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Inflammation in HIV+ Causes Mood Emotions
Changes & Alters Social Interaction
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Researching HIV & Aging, Cormorbidities Should Include Consideration of These Affects
Clinically, although still somewhat speculatively at this point, the current findings suggest that individuals with inflammation find social interactions more complex, which could possibly contribute to social withdrawal and further amplification of depressive symptoms (Cacioppo et al., 2006, Heinrich and Gullone, 2006). Likewise, impairments in social emotion recognition may hinder optimal support seeking, whereby patients might be less in tune with their social environment, e.g., less sensitive in picking up social cues that would otherwise guide symptom reporting and help-seeking behavior. The inflammatory component of depressive disorders may similarly contribute to social impairments and withdrawal that characterize these disorders (Miller and Raison, 2016).
The present study tested whether inflammation would lead to a decrement in the ability to accurately identify mental states in others and whether interpretation of positive versus negative facial expressions would be equally affected. The latter consideration stems from previous research showing that inflammation increased sensitivity to both positive and negative social feedback
The current findings provide further experimental support to the idea that inflammation may drive social-cognitive deficits in psychopathologies that exhibit enhanced inflammation, such as major depression
"inflammation induces heightened feelings of social disconnection and alters sensitivity to social threats and rewards"
Meta-analyses have consistently established that depression is associated with a state of low-grade inflammation (although there is marked heterogeneity between studies)
Impaired ToM is thought to explain why depressed individuals tend to withdraw from social contacts, report less enjoyment in social interactions, and have fewer social contacts than non-depressed individuals.
whereby mood and social interactions may operate in a bidirectional manner
More recently, experimental human research revealed that inflammation-induction reduces the ability to infer the affect and mental states of other people on the basis of facial expressions (Moieni et al., 2015), which is considered indicative of impaired Theory of Mind (ToM). The concept of ToM, sometimes called mentalizing (Frith and Frith, 2006), was developed in the context of research on autism-spectrum disorders and refers to the ability to interpret someone else's desires, beliefs, and intentions, all of which are essential to human social interaction (Premack and Woodruff, 1978). However, impairments of ToM more broadly characterize a number of mental health disorders, most notably depression.
Inflammation May Cause Mood Changes/deterioration, Affects Emotional Interaction & Social Engagement & Processing Emotional Information from Faces, Can Increase Depression - 2 studies
immune activation impairs ToM. Such impairment may provide a mechanistic link explaining social-cognitive deficits in psychopathologies that exhibit low-grade inflammation, such as major depression. - ability to adequately interpret the mental state of another person is key to complex human social interaction. Recent evidence suggests that this ability, considered a hallmark of 'theory of mind' (ToM)
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Low-grade inflammation decreases emotion recognition – Evidence from the vaccination model of inflammation
Highlights
• Typhoid vaccination elicited low-grade inflammation without sickness symptoms.
• Inflammation resulted in lower ability to interpret the mental state of someone else.
• Inflammation may contribute to social-cognitive deficits in inflammatory states.
Abstract
The ability to adequately interpret the mental state of another person is key to complex human social interaction. Recent evidence suggests that this ability, considered a hallmark of 'theory of mind' (ToM), becomes impaired by inflammation. However, extant supportive empirical evidence is based on experiments that induce not only inflammation but also induce discomfort and sickness, factors that could also account for temporary social impairment. Hence, an experimental inflammation manipulation was applied that avoided this confound, isolating effects of inflammation and social interaction.
Forty healthy male participants (mean age = 25, SD = 5 years) participated in this double-blind placebo-controlled crossover trial. Inflammation was induced using Salmonella Typhi vaccination (0.025 mg; Typhim Vi, Sanofi Pasteur, UK); saline-injection was used as a control. About 6 h 30 m after injection in each condition, participants completed the Reading the Mind in the Eyes Test (RMET), a validated test for assessing how well the mental states of others can be inferred through observation of the eyes region of the face.
Vaccination induced systemic inflammation, elevating IL-6 by +419% (p < .001), without fever, sickness symptoms (e.g., nausea, light-headedness), or mood changes (all p's > .21). Importantly, compared to placebo, vaccination significantly reduced RMET accuracy (p < .05). RMET stimuli selected on valence (positive, negative, neutral) provided no evidence of a selective impact of treatment.
By utilizing an inflammation-induction procedure that avoided concurrent sicknesses or symptoms in a double-blinded design, the present study provides further support for the hypothesis that immune activation impairs ToM. Such impairment may provide a mechanistic link explaining social-cognitive deficits in psychopathologies that exhibit low-grade inflammation, such as major depression.
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Inflammation Causes Mood Changes Through Alterations in Subgenual Cingulate Activity and Mesolimbic Connectivity
https://www.sciencedirect.com/science/article/pii/S0006322309003965
Our connectivity analysis showed that—consistent with theoretical models of mood regulation—inflammation-associated changes in total mood modulated the connectivity of sACC and nucleus accumbens with reduction in effective interconnectivity predicting greater deterioration in total mood.
The results of this study illustrate that experimental inflammation induced by typhoid vaccination produces a robust increase in pro-inflammatory cytokines (IL-6) and reduction in a composite measure of mood (that includes both cognitive-mood and neurovegetative contributions) in normal healthy male volunteers at 3 hours. This was not associated with an increase in temperature or salivary cortisol or ratings of illness symptoms, including fever, nausea, and aching joints, suggesting that the reduction in total mood is likely a direct result of associated cytokine responses. As has been observed previously, greater sensitivity to inflammation-associated deterioration in this mood measure was associated with higher trait-anxiety (10). This is in keeping with the broader literature on predisposing factors for clinical depression (32) and studies of IFN-α–induced depression where personality traits predict patients most at risk of developing depression during treatment of hepatitis C or malignant melanoma (33).
