown the efficacy of MIs in mitigating adverse psychological, behavioral, and biological outcomes in breast cancer survivors, at least in the short term and in comparison to usual care or wait list controls. Research is now moving towards evaluating the effectiveness of MIs, determining whether MIs produce lasting benefits, and identifying mechanisms of action. Preliminary research supports the feasibility and efficacy of MIs for use with breast cancer survivors. There are gaps in our understanding, however, of how and for whom MIs are most effective. Future research to enhance current methodologies is warranted.

Objective Mindfulness meditation reduces psychological distress among individuals with cancer. However, mechanisms for intervention effects have not been fully determined. This study tested emotion regulation strategies as mediators of intervention effects in a sample of younger women treated for breast cancer, a group at risk for psychological distress. We focused on two distinct strategies targeted by the intervention-rumination and self-kindness-and further examined the broader construct of mindfulness as a potential mediator. Method Women (n = 71) with Stage 0-III breast cancer diagnosed at or before age 50 who had completed cancer treatment were randomly assigned to a 6-week mindfulness intervention or wait-list control group. Assessments occurred at study entry, postintervention, and a 3-month follow-up. Results In single mediator analyses, increases in self-kindness (CIB [-7.83, -1.93]), decreases in rumination (CIB [-5.05, -.31]), and increases in mindfulness (CIB [-6.58, -.82]) each mediated reductions in depressive symptoms from pre- to postintervention. Increases in self-kindness also mediated reductions in perceived stress (CIB [-5.37, -.62]) from pre- to postintervention, and increases in self-kindness (CIB [-5.67, -.22]) and in mindfulness (CIB [-5.51, -.16]) each mediated intervention effects on perceived stress from preintervention to 3-month follow-up. In multiple mediator analysis, only self-kindness mediated intervention effects on depressive symptoms from pre- to postintervention (CIB [-6.41, -.61]), and self-kindness and mindfulness together mediated intervention effects on perceived stress from preintervention to follow-up (CIB [-6.77, -.35]). Conclusions Self-kindness played a consistent role in reducing distress in younger women with breast cancer. The efficacy of this understudied emotion regulation strategy should be evaluated in other clinical populations. (PsycINFO Database Record

The field of psychoneuroimmunology (PNI) examines interactions among psychological and behavioral states, the brain, and the immune system. Research in PNI has elegantly documented effects of stress at multiple levels of the neuro-immune network, with profound implications for both physical and mental health. In this review, we consider how the neuro-immune network might be influenced by “positive” psychological and behavioral states, focusing on positive affect, eudaimonic well-being, physical activity, and sleep. There is compelling evidence that these positive states and behaviors are associated with changes in immune activity in the body, including reductions in peripheral inflammatory processes relevant for physical health. Growing evidence from animal models also suggests effects of positive states on immune cells in the brain and the blood-brain barrier, which then impact critical aspects of mood, cognition, and behavior. Tremendous advances are being made in our understanding of neuro-immune dynamics; one of the central goals of this review is to highlight recent preclinical research in this area and consider how we can leverage these findings to investigate and cultivate a healthy neuro-immune network in humans.

Background The influenza vaccine has shown promise as a mild, exogenous inflammatory challenge, but use of this model is limited by lack of knowledge about the timing of the inflammatory response. This study was designed to characterize the time-course of the acute inflammatory response and explore psychological and behavioral predictors of that response. Methods Twenty-one young, healthy individuals were recruited to receive the annual influenza vaccine. Serial blood samples were collected immediately before, and 24, 48, and 72 ​h following influenza vaccination. Interleukin (IL)-6 concentrations were assayed at each time-point and psychological and behavioral factors (anxiety and depressive symptoms, sleep disturbance, and childhood adversity) were assessed at baseline. Results Significant elevations in IL-6 were observed at 24 ​h post-vaccination (mean increase ​= ​0.70 ​pg/mL, Cohen’s d ​= ​0.54, p ​= ​.018)), with 61.9% of participants exhibiting peak concentrations at that time point, χ2 ​= ​22.54, p ​, Highlights • Influenza vaccination has shown promise as a mild, exogenous inflammatory challenge, the timing of the inflammatory response is unknown. • Significant elevations in IL-6 concentrations were observed at 24 ​h post-vaccination, with 62% of participants exhibiting peak concentrations at that time point. • Sleep disturbance was associated with greater increases in IL-6 at 24 ​h.

