Aric A. Prather

Cytokine-induced depression during IFN-α treatment: the role of IL-6 and sleep quality

Depressive symptoms, poor sleep quality, and systemic markers of inflammation (e.g., interleukin (IL)-6) are frequently associated. Interferon-alpha (IFN-alpha) therapy results in Major Depressive Disorder (MDD) in some people, offering the possibility to elucidate the relationship of MDD to sleep and inflammation during treatment. In particular, delineating the temporal relations among these factors could help inform their causal relationships. To this end, a cohort of 95 non-depressed hepatitis C patients was followed prospectively for four consecutive months during IFN-alpha therapy. We found that higher pre-treatment levels of circulating IL-6 predicted incidence of MDD (X(2)(1)=7.7; p<0.05). Time-lagged mixed-effect analyses supported uni-directional associations in which IL-6 predicted next months PSQI scores (F(47,11.6)=78.4; p<0.0005), and PSQI scores predicted next months depressive Beck Depression Inventory-II (BDI) scores (F(16,22.6)=3.4; p<0.005). In addition, on any given month of treatment, IL-6 levels predicted BDI symptoms the following month (F(16,97.5)=7.3; p<0.0005), and conversely BDI predicted next months IL-6 (F(14,7.4)=5.2; p<0.05) - providing evidence for a positive feedback relationship between depressive symptoms and systemic inflammation. These data provide further evidence that high levels of inflammation and poor sleep quality may be risk factors for IFN-alpha induced depression. Furthermore, these findings highlight the complex temporal relationships that exist among sleep, depression, and inflammation, and support the need for further prospective investigations to elucidate the dynamics that underlie depression during IFN-alpha treatment.

Stimulated production of proinflammatory cytokines covaries inversely with heart rate variability.

Objective: To examine whether high-frequency heart rate variability, an indirect measure of parasympathetic (vagal) control over variations in heart rate, is associated with immune reactivity to an in vitro inflammatory challenge. Convergent evidence from the animal literature shows that the autonomic nervous system plays a key role in regulating the magnitude of immune responses to inflammatory stimuli. Signaling by the parasympathetic system inhibits the production of proinflammatory cytokines by activated monocytes/macrophages and thus decreases local and systemic inflammation. As yet, no direct human evidence links parasympathetic activity to inflammatory competence. Methods: We examined the relationship of variations in heart rate, recorded during paced respiration, to lipopolysaccharide-induced production of the inflammatory cytokines interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and IL-10 among a community sample of 183 healthy adults (mean age = 45 years; 59% male; 92% White, 7% African-American). Results: Consistent with animal findings, higher derived estimates of vagal activity measured during paced respiration were associated with lower production of the proinflammatory cytokines TNF-α and IL-6 (r = −.18 to −.30), but were not related to production of the anti-inflammatory cytokine IL-10. These associations persisted after controlling for demographic and health characteristics, including age, gender, race, years of education, smoking, hypertension, and white blood cell count. Conclusions: These data provide initial human evidence that vagal activity is inversely related to inflammatory competence, raising the possibility that vagal regulation of immune reactivity may represent a pathway linking psychosocial factors to risk for inflammatory disease. ANS = autonomic nervous system; HRV = heart rate variability; HF = high frequency; LF = low frequency; rMSSD = root mean square of successive differences; IL = interleukin; TNF = tumor necrosis factor; LPS = lipopolysaccharide; WBC = white blood count; BMI = body mass index; SBP = systolic blood pressure; DBP = diastolic blood pressure.

Antagonistic Characteristics are Positively Associated with Inflammatory Markers Independently of Trait Negative Emotionality

Recent evidence suggests that individuals with certain personality traits are at elevated risk for chronic systemic inflammation. To date, this literature has focused on the related traits of hostility and negative affect (NA). In this study, we examine the covariation of trait measures of hostility and NA with the inflammatory mediators interleukin-6 and C-reactive protein. We also explore whether observed associations reflect independent contributions of cognitive, affective and behavioral components of hostile dispositions or shared trait variance with global negative affectivity. Subjects were a diverse sample of 855 relatively healthy middle-aged community volunteers (50% male) from the Adult Health and Behavior Project. The Buss and Perry Aggression Questionnaire (BPAQ) and an Abbreviated Cook-Medley Hostility Scale (ACM) were used to measure dimensions of hostility, and the Multidimensional Personality Questionnaire was used to measure trait NA. Regression analyses accounting for demographic characteristics and medical covariates showed a positive relationship of all components of hostility and trait NA with both IL-6 and CRP. After controlling for trait NA, only the behavioral component of hostility was independently associated with the inflammatory markers. The relationships of cognitive and affective components of hostility with inflammatory markers were largely explained by lifestyle factors, particularly body mass index and smoking. In contrast, lifestyle factors did not explain the covariation of hostile behavioral tendencies and inflammation. These findings suggest that unique attributes of aggressive behavioral tendencies account for much of the variability in inflammation associated with hostility and negative emotions, raising the possibility that individuals high in aggression are at increased risk of inflammatory disease.

