Naomi I. Eisenberger - US grants

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DESCRIPTION (provided by applicant): This application is submitted to the NIMH DATR Mood/Sleep Research Program A2-AID. Depressive disorders occur at a high rate in patients with inflammatory disorders, with a point prevalence of 15-29%, which is two to three times greater than that observed in the general population. Substantial evidence has shown that inflammation and increases in proinflammatory cytokine activity play a critical role in the onset and perpetuation of depression and depressive symptoms (e.g. insomnia, fatigue) in those who are co-morbid for inflammatory disorders (Miller et al., 2009). Consistent with this, experimental work has shown that an inflammatory challenge can increase depressed mood in an otherwise healthy sample (Reichenberg et al., 2001). Based on these findings, there has been a growing interest in whether inflammatory processes can contribute to depression in a causal manner and how these effects might occur. Given the observation that inflammatory processes trigger social withdrawal (Dantzer, 2001;Hart, 1988), coupled with evidence that feelings of 'social disconnection'play a critical role in the onset and perpetuation of (non-inflammatory forms of) depression (Heinrich &Gullone, 2006), it is surprising that the social psychological consequences of inflammation and their contribution to depression have not been more fully explored. Here, we suggest that inflammation may increase feelings of social disconnection and that these social psychological changes may be an important contributor to inflammation-associated depression. Indeed, preliminary data demonstrated that an experimentally-induced inflammatory challenge (endotoxin) led to increases in self-reported feelings of social disconnection (e.g., "I feel disconnected from others") in addition to increases in depressed mood (Eisenberger et al., 2009b). Aside from these findings, however, there are no studies that have explored the effect of inflammatory processes on social experience in humans. The over- arching objective of this proposal is to explore the experiential and neural correlates of inflammatory- induced changes in social experience (e.g., feelings of social disconnection), which may provide a critical missing link in understanding the relationship between inflammation and depression. Participants (n=100) will be randomly assigned to receive either endotoxin or placebo and will then be monitored for the next six hours. Blood draws to assess cytokine levels as well as self-reported feelings of social disconnection and depressed mood will be collected hourly. In addition, at the time of peak cytokine response, participants will complete a neuroimaging session to examine the effect of inflammatory challenge on neural sensitivity to social rejection and social acceptance. It is hypothesized that endotoxin will increase feelings of social disconnection over time, and that the underlying neural sensitivities that give rise to these feelings (e.g., increased neural sensitivity to social rejection;decreased neural sensitivity to social acceptance) will contribute to inflammatory-induced depressed mood. PUBLIC HEALTH RELEVANCE: Although substantial evidence has demonstrated links between inflammation and depression, the mechanisms underlying this relationship are poorly understood. Based on the observation that inflammation triggers social withdrawal, coupled with evidence that feelings of social disconnection play a critical role in depression, the proposed research will examine the social psychological consequences of inflammation and their relation to depressive symptoms for the first time. In addition, the proposed research will examine the neural correlates that underlie these social psychological changes to better understand the central mechanisms that contribute to inflammatory-induced depressive symptoms.

? DESCRIPTION (provided by applicant): The proportion of the world's population over age 60 is increasing at an unprecedented rate. Given this trend, it is imperative to study the mental and physical health of older adults. Psychosocial factors, such as loneliness, are critical in understanding the overall health of older adults, given that increased feelings of loneliness have been linked to functional decline and increased risk of mortality in older adults. Loneliness in older adults may be partially driven by disruptions in meaningful social engagement. In fact, generativity defined as concern and activity dedicated to the well-being of others, especially younger generations and its related components, such as feeling socially useful or needed, are often included in models of successful aging. Furthermore, greater perceptions of generativity have been linked to better health outcomes and longevity in older adults. Thus, lonely older adults may especially benefit from a targeted psychological intervention aimed at increasing perceptions of generativity, which may improve feelings of social connection through increased feelings of social usefulness, as well as improve health outcomes. The objective of this NIA R03 application is to investigate the relationships between social psychological processes and pro-inflammatory responses in the context of health and aging. To do so, the proposed study will investigate the effect of an intervention aimed at increasing perceptions of generativity in lonely older adults on physical and mental health outcomes. Given that pro-inflammatory activity has been linked to both loneliness and poor health outcomes, the study will also examine the effect of the intervention on biological markers of inflammation (i.e., circulating and stimulated pro-inflammatory cytokines and pro-inflammatory gene expression). Participants (n=70) will be randomly assigned to a 6-week intervention aimed at increasing perceptions of generativity or a control condition. During pre- and post-intervention sessions, all participants will complete self-report measures of physical and mental health and have blood drawn (in order to assess biological markers of inflammation). It is hypothesized that participants in the generativity intervention, compared to those in the control condition, will show: 1) improved physical and mental health outcomes and 2) decreased pro-inflammatory activity from pre- to post-intervention. Furthermore, it is hypothesized that decreases in biological pro-inflammatory activity will mediate improvements in health outcomes. The present study will help advance the understanding of the impact of generativity on the lives of older adults, including its effects on health and inflammatory activity. This may inform a low-cost and low-effort way to improve health outcomes in older adults, especially those who may be most vulnerable to poor health outcomes, such as those who are lonely.

