When grief heats up: Pro-inflammatory cytokines predict regional brain activation
Introduction
It has become increasingly clear that the symptoms associated with inflammation (e.g., reduced appetite, social withdrawal) are part of a full-body orchestration described as “sickness behavior”, which together have overlapping features with depressive symptoms in humans (Dantzer et al., 2008). This sickness behavior arises from a change in motivational state that occurs when the brain receives signals of peripheral inflammation, which yields “a re-organization of perceptions and actions (Dantzer et al., 2008, p. 46)”. However, what is not known is what brain regions in humans are responsible for this change in motivational state associated with high levels of peripheral inflammation.
To investigate the relationship between peripheral inflammation and “sickness behavior”, attention has recently focused on the influence of inflammation that is found within peripheral, localized sites such as the mouth. Indeed, several types of evidence have provided the background rationale for this relationship, including experimental and naturalistic correlational studies. This literature can be grouped into 1) the relationship between chronic stress and poor oral health, 2) the relationship between acute and chronic stress and pro-inflammatory cytokines in oral fluids (other than saliva).
First, gingival inflammation is correlated with depression (Klages et al., 2005) and periodontal disease is increased in chronic stress (e.g., exam stress and widow(er)hood) (Deinzer et al., 2005, Hugoson et al., 2002). Marcenes and Sheiham (1992) showed that in 158 participants, marital quality and work demand were the best predictors of periodontal disease in multiple linear regression analysis, even after including a number of other predictors, such as frequency of dental appointments and tooth brushing frequency.
Second, the localized expression of inflammatory markers in the mouth (i.e., gingival crevicular fluid) occurs following acute, experimental social stress (Deinzer et al., 2004, Weik et al., 2008). Localized expression of inflammatory markers in crevicular fluid has also been found in chronic stress (e.g., examination periods) and depression (Johannsen et al., 2007, Waschul et al., 2003). These findings are similar to the well-recognized impact of psychological stress on cellular inflammatory signaling, activation of nuclear factor κB, and expression of systemic markers of inflammation (Bierhaus et al., 2003, Pace et al., 2006). The mouth is a critical aspect of immune surveillance and response, as it is constantly in contact with bacterial, viral and other airborne pollutants. The variation in inflammatory response to these immune challenges is varied based upon the level of concurrent stress.
The strongest evidence for the relationship between salivary cytokines and sickness behavior symptoms in humans is from a study comparing participants with periodontitis who were exposed to war and those who were not (all from Croatia) (Aurer et al., 1999). Irritability, anxiety, and tiredness were symptoms associated with the stress of war exposure. These are symptoms of sickness behavior (Dantzer et al., 2008), and in this report there was higher IL-6 in saliva in a group exposed to war stress (with sickness behavior symptoms) in comparison to a group not exposed to war.
Neural pathways involving the trigeminal nerve directly communicate local inflammation from the mouth to the brain (Navarro et al., 2006). In rats, surgical transection of the trigeminal nerve abrogated the pyrogenic effects of Escherichia coli lipopolysaccharide (E. coli LPS) when doses were injected into periodontal tissues of the mouth. In addition, immunohistochemistry demonstrated neuronal activation where the trigeminal makes its first synapse in the brain. In humans, it is not known whether peripheral, localized increases of inflammatory markers in the mouth are associated with behavioral changes and/or alterations in brain activation.
Given the association between psychological stress and increases of inflammatory markers in the mouth, we investigated the influence of bereavement, the most significantly rated life stressor (Hobson et al., 1998), on localized levels of inflammation in saliva and whether varying levels of markers of pro-inflammatory cytokine activity are associated with brain activation during an emotion paradigm. To our knowledge, no study has examined the relationship between local inflammation (i.e., oral cavity) and brain activation as measured by fMRI in humans. A few studies have investigated the relationship between systemic inflammation and regional brain activation (Brydon et al., 2008, Capuron et al., 2005, Rocca et al., 2007). Because of our interest in the change in motivational state associated with sickness behavior, emotion tasks during neuroimaging are most relevant to the present study. A study that has used an emotion paradigm demonstrated that increases of the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) correlated with activation of the subgenual anterior cingulate cortex (sACC) (Rosenkranz et al., 2005). Rosenkranz et al. interpreted this data as evidence that the sACC could integrate the afferent information regarding homeostatic processes in the periphery such as inflammation and emotion processing.