Sleep and Antibody Response to Hepatitis B Vaccination

STUDY OBJECTIVES Experimental evidence links poor sleep with susceptibility to infectious illness; however, it remains to be determined if naturally occurring sleep is associated with immune responses known to play a role in protection against infection. The aim of this study was to determine whether sleep duration, sleep efficiency, and sleep quality, assessed in the natural environment, predict magnitude of antibody responses to a novel antigen among community volunteers in midlife. DESIGN Observational. MEASUREMENTS AND RESULTS Healthy midlife adults (n = 125; 70 female; age 40-60 yr) received the standard 3-dose hepatitis B vaccination series. Actigraphy and electronic sleep diaries were used to assess sleep duration, sleep efficiency, and subjective sleep quality. Viral-specific antibody titers were obtained prior to the 2nd and 3rd vaccination to assess primary and secondary antibody responses. Clinical protection status (anti-hepatitis B surface antigen immunoglobulin G ≥ 10 mIU/ml) was assessed 6 mo after the final immunization. Regression analyses revealed that shorter actigraphy-based sleep duration was associated with a lower secondary antibody response independent of age, sex, body mass index, and response to the initial immunization. Shorter sleep duration, measured by actigraphy and sleep diary, also predicted a decreased likelihood of being clinically protected from hepatitis B at the conclusion of the vaccination series. Neither sleep efficiency nor subjective sleep quality were significant predictors of antibody response. CONCLUSIONS Short sleep duration in the natural environment may negatively affect in vivo antibody responses to novel antigens, providing a possible explanation for observed associations of poor sleep with increased susceptibility to infectious disease.

Negative Affective Responses to a Speech Task Predict Changes in Interleukin(IL)-6

Laboratory studies show that individuals differ appreciably in the magnitude of their inflammatory responses to acute psychological stress. These individual differences are poorly understood, yet may contribute to variation in stress-associated disease vulnerability. The present study examined the possibility that affective responses to acute stress contribute to these differences. For this purpose, 102 relatively-healthy community volunteers (mean age 50 years; 60% female; 91.2% white) performed an acute stress protocol and measures of affective state and serum levels of the proinflammatory cytokine, interleukin (IL)-6 were collected at the end of a 30-min resting baseline, a 5-min evaluative public speaking task, and a 30-min recovery period. Results of regression analyses, controlling for age, race, gender, menopausal status, and body mass index, revealed a positive association of task-related increases in anger and anxiety with increases in IL-6 (R² change = .08, p = .004; R² change = .08, p = .005, respectively). Further examination showed that these affective responses to the task were independent predictors of change in IL-6. Cardiovascular reactivity to the task did not explain the association. These results suggest that individuals who exhibit angry or anxious responses to acute challenge are more vulnerable to stress-related increases in markers of systemic inflammation, possibly rendering them more susceptible to inflammatory disease.

Behaviorally Assessed Sleep and Susceptibility to the Common Cold

STUDY OBJECTIVES Short sleep duration and poor sleep continuity have been implicated in the susceptibility to infectious illness. However, prior research has relied on subjective measures of sleep, which are subject to recall bias. The aim of this study was to determine whether sleep, measured behaviorally using wrist actigraphy, predicted cold incidence following experimental viral exposure. DESIGN, MEASUREMENTS, AND RESULTS A total of 164 healthy men and women (age range, 18 to 55 y) volunteered for this study. Wrist actigraphy and sleep diaries assessed sleep duration and sleep continuity over 7 consecutive days. Participants were then quarantined and administered nasal drops containing the rhinovirus, and monitored over 5 days for the development of a clinical cold (defined by infection in the presence of objective signs of illness). Logistic regression analysis revealed that actigraphy- assessed shorter sleep duration was associated with an increased likelihood of development of a clinical cold. Specifically, those sleeping < 5 h (odds ratio [OR] = 4.50, 95% confidence interval [CI], 1.08-18.69) or sleeping between 5 to 6 h (OR = 4.24, 95% CI, 1.08-16.71) were at greater risk of developing the cold compared to those sleeping > 7 h per night; those sleeping 6.01 to 7 h were at no greater risk (OR = 1.66; 95% CI 0.40-6.95). This association was independent of prechallenge antibody levels, demographics, season of the year, body mass index, psychological variables, and health practices. Sleep fragmentation was unrelated to cold susceptibility. Other sleep variables obtained using diary and actigraphy were not strong predictors of cold susceptibility. CONCLUSIONS Shorter sleep duration, measured behaviorally using actigraphy prior to viral exposure, was associated with increased susceptibility to the common cold.

