Tristen K. Inagaki

Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward.

BACKGROUND Although inflammatory activity is known to play a role in depression, no work has examined whether experimentally induced systemic inflammation alters neural activity that is associated with anhedonia, a key diagnostic symptom of depression. To investigate this, we examined the effect of an experimental inflammatory challenge on the neural correlates of anhedonia-namely, reduced ventral striatum (VS) activity to reward cues. We also examined whether this altered neural activity related to inflammatory-induced increases in depressed mood. METHODS Participants (n = 39) were randomly assigned to receive either placebo or low-dose endotoxin, which increases proinflammatory cytokine levels in a safe manner. Cytokine levels were repeatedly assessed through hourly blood draws; self-reported and observer-rated depressed mood were assessed regularly as well. Two hours after drug administration, neural activity was recorded as participants completed a task in which they anticipated monetary rewards. RESULTS Results demonstrated that subjects exposed to endotoxin, compared with placebo, showed greater increases in self-reported and observer-rated depressed mood over time, as well as significant reductions in VS activity to monetary reward cues. Moreover, the relationship between exposure to inflammatory challenge and increases in observer-rated depressed mood was mediated by between-group differences in VS activity to anticipated reward. CONCLUSIONS The data reported here show, for the first time, that inflammation alters reward-related neural responding in humans and that these reward-related neural responses mediate the effects of inflammation on depressed mood. As such, these findings have implications for understanding risk of depression in persons with underlying inflammation.

Attachment figures activate a safety signal-related neural region and reduce pain experience

Although it has long been hypothesized that attachment figures provide individuals with a sense of safety and security, the neural mechanisms underlying attachment-induced safety have not been explored. Here, we investigated whether an attachment figure acts as a safety signal by exploring whether viewing an attachment figure during a threatening experience (physical pain) led to increased activity in a neural region associated with safety signaling, the ventromedial prefrontal cortex (VMPFC), and corresponding reductions in pain. Female participants in long-term romantic relationships were scanned as they received painful stimuli while viewing pictures of their partner and control images (stranger, object). Consistent with the idea that the attachment figure may signal safety, results revealed that viewing partner pictures while receiving painful stimulation led to reductions in self-reported pain ratings, reductions in pain-related neural activity (dorsal anterior cingulate cortex, anterior insula), and increased activity in the VMPFC. Moreover, greater VMPFC activity in response to partner pictures was associated with longer relationship lengths and greater perceived partner support, further highlighting a role for the VMPFC in responding to the safety value of the partner. Last, greater VMPFC activity while viewing partner pictures was associated with reduced pain ratings and reduced pain-related neural activity. An implication of these findings is that, in the same way that stimuli that historically have threatened survival (e.g., snakes, spiders) are considered to be prepared fear stimuli, attachment figures, who have historically benefited survival, may serve as prepared safety stimuli, reducing threat- or distress-related responding in their presence.

An fMRI Study of Cytokine-Induced Depressed Mood and Social Pain: The Role of Sex Differences

Although research has demonstrated a relationship between proinflammatory cytokine activity and depressive symptoms, the neurocognitive processes underlying this relationship have remained largely unexplored. Here, we examined the effect of proinflammatory cytokine activation on the neural correlates of socially painful experience and associated depressed mood. Participants received either low-dose endotoxin or placebo through intravenous injection. Levels of the proinflammatory cytokine, IL-6, were repeatedly assessed through hourly blood draws; self-reported depressed mood was assessed hourly as well. Two hours post-injection, participants completed a neuroimaging session in which they were socially excluded during an online ball-tossing game. Replicating previous research, individuals exposed to endotoxin, compared to placebo, showed increases in IL-6 levels and depressed mood. Although there were no meaningful differences between the endotoxin and control groups in neural responses to social exclusion, there were sex differences in the relationships between IL-6 increases and neural responses to exclusion among subjects exposed to endotoxin. Among females, but not males, exposed to endotoxin, increases in IL-6 were associated with increases in social pain-related neural activity (dorsal anterior cingulate cortex, anterior insula) that mediated the relationship between IL-6 increases and depressed mood increases. Implications of these sex differences in the neural correlates of cytokine-associated depressed mood and social pain are discussed.