Predictions about the future are susceptible to mood-congruent influences of emotional state. However, recent work suggests individuals also differ in the degree to which they incorporate emotion into cognition. This study examined the role of such individual differences in the context of state negative emotion. We examined whether trait tendencies to use negative or positive emotion as information affect individuals' predictions of what will happen in the future (likelihood estimation) and how events will feel (affective forecasting), and whether trait influences depend on emotional state. Participants (N=119) reported on tendencies to use emotion as information (“following feelings”), underwent an emotion induction (negative versus neutral), and made likelihood estimates and affective forecasts for future events. Views of the future were predicted by both emotional state and individual differences in following feelings. Whereas following negative feelings affected most future-oriented cognition across emotional states, following positive feelings specifically buffered individuals' views of the future in the negative emotion condition, and specifically for positive future events, a category of future-event prediction especially important in psychological health. Individual differences may confer predisposition toward optimistic or pessimistic expectations of the future in the context of acute negative emotion, with implications for adaptive and maladaptive functioning.

Objective Many women report positive life changes, or posttraumatic growth (PTG), as a result of their experience with breast cancer. However, despite compelling evidence that younger age at diagnosis is associated consistently with greater distress, age has not been integrated into models of PTG. Drawing from the theoretical and empirical literature, we tested whether key correlates (i.e., cancer-related impact and engagement, positive mood) of PTG varied by age at breast cancer diagnosis. Methods Participants were 175 women with early stage breast cancer followed from completion of primary treatment through one year post-treatment. Analyses involved data collected at the one-year assessment. Results As hypothesized, correlates of PTG varied significantly as a function of age. Perceived negative impact of the cancer experience was associated with growth for older women (p = .046), whereas approach-oriented coping (p = .004), an expansive time perspective (p = .007), and positive mood were associated with growth for younger women (p = .007). Conclusions PTG may involve distinct processes for women diagnosed at different ages. Consideration of lifespan developmental processes is necessary when studying positive adjustment to cancer. Copyright © 2016 John Wiley & Sons, Ltd.

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.

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.

Evidence suggests an association between inflammation and depression, although findings are mixed. Focusing on core processes in depression may clarify associated biological underpinnings. Negative cognitive bias is a key component of depression, but has not been examined in relation to inflammation. Thus, we tested the hypothesis that elevated inflammatory markers would be associated with negative attentional bias in a sample of 91 breast cancer survivors. Participants were drawn from a larger study and provided blood samples for assessment of peripheral markers of inflammation and completed questionnaires and neuropsychological testing. Attentional bias towards emotional stimuli was assessed with a dot-probe computer task using emotional (sad, happy, angry) and neutral faces. Circulating concentrations of C-reactive protein (CRP) were positively correlated with negative attentional bias (p = .03), such that women with higher CRP allocated greater attention towards sad faces. This association held when controlling for attention function and current depressive symptoms. While cross-sectional, results are consistent with research showing that inflammation heightens the salience of negative emotional stimuli, and identify a novel pathway through which inflammation may lead to depression.

Dysregulated reward processing is a multifaceted and transdiagnostic feature of psychopathology. The psychobiological processes that contribute to reward dysregulation have not been delineated. The current study tested effects of stress-induced inflammation on three dimensions of reward: motivation, learning and sensitivity. Fifty-four healthy, female young adults (age 18–25) were randomized to an acute psychosocial laboratory stressor or a no-stress active control condition, and provided blood samples before, 60, 90 and 120 min after the stressor for assessment of plasma IL-6. Participants completed behavioral measures of reward-related learning (Probabilistic Reward Task) reward motivation (Effort Expenditure for Rewards Task) and reward sensitivity (emotional dot probe task) before and 90 min after the stressor. The stress group had significantly greater increases in circulating IL-6 from study entry to 120 min post-stressor than the control group, β = .25, p = .03. In mediation analyses, stress-induced inflammation predicted decreased sensitivity to social reward, as indicated by decreased positive attentional bias to happy faces (b = −19.70, p = .04). Stress-induced inflammation also increased reward motivation when the probability of winning monetary reward was low (b = .08, p = .01), and marginally increased sensitivity to monetary reward during reward learning (b = .06, p = .07). These findings indicate that stress-induced inflammation differentially alters dimensions of reward, potentially as a function of stimuli type (social vs. monetary), and contribute to a growing literature characterizing the nuanced effects of inflammation on behavior.

