Extensive developmental research has linked peer rejection during adolescence with a host of psychopathological outcomes, including depression. Moreover, recent neuroimaging research has suggested that increased activity in the subgenual region of the anterior cingulate cortex (subACC), which has been consistently linked with depression, is related to heightened sensitivity to peer rejection among adolescents. The goal of the current study was to directly test the hypothesis that adolescents’ subACC responses are predictive of their risk for future depression, by examining the relationship between subACC activity during peer rejection and increases in depressive symptoms during the following year. During a functional magnetic resonance imaging scan, 20 13-year-olds were ostensibly excluded by peers during an online social interaction. Participants’ depressive symptoms were assessed via parental reports at the time of the scan and 1 year later. Region of interest and whole-brain analyses indicated that greater subACC activity during exclusion was associated with increases in parent-reported depressive symptoms during the following year. These findings suggest that subACC responsivity to social exclusion may serve as a neural marker of adolescents’ risk for future depression and have implications for understanding the relationship between sensitivity to peer rejection and the increased risk of depression that occurs during adolescence.

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.

Experiences of social rejection or loss have been described as some of the most ‘painful’ experiences that we, as humans, face and perhaps for good reason. Because of our prolonged period of immaturity, the social attachment system may have co-opted the pain system, borrowing the pain signal to prevent the detrimental consequences of social separation. This review summarizes a program of research that has explored the idea that experiences of physical and social pain rely on shared neural substrates. First, evidence showing that social pain activates pain-related neural regions is reviewed. Then, studies exploring some of the expected consequences of such a physical-social pain overlap are summarized. These studies demonstrate: 1) that individuals who are more sensitive to one kind of pain are also more sensitive to the other and 2) that factors that increase or decrease one kind of pain alter the other in a similar manner. Finally, what these shared neural substrates mean for our understanding of socially painful experience is discussed.

Social bonds fulfill the basic human need to belong. Being rejected thwarts this basic need, putting bonds with others at risk. Attachment theory suggests that people satisfy their need to belong through different means. Whereas anxious attachment is associated with craving acceptance and showing vigilance to cues that signal possible rejection, avoidant attachment is associated with discomfort with closeness and using avoidant strategies to regulate one’s relationships. Given these different styles by which people satisfy their need to belong (that can operate simultaneously within the same individual), responses to social rejection may differ according to these individual differences in attachment anxiety and avoidance. To test this hypothesis, we used neuroimaging techniques to examine how the degree to which people display each of the two attachment dimensions (anxiety and avoidance) uniquely correlated with their neural activity during a simulated experience of social exclusion. Anxious attachment related to heightened activity in the dorsal anterior cingulate cortex (dACC) and anterior insula, regions previously associated with rejection-related distress. In contrast, avoidant attachment related to less activity in these regions. Findings are discussed in terms of the strategies that individuals with varying attachment styles might use to promote maintenance of social bonds.

Involvement with friends carries many advantages for adolescents, including protection from the detrimental effects of being rejected by peers. However, little is known about the mechanisms through which friendships may serve their protective role at this age, or the potential benefit of these friendships as adolescents transition to adulthood. As such, this investigation tested whether friend involvement during adolescence related to less neural sensitivity to social threats during young adulthood. Twenty-one adolescents reported the amount of time they spent with friends outside of school using a daily diary. Two years later they underwent an fMRI scan, during which they were ostensibly excluded from an online ball-tossing game by two same-age peers. Findings from region of interest and whole brain analyses revealed that spending more time with friends during adolescence related to less activity in the dorsal anterior cingulate cortex and anterior insula—regions previously linked with negative affect and pain processing—during an experience of peer rejection 2 years later. These findings are consistent with the notion that positive relationships during adolescence may relate to individuals being less sensitive to negative social experiences later on.

Although amygdala and frontal lobe functional abnormalities have been reported in patients with mood disorders, the literature regarding Major Depressive Disorder (MDD) is inconsistent. Likely confounds include heterogeneity of patient samples, medication status, and analytic approach. This study evaluated amygdala and frontal lobe activation in unmedicated MDD patients. Fifteen MDD patients and 15 matched healthy controls were scanned using fMRI during the performance of an emotional faces task known to robustly activate the amygdala and prefrontal cortex (PFC). Whole-brain and region of interest analyses were performed, and correlations between clinical features and activation were examined. Significant amygdala and lateral PFC activation were seen within patient and control groups. In a between-group comparison, patients showed significantly reduced activation in the insula, temporal and occipital cortices. In MDD, the presence of anxiety symptoms was associated with decreased orbitofrontal activation. We found robust activation in both the MDD and control groups in fronto-limbic regions with no significant between-group differences using either analytic approach. The current study replicates previous research on unmedicated subjects showing no significant differences in amygdala function in depressed vs. control subjects with respect to simple tasks involving emotion observation.