Subjective Responses to Emotional Stimuli During Labeling, Reappraisal, and Distraction

Although multiple neuroimaging studies suggest that affect labeling (i.e., putting feelings into words) can dampen affect-related responses in the amygdala, the consequences of affect labeling have not been examined in other channels of emotional responding. We conducted four studies examining the effect of affect labeling on self-reported emotional experience. In study one, self-reported distress was lower during affect labeling, compared to passive watching, of negative emotional pictures. Studies two and three added reappraisal and distraction conditions, respectively. Affect labeling showed similar effects on self-reported distress as both of these intentional emotion regulation strategies. In each of the first three studies, however, participant predictions about the effects of affect labeling suggest that unlike reappraisal and distraction, people do not believe affect labeling to be an effective emotion regulation strategy. Even after having the experience of affect labels leading to lower distress, participants still predicted that affect labeling would increase distress in the future. Thus, affect labeling is best described as an incidental emotion regulation process. Finally, study four employed positive emotional pictures and here, affect labeling was associated with diminished self-reported pleasure, relative to passive watching. This suggests that affect labeling tends to dampen affective responses in general, rather than specifically alleviating negative affect.

The neural sociometer: Brain mechanisms underlying state self-esteem

On the basis of the importance of social connection for survival, humans may have evolved a “sociometer”—a mechanism that translates perceptions of rejection or acceptance into state self-esteem. Here, we explored the neural underpinnings of the sociometer by examining whether neural regions responsive to rejection or acceptance were associated with state self-esteem. Participants underwent fMRI while viewing feedback words (“interesting,” “boring“) ostensibly chosen by another individual (confederate) to describe the participants previously recorded interview. Participants rated their state self-esteem in response to each feedback word. Results demonstrated that greater activity in rejection-related neural regions (dorsal ACC, anterior insula) and mentalizing regions was associated with lower-state self-esteem. Additionally, participants whose self-esteem decreased from prescan to postscan versus those whose self-esteem did not showed greater medial prefrontal cortical activity, previously associated with self-referential processing, in response to negative feedback. Together, the results inform our understanding of the origin and nature of our feelings about ourselves.

Inflammation selectively enhances amygdala activity to socially threatening images

Although social withdrawal is a prominent symptom of sickness, the mechanisms associated with this behavioral change remain unclear. In animals, the amygdala is a key neural region involved in sickness-induced social withdrawal. Consistent with this, in humans, heightened amygdala activity to negative social cues is associated with social avoidance tendencies. Based on these findings, we investigated whether an experimental inflammatory challenge selectively increased amygdala activity to socially threatening images as well as whether this activity related to feelings of social disconnection. Thirty-nine participants were randomly assigned to receive either placebo or low-dose endotoxin, which increases inflammatory activity. Pro-inflammatory cytokines were assessed at 7 hourly time points via blood draws; self-reported feelings of social disconnection and physical sickness symptoms were assessed hourly as well. Two hours post-injection, participants underwent an fMRI procedure to assess amygdala reactivity during the presentation of socially threatening images (fear faces) as well as non-socially threatening images (guns), socially non-threatening images (happy faces), and non-social, non-threatening images (household objects). Endotoxin led to greater amygdala activity in response to socially threatening vs. all other types of images. No such differences were found for placebo participants. Additionally, increased amygdala activity in endotoxin participants during the viewing of socially vs. non-socially threatening images was associated with increased feelings of social disconnection. These findings highlight the amygdala as a neural region that may be important for sickness-induced social withdrawal. The implications of amygdalar involvement in sickness-induced social withdrawal are discussed.

Shared Neural Mechanisms Underlying Social Warmth and Physical Warmth

Many of people’s closest bonds grow out of socially warm exchanges and the warm feelings associated with being socially connected. Indeed, the neurobiological mechanisms underlying thermoregulation may be shared by those that regulate social warmth, the experience of feeling connected to other people. To test this possibility, we placed participants in a functional MRI scanner and asked them to (a) read socially warm and neutral messages from friends and family and (b) hold warm and neutral-temperature objects (a warm pack and a ball, respectively). Findings showed an overlap between physical and social warmth: Participants felt warmer after reading the positive (compared with neutral) messages and more connected after holding the warm pack (compared with the ball). In addition, neural activity during social warmth overlapped with neural activity during physical warmth in the ventral striatum and middle insula, but neural activity did not overlap during another pleasant task (soft touch). Together, these results suggest that a common neural mechanism underlies physical and social warmth.

