The present study investigated the hypothesis that local inflammation, as measured by salivary concentrations of two markers of proinflammatory 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 proinflammatory 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 motivational state. In summary, the present study found that local levels of both inflammatory markers in the mouth were positively associated with ventral prefrontal activation (e.g., sACC and OFC) as well as other regions important in the emotional task such as noun retrieval (e.g., temporal cortex), and visual processing (e.g., cuneus and fusiform gyrus).
Activation of the sACC and the OFC are both related to monitoring the affective valence of stimuli (Kringelbach, 2005). The sACC is one of the most reliably activated regions in major depression, and shows a relationship to mood in other studies (for a review, see Ressler and Mayberg, 2007
). The OFC is also associated with depression, showing elevated activation in depressed vs. remitted persons (Drevets, 2001
). The hypothesis that a motivational state is changed under conditions of higher inflammation, and that this state includes low mood, is in keeping with the positive association between local inflammation and these regional activations.
We used a behavioral measure in order to test the association between ventral prefrontal regions and memory for grief-related words (in contrast to neutral words). The sACC and OFC activations, each associated with increased local inflammation, were correlated specifically with the recall of grief-related words. We hypothesized sACC activation, and indeed that correlation was strongest, while the correlation between grief-related words and the OFC activation was a trend. Biased memory retrieval for mood-congruent words has been found in other mood disorders, such as anxiety and depression (Mathews and MacLeod, 2005
). The strong positive correlation between the recall of grief-related words and ventral prefrontal activation (and the absence of a correlation with neutral words) suggests that those with the highest local inflammation are in a motivational state that preferentially attends to mood congruent information, which could be expected from the sickness behavior hypothesis.
Other areas of activation were related to functions required during the grief-eliciting tasks. The cuneus region, activated in both IL-1β and sTNFrII analyses, is an area important in visual processing, as seen in emotion induction with other visual tasks (Ganis et al., 2004
). The fusiform gyrus is a brain region specifically activated during the visual processing of human faces (Critchley et al., 2000
; Kanwisher et al., 1997
). These two areas were activated in the Deceased > Stranger condition. This condition relies upon visual stimuli for grief elicitation. The inferior temporal region, also activated in both IL-1β and sTNFrII analyses, functions in noun retrieval and is seen in the Grief Word > Neutral Word. This condition relies upon words for grief elicitation. The pons activation in the present study may reflect activation of the sensory pathway positively correlated with local inflammation. The trigeminal nerve carries sensory information from the mouth to the brain, and enters the brainstem at the pons (Bowsher, 1997
Our data is not evidence that peripherally measured IL-1β or TNF-α is binding to receptors in the prefrontal cortex; however, the present results support the idea that peripheral inflammation at a local site (i.e., mouth) is communicated to the brain, and that the resulting changes in motivational state may influence emotional processing. If sickness behavior is the output of a motivational state of the brain, it may influence the regional processing of emotional stimuli (e.g., greater use of sACC) upon presentation of reminders of a recently deceased loved one.
Several limitations of the present study should be noted. While it is clear that pro-inflammatory cytokine levels in the mouth have been linked to sickness behaviors (e.g., social withdrawal, depressed mood), a limitation of the present study is that periodontal disease was not evaluated in each participant. Therefore, alternative interpretations of the data are possible. However, levels of IL-1β in the present study are in line with the levels published by other laboratories (Al-Harthi et al., 2000
; Miller et al., 2006
; Nishanian et al., 1998
; Tobon-Arroyave et al., 2008
; Winkler et al., 2001
). The present study is cross-sectional, and therefore it is not possible to state a causal relationship. The reverse causation must be considered: bereaved individuals with greater medial prefrontal activation may have lower mood and motivation for health behaviors, such as oral care, and this may cause greater oral inflammation. It is impossible to rule out another interpretations, because there was only one assessment of pro-inflammatory markers. Those participants who found the task most emotionally arousing may have had both the greatest emotional recall scores and pro-inflammatory responses. Although few studies of the kinetics of oral cytokine production exist, Mastrolonardo and colleagues (2007)
, report a rise in IL-1β in saliva after 20 minutes following a stress task in control subjects and Dickerson and colleagues (2004)
report a stress-related change in sTNFrII in other oral fluids after 30 minutes. However, samples were not taken earlier than these time points in either report, and therefore it is possible that measures taken immediately following the task in the present study could reflect the result of acute stress of the emotional arousing task or could reflect the individual variability in response to chronic bereavement stress. Finally, future research should include a nonbereaved comparison group, in order to determine whether the associations are specific to a chronically stressed state, and include men to examine generalizability.
This is the first study to demonstrate the relationship between emotional processing, brain activation and local immune system activation in a chronically stressed population of adults. Future research should investigate the direction of causality in this relationship. For example, a directional hypothesis could test whether it is more difficult for those with high levels of local inflammation to adjust to stressful life events, or conversely, whether mood-related brain activation leads to prolonged inflammation in the periphery. In summary, the present data demonstrates that higher salivary levels of sTNFrII and interleukin-1β (IL-1β), in separate analyses, are both associated with activation of the ventral prefrontal cortex in persons undergoing the chronic emotional stress of bereavement, and adds to a growing literature on the relationship between local inflammation, the brain, and behavior.