It is crucial that people develop the ability to identify and respond to threats as they navigate the world. Yet, the process by which people learn about threatening cues is inexact, often producing excessive fears, disruptive fear responses, and anxiety. Based on the importance that close social ties have for survival, this research examines social support figures as stimuli that promote survival. Such 'prepared safety stimuli' promote feelings of safety and may reduce threat responses. This is in contrast to 'prepared fear stimuli' that have historically threatened human survival (e.g., snakes, spiders). Considerable research has focused on prepared fear stimuli, but little prior work has examined prepared safety stimuli. This research will develop an understanding of these unique safety signals and the beneficial role they might play in both preventing people from learning new fears and aiding people in extinguishing old ones. This research will also help to develop a deeper understanding of the role of social support figures as prepared safety stimuli. In addition, this research may illuminate avenues for improving current interventions targeted at reducing maladaptive fears and anxiety, thereby improving well-being.

The proposed research will bridge the social support and fear learning literatures, employing a combination of fear conditioning, social buffering, and neuroimaging methods. In a series of studies, Dr. Naomi Eisenberger at the University of California, Los Angeles, will define prepared safety stimuli and test whether social support figures fulfill those parameters. The proposed studies will further the examination of social support figures as prepared safety stimuli by examining: 1) whether social support figures, but not other familiar or rewarding stimuli (which are not turned to for social support), serve as prepared safety stimuli, 2) whether ambivalent support figures, who are sources of both positivity (support) and negativity (stress/negative affect), can serve as prepared safety stimuli, 3) whether stimuli historically associated with the presence of social support (warmth, softness) act as prepared safety stimuli, 4) the neural regions that underlie the safety effects of social support figures, and 5) whether support figures inhibit fear learning and enhance fear extinction to other stimuli. Given the prevalence of anxiety and fear-related disorders in the United States, understanding the unique functions of prepared safety stimuli and the role they might play in preventing fear learning or extinguishing learned fears has the potential to pave the way for new interventions targeted at reducing maladaptive fear and anxiety.

Adolescents' risky decision making and antisocial behaviors have received a great deal of public and scientific attention. Less is known about prosocial behaviors among adolescents, such as sharing and supportiveness. How do changes in the adolescent brain relate to the development of these more positive behaviors? And how does adolescents' tendency to engage in positive behaviors vary depending upon the social context? This project brings together a team of developmental and social psychologists and neuroscientists to study how one particular aspect of prosocial behavior, giving to others, changes across adolescence, and how brain changes relate to the age-related changes in prosocial behavior. One specific goal is to explore whether giving behaviors become more sensitive to the situation (such as the recipient and the cost of giving) across development. Another goal is to understand the involvement of different brain systems (such as those responsible for processing rewards and inhibiting impulsive behaviors) in giving behaviors. A final goal is to understand how other social skills such as perspective-taking and empathy relate to giving and brain developments.

A total of 120 participants at 9, 14, and 19 years of age will participate in an experimental giving task while having their brains scanned in an MRI machine. They also will complete questionnaires and daily checklists that assess social experience, perspective-taking, empathy, and values. Giving to friends and strangers is expected to increase and decrease, respectively, and giving to family will remain stable across the years of adolescence. This differential giving should correlate with greater activation and connectivity among neural networks associated with reward, mentalizing, and cognitive control when giving to friends as compared to family and strangers, and when giving to family as compared to strangers. Differential giving and neural activation according to recipient is expected to be linked with greater valuing and orientation toward peers and family, and individual differences among participants in overall giving and activation will be correlated with social experience, perspective-taking, and empathy. Findings will enrich the field's understanding of the developing adolescent brain for behavior by highlighting the role of neural development in positive, prosocial behavior and the potential impact of social experience in these dynamics.