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.

Peer rejection is particularly pervasive among adolescents with autism spectrum disorders (ASD). However, how adolescents with ASD differ from typically developing adolescents in their responses to peer rejection is poorly understood. The goal of the current investigation was to examine neural responses to peer exclusion among adolescents with ASD compared to typically developing adolescents. Nineteen adolescents with ASD and 17 typically developing controls underwent fMRI as they were ostensibly excluded by peers during an online game called Cyberball. Afterwards, participants reported their distress about the exclusion. Compared to typically developing adolescents, those with ASD displayed less activity in regions previously linked with the distressing aspect of peer exclusion, including the subgenual anterior cingulate and anterior insula, as well as less activity in regions previously linked with the regulation of distress responses during peer exclusion, including the ventrolateral prefrontal cortex and ventral striatum. Interestingly, however, both groups self-reported equivalent levels of distress. This suggests that adolescents with ASD may engage in differential processing of social experiences at the neural level, but be equally aware of, and concerned about, peer rejection. Overall, these findings contribute new insights about how this population may differentially experience negative social events in their daily lives.

Neuroimaging studies with adults have begun to reveal the neural bases of empathy; however, this research has focused on empathy for physical pain, rather than empathy for negative social experiences. Moreover, this work has not examined adolescents who may frequently witness and empathize with others who experience negative social experiences like peer rejection. Here, we examined neural activity among early adolescents observing social exclusion compared to observing inclusion, and how this activity related to both trait empathy and subsequent prosocial behavior. Participants were scanned while they observed an individual whom they believed was being socially excluded. At least one day prior to the scan they reported their trait empathy, and following the scan they wrote emails to the excluded victim that were rated for prosocial behavior (e.g., helping, comforting). Observing exclusion compared to inclusion activated regions involved in mentalizing (i.e., dorsomedial prefrontal cortex; DMPFC), particularly among highly empathic individuals. Additionally, individuals who displayed more activity in affective, pain-related regions during observed exclusion compared to inclusion subsequently wrote more prosocial emails to excluded victims. Overall findings suggest that when early adolescents witness social exclusion in their daily lives, some may actually ‘feel the pain’ of the victims and act more prosocially toward them as a result.

Although research has established links between feelings of social isolation and inflammation, the direction of these effects is unclear. Based on the role that proinflammatory cytokines play in initiating “sickness behavior,” which includes symptoms such as social withdrawal, it is possible that inflammatory processes heighten feelings of ‘social disconnection.’ Here, we examined whether exposure to an inflammatory challenge increased self-reported feelings of social disconnection. In addition, because both inflammatory processes and feelings of social disconnection contribute to depressive symptoms, we also explored whether increases in feelings of social disconnection played a role in the link between inflammation and depressed mood. Participants were randomly assigned to either receive endotoxin, an inflammatory challenge, or placebo. Proinflammatory cytokines (IL-6, TNF-α) were collected at baseline and then hourly for six hours. Participants completed self-reports of sickness symptoms (“fatigue”), social disconnection (“I feel disconnected from others”), and depressed mood (“unhappy”) hourly. Results revealed that endotoxin led to significant increases (from baseline) in IL-6 and TNF-α levels as well as feelings of social disconnection and depressed mood. Moreover, controlling for increases in social disconnection eliminated the relationship between exposure to inflammatory challenge and depressed mood. This study demonstrates that inflammation can have social psychological consequences, which may play a role in cytokine-related depressive symptoms.

To better understand the relationship between mindfulness and depression, we studied normal young adults (n=27) who completed measures of dispositional mindfulness and depressive symptomatology, which were then correlated with: a) Rest: resting neural activity during passive viewing of a fixation cross, relative to a simple goal-directed task (shape-matching); and b) Reactivity: neural reactivity during viewing of negative emotional faces, relative to the same shape-matching task. Dispositional mindfulness was negatively correlated with resting activity in self-referential processing areas, while depressive symptomatology was positively correlated with resting activity in similar areas. In addition, dispositional mindfulness was negatively correlated with resting activity in the amygdala, bilaterally, while depressive symptomatology was positively correlated with activity in the right amygdala. Similarly, when viewing emotional faces, amygdala reactivity was positively correlated with depressive symptomatology and negatively correlated with dispositional mindfulness, an effect that was largely attributable to differences in resting activity. These findings indicate that mindfulness is associated with intrinsic neural activity and that changes in resting amygdala activity could be a potential mechanism by which mindfulness-based depression treatments elicit therapeutic improvement.