Shorter Leukocyte Telomere Length in Midlife Women with Poor Sleep Quality

Background. Accumulating evidence supports leukocyte telomere length (LTL) as a biological marker of cellular aging. Poor sleep is a risk factor for age-related disease; however, the extent to which sleep accounts for variation in LTL is unknown. Methods. The present study examined associations of self-reported sleep duration, onset latency, and subjective quality with LTL in a community-dwelling sample of 245 healthy women in midlife (aged 49–66 years). Results. While sleep duration and onset latency were unrelated to LTL, women reporting poorer sleep quality displayed shorter LTL (r = 0.14, P = 0.03), independent of age, BMI, race, and income (b = 55.48, SE = 27.43, P = 0.04). When analyses were restricted to participants for whom sleep patterns were chronic, poorer sleep quality predicted shorter LTL independent of covariates and perceived psychological stress. Conclusions. This study provides the first evidence that poor sleep quality explains significant variation in LTL, a marker of cellular aging.

Normative variation in self-reported sleep quality and sleep debt is associated with stimulated pro-inflammatory cytokine production.

Activation of innate inflammatory pathways, marked by increased production of pro-inflammatory cytokines, has been proposed as a potential mechanism linking poor sleep and inflammatory disease risk. In the present study, we examined associations of self-reported sleep quality and duration, and a calculated measure of sleep debt with the production of pro-inflammatory cytokines, interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)-alpha among a community sample of 156 healthy adults. Bivariate correlations revealed an inverse association between sleep quality and production of all the three pro-inflammatory cytokines that was retained for IL-1beta after controlling for demographic and health characteristics. Hierarchical linear regressions also revealed that higher sleep debt scores predicted greater production of IL-1beta and IL-6 after adjusting for covariates. Secondary analyses showed an interaction between sleep debt and body mass index (BMI) in the prediction IL-1beta, suggesting that the impact of sleep debt on cytokine production is greater among participants with lower BMI scores. Further exploration of this potential psychophysiological pathway linking sleep difficulty and inflammatory disease susceptibility is warranted.

Maintenance of a positive outlook during acute stress protects against pro-inflammatory reactivity and future depressive symptoms

UNLABELLED Cognitive and affective responses to acute stress influence pro-inflammatory cytokine reactivity, and peripheral cytokines (particularly interleukin-1 beta (IL-1β)), can act on the brain to promote depressive symptoms. It is unknown whether acute stress-induced changes in positive affect and cognitions (POS) and pro-inflammatory reactivity predict future depressive symptoms. We examined acute stress responses among women, to determine prospective predictors of depressive symptoms. HYPOTHESES (1) Stress-induced decreases in POS will be associated with stress-related increases in circulating IL-1β. (2) Acute stress-induced decreases in POS and increases in IL-1β reactivity will predict increases in depressive symptoms 1 year later. Thirty-five post-menopausal women were exposed to acute stress with the Trier Social Stress Task (TSST) and provided blood samples under resting conditions and 30 min after the conclusion of the TSST, which were assayed for IL-1β. IL-1β reactivity was quantified as post minus pre-TSST. Failure to maintain POS was quantified as the decrease in POS during the TSST. Change in depressive symptoms from the study baseline to the following year was determined. Greater acute stress-induced declines in POS were significantly associated with increased IL-1β reactivity (p≤.02), which significantly predicted increases in depressive symptoms over the following year (p<.01), controlling for age, body mass index, chronic stress, antidepressant use and baseline depressive symptoms. IL-1β reactivity was a significant mediator of the relationship between POS decline and future increases in depressive symptoms (p=.04). Difficulty maintaining positivity under stress and heightened pro-inflammatory reactivity may be markers and/or mechanisms of risk for future increases in depressive symptoms.

Impact of Sleep Quality on Amygdala Reactivity, Negative Affect, and Perceived Stress

Objective Research demonstrates a negative impact of sleep disturbance on mood and affect; however, the biological mechanisms mediating these links are poorly understood. Amygdala reactivity to negative stimuli has emerged as one potential pathway. Here, we investigate the influence of self-reported sleep quality on associations between threat-related amygdala reactivity and measures of negative affect and perceived stress. Methods Analyses on data from 299 participants (125 men, 50.5% white, mean [standard deviation] age = 19.6 [1.3] years) who completed the Duke Neurogenetics Study were conducted. Participants completed several self-report measures of negative affect and perceived stress. Threat-related (i.e., angry and fearful facial expressions) amygdala reactivity was assayed using blood oxygen level–dependent functional magnetic resonance imaging. Global sleep quality was assessed using the Pittsburgh Sleep Quality Index. Results Amygdala reactivity to fearful facial expressions predicted greater depressive symptoms and higher perceived stress in poor (&bgr; values = 0.18–1.86, p values < .05) but not good sleepers (&bgr; values = −0.13 to −0.01, p values > .05). In sex-specific analyses, men reporting poorer global sleep quality showed a significant association between amygdala reactivity and levels of depression and perceived stress (&bgr; values = 0.29–0.44, p values < .05). In contrast, no significant associations were observed in men reporting good global sleep quality or in women, irrespective of sleep quality. Conclusions This study provides novel evidence that self-reported sleep quality moderates the relationships between amygdala reactivity, negative affect, and perceived stress, particularly among men.