Increases in inflammation have been linked to meaningful changes in mood and behavior. Individuals exposed to ELS may be particularly vulnerable to the behavioral effects of inflammation. In the present study, participants reported on exposure to early life stress via the Early Trauma Inventory (ETI). Participants then completed a daily mood diary for 14 days. On the 7th day, participants received the flu vaccine. Plasma IL-6 assessed immediately prior to vaccination and 24-h later was used as the measure of inflammatory activation. Individuals in this study (n = 41; Mage = 18.48, SDage = 0.74) were exposed to a wide range of stressful life events during childhood, METI = 4.49, SDETI = 4.02. Exposure to more ELS was not associated with higher baseline IL-6, r=.03, p=.87, or increase in IL-6 following vaccine exposure, r=-.13, p=.40. However, there was a significant interaction between ELS and the magnitude of IL-6 increase, b=.14, SE=.06, p=.029. There was no association between IL-6 response and depressed mood among individuals with 5 or fewer early life events, b=-.49, SE=.69, p=.49, whereas individuals with a score of 6 or more showed greater decrements in mood with a larger IL-6 response, b = 1.68, SE=.53, p=.01. Exposure to ELS may sensitize individuals to the behavioral effects of acute increases in inflammation. Increased vulnerability to the behavioral effects of inflammation may explain the lifelong health disparities associated with childhood adversity.

Many women report positive life changes, or posttraumatic growth (PTG), as a result of their experience with breast cancer. However, despite compelling evidence that younger age at diagnosis is associated consistently with greater distress, age has not been integrated into models of PTG. Drawing from the theoretical and empirical literature, we tested whether key correlates (i.e., cancer-related impact and engagement, positive mood) of PTG varied by age at breast cancer diagnosis.Participants were 175 women with early stage breast cancer followed from completion of primary treatment through one year post-treatment. Analyses involved data collected at the one-year assessment.As hypothesized, correlates of PTG varied significantly as a function of age. Perceived negative impact of the cancer experience was associated with growth for older women (p = .046), whereas approach-oriented coping (p = .004), an expansive time perspective (p = .007), and positive mood were associated with growth for younger women (p = .007).PTG may involve distinct processes for women diagnosed at different ages. Consideration of lifespan developmental processes is necessary when studying positive adjustment to cancer. Copyright © 2016 John WileySons, Ltd.

Alterations in reward processing are a central feature of depression and may be influenced by inflammation. Indeed, elevated inflammation is associated with dysregulation in reward-related neural circuitry. However, the downstream behavioral manifestations of such impairments are rarely examined in humans. In this study, 42 healthy young adults (age 18–22, 31 female), provided blood samples and completed behavioral measures of two key aspects of reward – reward-related learning (Probabilistic Reward Task) and reward motivation (Effort Expenditure for Rewards Task) - before and one day after receiving an influenza vaccine. The influenza vaccine led to mild but significant increases in circulating IL-6 ( Mpre = 1.16, SD = .94; Mpost = 1.46, SD = 1.21; d = 0.39). Contrary to hypotheses, increases in IL-6 predicted increases in reward learning, b = 0.167, p = 0.005. While change in IL-6 did not predict reward motivation, higher baseline levels of IL-6 predicted increased reward motivation following the vaccine for reward of moderate (versus low and high) magnitude, b = 0.034, p = 0.034. Results were not substantively altered when controlling for current depressive symptoms and sex. These findings suggest that reward-related learning is facilitated by modest increases in circulating inflammation, and that higher levels of IL-6 are also positively associated with reward motivation. While this is contrary to prior findings that inflammation dampens reward reactivity, it is possible that the relatively small increases in inflammation seen here may drive engagement with the environment.