Inflammation-associated deterioration in total mood was also associated with a marked decrease in activity within amygdala, a region central to processing emotional information from faces. Connectivity analysis also showed that inflammation-associated mood change modulated the connectivity between sACC and arMPFC, a region activated when thinking about others, and with right STS and amygdala, regions implicated in processing social/emotional information from faces. These changes might underpin the marked reduction in social behavior associated with acute sickness, possibly reflecting an internal self-reorientation of attentional focus (9) and the heterogeneity of symptoms associated with inflammation-associated mood change. Interestingly, depression is typically associated with an increase in amygdala activity (41) to emotional faces (42), suggesting that sustained mood change might modulate connectivity within this circuitry. It is noteworthy that our composite measure of mood change that was sensitive to heterogeneous mood-related symptoms also revealed modulation of activity within a network of regions connected to sACC, a region itself implicated in integrating multiple components of mood homeostasis. Future studies should focus on whether differential influences of inflammation on each of these circuits underlie differences in the temporal evolution of individual components of depression associated with repeated and prolonged cytokine administration.
Results
Typhoid but not placebo injection produced an inflammatory response indexed by increased circulating interleukin-6 and significant mood reduction at 3 hours. Inflammation-associated mood deterioration correlated with enhanced activity within subgenual anterior cingulate cortex (sACC) (a region implicated in the etiology of depression) during emotional face processing. Furthermore, inflammation-associated mood change reduced connectivity of sACC to amygdala, medial prefrontal cortex, nucleus accumbens, and superior temporal sulcus, which was modulated by peripheral interleukin-6.
Examination of the subscales contributing to the POMS total mood score showed that inflammation-associated change in total mood score was driven by an increase in both mood/cognitive (confusion) and neurovegetative (fatigue) symptoms. Smaller contributions to change in total mood score came from an increase in inflammation-associated tension-anxiety. Changes in depression-dejection and vigor subscales showed little contribution suggesting that inflammation-associated changes in total mood largely reflected increases in confusion, fatigue, and to a lesser extent tension-anxiety rather than depression-dejection or vigor (see Supplement 1 in [16]). Although we did not observe a significant linear correlation between total mood change and magnitude of IL-6 response, there was a trend toward a greater deterioration in mood in those individuals with the greatest IL-6 responses [T(15) = −1.77, p = .099, r = −.43]. There was no effect of vaccine on ratings of illness symptoms, including fever, nausea, aching joints, or headache.
The significant deterioration in total mood after inflammation but not placebo at 3 hours was highly correlated with enhancement of evoked responses to emotional facial expressions within the sACC (including cytoarchitectonically defined Cg25), Montreal Neurological Institute (MNI) coordinates (−2, 22, −28) (Figures 2A and 2B, Table 3). This region is critically implicated in neurobiological mechanisms of depression and the target for successful treatment of depression with deep brain stimulation (Figure 2C). Activity within amygdala, a key region in processing emotional information from faces, was correspondingly attenuated (Table 1). The sACC activity reflected the interaction between processing of emotional facial expressions and inflammation-associated total mood change rather than as a main effect of processing emotional faces.
The sACC activity reflected the interaction between processing of emotional facial expressions and inflammation-associated total mood change rather than as a main effect of processing emotional faces.
The significant deterioration in total mood after inflammation but not placebo at 3 hours was highly correlated with enhancement of evoked responses to emotional facial expressions within the sACC (including cytoarchitectonically defined Cg25), Montreal Neurological Institute (MNI) coordinates (−2, 22, −28) (Figures 2A and 2B, Table 3). This region is critically implicated in neurobiological mechanisms of depression and the target for successful treatment of depression with deep brain stimulation (Figure 2C). Activity within amygdala, a key region in processing emotional information from faces, was correspondingly attenuated (Table 1).
Individuals who experienced the greatest deterioration in total mood after peripheral inflammation showed a highly significant reduction in the functional relationship between sACC and activity within anterior rostral medial prefrontal cortex (arMPFC), (Brodmann area [BA]32, BA10), MNI coordinates (10, 48, 8), nucleus accumbens (Figures 3B and 3A, respectively), right amygdala, STS (Figure 3C), and FFAs.
Conclusions
Inflammation-associated mood deterioration is reflected in changes in sACC activity and functional connectivity during evoked responses to emotional stimuli. Peripheral cytokines modulate this mood-dependent sACC connectivity, suggesting a common pathophysiological basis for major depressive disorder and sickness-associated mood change and depression.
The neurobiological basis for differential evolution of individual features of inflammation-associated clinical depression is currently uncertain; however, the ability of acute inflammation to rapidly induce multiple depression-like symptoms suggests that the immune system can rapidly modulate neuronal circuits central to the organization and reorganization of complex motivational behavior that might lead to the establishment of mood disorder.
In a separate report published in this journal, we use functional magnetic resonance imaging (fMRI) to show that Salmonella typhi vaccine-induced inflammation modulates activity within the hierarchy of brain regions representing internal bodily state (16). These observations in human participants are consistent with rodent studies that suggest cytokines act on autonomic afferent nerves to mediate motivational reorientation during the early phase of inflammation (17, 18). Furthermore, this and another recent study showed that fatigue and psychomotor slowing were associated with corresponding changes in activity within insula (16) and substantia nigra (19).
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