Neural correlates of giving support to a loved one.

Objective Social support may benefit mental and physical well-being, but most research has focused on the receipt, rather than the provision, of social support. We explored the potentially beneficial effects of support giving by examining the neural substrates of giving support to a loved one. We focused on a priori regions of interest in the ventral striatum and septal area (SA) because of their role in maternal caregiving behavior in animals. Methods Twenty romantic couples completed a functional magnetic resonance imaging session in which the female partner underwent a scan while her partner stood just outside the scanner and received unpleasant electric shocks. Results Support giving (holding a partner’s arm while they experienced physical pain), compared with other control conditions, led to significantly more activity in the ventral striatum, a reward-related region also involved in maternal behavior (p values < .05). Similar effects were observed for the SA, a region involved in both maternal behavior and fear attenuation. Greater activity in each of these regions during support giving was associated with greater self-reported support giving effectiveness and social connection (r values = 0.55–0.64, p values < .05). In addition, in line with the SA’s role in fear attenuation (presumably to facilitate caregiving during stress), increased SA activity during support giving was associated with reduced left (r = −0.44, p < .05) and right (r = −0.42, p < .05) amygdala activity. Conclusions Results suggest that support giving may be beneficial not only for the receiver but also for the giver. Implications for the possible stress-reducing effects of support giving are discussed. Abbreviations VS = ventral striatum; SA = septal area; ROI = region of interest

The neural correlates of persuasion: A common network across cultures and media

Persuasion is at the root of countless social exchanges in which one person or group is motivated to have another share its beliefs, desires, or behavioral intentions. Here, we report the first three functional magnetic resonance imaging studies to investigate the neurocognitive networks associated with feeling persuaded by an argument. In the first two studies, American and Korean participants, respectively, were exposed to a number of text-based persuasive messages. In both Study 1 and Study 2, feeling persuaded was associated with increased activity in posterior superior temporal sulcus bilaterally, temporal pole bilaterally, and dorsomedial prefrontal cortex. The findings suggest a discrete set of underlying mechanisms in the moment that the persuasion process occurs, and are strengthened by the fact that the results replicated across two diverse linguistic and cultural groups. Additionally, a third study using region-of-interest analyses demonstrated that neural activity in this network was also associated with persuasion when a sample of American participants viewed video-based messages. In sum, across three studies, including two different cultural groups and two types of media, persuasion was associated with a consistent network of regions in the brain. Activity in this network has been associated with social cognition and mentalizing and is consistent with models of persuasion that emphasize the importance of social cognitive processing in determining the efficacy of persuasive communication.

The role of the ventral striatum in inflammatory-induced approach toward support figures

Although considerable research has shown that inflammation leads to social withdrawal more generally, it is also possible that inflammation leads to social approach when it comes to close others. Whereas it may be adaptive to withdraw from strangers when sick, it may be beneficial to seek out close others for assistance, protection, or care when sick. However, this possibility has never been explored in humans nor have the neural substrates of these behavioral changes. Based on the role of the ventral striatum (VS) in responding to: (1) the anticipation of and motivation to approach rewarding outcomes and (2) viewing social support figures, the VS may also be involved in sickness-induced approach toward support figures. Thus, the goal of the present study was to examine whether inflammation leads to a greater desire to approach support figures and greater VS activity to viewing support figures. To examine this, 63 participants received either placebo or low-dose endotoxin, which safely triggers an inflammatory response. Participants reported how much they desired to be around a self-identified support figure, and viewed pictures of that support figure while undergoing an fMRI scan to assess reward-related neural activity. In line with hypotheses, endotoxin (vs. placebo) led participants to report a greater desire to be around their support figure. In addition, endotoxin (vs. placebo) led to greater VS activity to images of support figures (vs. strangers), and greater increases in inflammation (IL-6 levels) were associated with greater increases in VS activity. Together, these results reveal a possible neural mechanism important for sickness-induced social approach and highlight the need for a more nuanced view of changes in social behavior during sickness.