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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 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.

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.

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.

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.

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.