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.

Developmental research has demonstrated the harmful effects of peer rejection during adolescence; however, the neural mechanisms responsible for this salience remain unexplored. In this study, 23 adolescents were excluded during a ball-tossing game in which they believed they were playing with two other adolescents during an fMRI scan; in reality, participants played with a preset computer program. Afterwards, participants reported their exclusion-related distress and rejection sensitivity, and parents reported participants’ interpersonal competence. Similar to findings in adults, during social exclusion adolescents displayed insular activity that was positively related to self-reported distress, and right ventrolateral prefrontal activity that was negatively related to self-reported distress. Findings unique to adolescents indicated that activity in the subgenual anterior cingulate cortex (subACC) related to greater distress, and that activity in the ventral striatum related to less distress and appeared to play a role in regulating activity in the subACC and other regions involved in emotional distress. Finally, adolescents with higher rejection sensitivity and interpersonal competence scores displayed greater neural evidence of emotional distress, and adolescents with higher interpersonal competence scores also displayed greater neural evidence of regulation, perhaps suggesting that adolescents who are vigilant regarding peer acceptance may be most sensitive to rejection experiences.

Complicated grief (CG) occurs when an individual experiences prolonged, unabated grief. The neural mechanisms distinguishing CG from noncomplicated grief (NCG) are unclear, but hypothesized mechanisms include both pain-related activity (related to the social pain of loss) and reward-related activity (related to attachment behavior). Bereaved women (11 CG, 12 NCG) participated in an event-related functional magnetic resonance imaging scan, during grief elicitation with idiographic stimuli. Analyses revealed that whereas both CG and NCG participants showed pain-related neural activity in response to reminders of the deceased, only those with CG showed reward-related activity in the nucleus accumbens (NA). This NA cluster was positively correlated with self-reported yearning, but not with time since death, participant age, or positive/negative affect. This study supports the hypothesis that attachment activates reward pathways. For those with CG, reminders of the deceased still activate neural reward activity, which may interfere with adapting to the loss in the present.

It is well established that a lack of social support constitutes a major risk factor for morbidity and mortality, comparable to risk factors such as smoking, obesity, and high blood pressure. Although it has been hypothesized that social support may benefit health by reducing physiological reactivity to stressors, the mechanisms underlying this process remain unclear. Moreover, to date, no studies have investigated the neurocognitive mechanisms that translate experiences of social support into the health outcomes that follow. To investigate these processes, thirty participants completed three tasks in which daily social support, neurocognitive reactivity to a social stressor, and neuroendocrine responses to a social stressor were assessed. Individuals who interacted regularly with supportive individuals across a ten-day period showed diminished cortisol reactivity to a social stressor. Moreover, greater social support and diminished cortisol responses were associated with diminished activity in the dorsal anterior cingulate cortex (dACC) and Brodmann's area (BA) 8, regions previously associated with the distress of social separation. Lastly, individual differences in dACC and BA 8 reactivity mediated the relationship between high daily social support and low cortisol reactivity, such that supported individuals showed reduced neurocognitive reactivity to social stressors, which in turn was associated with reduced neuroendocrine stress responses. This study is the first to investigate the neural underpinnings of the social support-health relationship and provides evidence that social support may ultimately benefit health by diminishing neural and physiological reactivity to social stressors.

Previous research has examined neural responses to threatening facial expressions such as those displaying anger, fear, and disgust. Here, we examined neural responses to a different type of threatening facial expression that primarily signifies a threat to social connection, namely a “disapproving” facial expression. We hypothesized that neural responses to disapproving facial expressions would be moderated by individual differences in rejection sensitivity. Using functional magnetic resonance imaging (fMRI), we scanned participants while they viewed brief video clips of facial expressions depicting disapproval, anger, and disgust. As expected, all three expressions yielded bilateral amygdala activation relative to a resting baseline. Additionally, individuals who scored higher on a measure of rejection sensitivity exhibited greater dorsal anterior cingulate cortex activity in response to disapproving facial expressions, but not in response to anger or disgust facial expressions. Results suggest that, at the neural level, individuals high in rejection sensitivity may be more sensitive to facial expressions signaling potential rejection, but not to threatening facial expressions in general. Results also suggest that disapproving facial expressions convey a distinct type of threat and should be considered in future studies of socially threatening facial expressions.