In addition to this data, we developed an a priori hypothesis for the brain regions that would be correlated with local inflammation based on the sickness behavior literature. Because the sickness behavior evidence suggests that mood regulation is perturbed during higher levels of inflammation, we hypothesized a priori that the brain regions involved in mood regulation would be positively correlated with higher levels of oral inflammation. Specifically, the ventral prefrontal cortex (PFC) has been shown to be associated with mood regulation in a number of types of neuroimaging (Drevets et al., 1997). The sACC is frequently found to have higher metabolism in affective disorders (for a review, see Drevets et al., 2008), and this region participates in a network of structures that modulate neuroendocrine responses during emotion processing (Drevets et al., 2002). For all of these reasons, we hypothesized that the ventral PFC would be associated with local inflammation.
Therefore, in the present study, we hypothesize that higher levels of markers of pro-inflammatory cytokine activity, as measured by the levels of the cytokine receptor soluble tumor necrosis factor receptor II (sTNFrII) and interleukin-1β (IL-1β), are associated with activation of the sACC in persons undergoing the chronic emotional stress of bereavement. IL-1β and TNF-α were chosen because they are implicated in sickness behavior (Dantzer et al., 2008). In contrast with IL-1β, levels of TNF-α are not routinely detected in saliva; hence levels of its cytokine receptor (i.e., sTNFrII), which correlate with cytokine levels (Schuld et al., 1999), were measured. Whole saliva has been used for the measurement of local pro-inflammatory cytokines in the mouth, including IL-1β (Miller et al., 2006, Tobon-Arroyave et al., 2008) and sTNFrII (Al-Harthi et al., 2000, Nishanian et al., 1998, Winkler et al., 2001).
Section snippets
Methods and materials
Eighteen women who had experienced the death of a mother or a sister to breast cancer in the past 5 years participated in an event-related fMRI study. The Institutional Review Board at UCLA approved the study and all participants gave written informed consent. All participants were screened for mood disorders through a structured clinical interview, and any with Axis I disorders (including major depression) were excluded. Smoking and diseases of the immune system (e.g., rheumatoid arthritis)
Pro-inflammatory cytokine results
Results from the ELISA analysis showed that participants had a raw IL-Iβ level of 198.2 pg/mL with a standard deviation (SD) of 264.2. The ELISA for sTNFrII had a mean of 251.3 pg/mL and SD of 271.2 (Table 3).
Neuroimaging results
The main effects of the study replicate prior grief neuroimaging results (Gündel et al., 2003) and are reported elsewhere (O'Connor et al., 2008). Results from the covariate analyses with Grief word > Neutral word and the pro-inflammatory markers are shown in Table 1. Of note, separate
Discussion
The present study investigated the hypothesis that local inflammation, as measured by salivary concentrations of two markers of pro-inflammatory cytokine activity (e.g., IL-1β and sTNFrII), is positively associated with greater sACC activation. This hypothesis was based upon evidence that local levels (e.g., mouth) of pro-inflammatory cytokines are associated with sickness behaviors, (a set of behaviors including low mood) which are orchestrated by the brain and described as a shift in
Acknowledgments
This research was supported by funds from the California Breast Cancer Research Program of the University of California, Grant Number 10IB-0048. M-F.O. was supported by Friends of the Semel Institute Research Fellowship. This work was supported in part by NIA grant K01 AG028404, NIMH T32-MH19925, and the Cousins Center for Psychoneuroimmunology. We would like to thank the UCLA Brain Mapping Center for their assistance and Heather L. Urry for comments on an earlier draft of this manuscript.
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