Project Summary/Abstract Almost one fifth of the adult population in the United States is afflicted with fear-related disorders, including diagnoses such as generalized anxiety disorder, phobias, and PTSD. Yet, despite significant advances in research regarding fear reduction, treatments for these disorders are only moderately effective. Therefore, building our understanding of how to reduce harmful fears is of paramount importance. One step in this process is to further explore the safety signal category. Current views hold that all safety signals are harmful in the context of fear reduction, such that their presence prevents fear extinction from occurring. However, recent findings indicate that certain safety signals?social support figures?may enhance, not prevent, fear extinction. Thus, the proposed research seeks to investigate the as-yet unexplored mechanism by which social support has the unique ability to enhance fear extinction, paving the way for future research investigating whether social support can enhance treatment outcomes for fear-related disorders. Given the important role of the opioid system in both supporting the negative feedback model of fear learning and reinforcing and maintaining social relationships, it is possible that by triggering the release of endogenous opioids, social support disrupts the typical function of the neurobiological associative circuit that that regulates fear learning. This associative circuit relies on opioid processes for fear extinction to occur, such that if opioid processes are blocked, fear extinction is prevented, or if opioid processes are augmented by the presence of a concurrent excitor (an additional fearful stimulus which increases fear and consequent opioid release), fear extinction is enhanced. Thus, unlike learned safety signals, which inhibit opioid processes and prevent fear extinction, social support stimuli might have the unique effect of increasing opioid release without increasing fear, ultimately enhancing fear extinction. This work will seek to more closely examine this mechanism by 1) distinguishing social support stimuli from typical, learned safety signals and determining whether social support stimuli perform the same functions as concurrent excitors but without increasing fear and 2) examining whether opioid processes underlie these effects. In the first study, we will examine whether healthy, adult participants (n=30, 15 females) undergo greater fear extinction when extinction procedures are conducted in the presence of social support stimuli or concurrent excitors compared to in the presence of learned safety signals. In the second study, we will examine whether these effects are still present in healthy, adult participants who are administered placebo (n=30, 15 females) vs. naltrexone (an opioid antagonist known to cross the blood brain barrier and block central opioid processes; n=30, 15 females). Together, the proposed studies will illuminate the mechanism whereby social support enhances fear extinction and may have the potential to shed light on simple, inexpensive ways to enhance current treatments for fear-related disorders.

Project Summary A large body of empirical work has focused on risky behavior and mental disorders during adolescence, but our knowledge of the neurobehavioral developments in prosocial behavior is quite limited. The result is a portrait of adolescent brain development that focuses risk and psychopathology over more positive behavior. This focus is unfortunate because several prosocial behaviors that involve giving to others ? ranging from volunteering to providing instrumental or social assistance ? have been linked to healthy psychological, behavioral, and physical profiles. Giving resources and assistance to others is associated with lower mortality, fewer objective and subjective health problems, and lower depression. The health benefits of giving to others warrant an increased focus on the neurobehavioral developments that underlie this core aspect of prosocial behavior during adolescence, a key point of development that sets the stage for lifelong health and well-being. We aim to advance the field by utilizing a longitudinal design to pursue four specific aims: (1) clarify developmental changes in prosocial behavior during adolescence by longitudinally examining a specific, fundamental prosocial behavior (i.e., giving) and how it increasingly depends upon the situation (i.e., the potential recipient, the cost of giving); (2) examine how neurodevelopment in the reward, mentalizing, and cognitive control neural networks tracks with giving behavior; (3) assess how social relationships, perspective- taking, empathy, and values may relate to giving and neural development; (4) explore potential gender differences in average levels of giving and neural processes. Using a cohort-sequential longitudinal design, a total of 180 participants will be assessed at three times, every two-years, across a five-year period. The total sample will consist of three overlapping age cohorts of 60 participants each and will cover the age span from 9 to 17 yrs. (Cohort 1: 9-13 yrs., Cohort 2: 11-15 yrs., Cohort 3: 13-17 yrs.). At each time point, participants will participate in an established decision-making task optimized for the fMRI scanner in which they will be asked to make real financial contributions to their families, friends, and a stranger under varying conditions of cost to themselves. While making decisions, participants' brains will be scanned for activation and functional connectivity between regions and networks that have been implicated in mentalizing, cognitive control, and reward-related behaviors. Adolescents also will complete questionnaires and daily diary checklists that will assess aspects of social relationships, perspective-taking, empathy, and values thought to predict prosocial behavior.

Project Summary/Abstract Due to the relationships between loneliness and a variety of poor health outcomes and mortality, loneliness is increasingly being recognized as an important public health issue. Despite the relevance of loneliness for health, including evidence suggesting the effects may be particularly pronounced for middle- aged adults, loneliness is a highly understudied topic in mid-life in need of further research. One potential mechanism for the effect of loneliness on health is inflammation. Lonely individuals have heightened inflammation, and inflammation can increase feelings of loneliness. Furthermore, loneliness and inflammation share similar psychological states, both marked by hypersensitivity to the social world, including increased sensitivity to both negative and positive social cues (i.e., social threat and social reward). Thus, by breaking the cycle between inflammation and loneliness, and altering the underlying hypersensitive psychological state, it is possible that an anti-inflammatory drug may lead to improvements in loneliness. However, to our knowledge, no studies have explicitly tested this. The objective of this NIA R21 application is to address this gap in the literature and test the effect of an anti-inflammatory medication on loneliness in a sample of middle-aged adults and to examine the social psychological mechanisms that may underlie any benefits. Participants (ntotal=100; aged 45-59) will be randomly assigned to receive naproxen (a nonsteroidal anti-inflammatory drug) or placebo for four weeks. Pre- and post-intervention, participants will complete self-report measures of loneliness, physical, and mental health, as well as experimental tasks intended to assess sensitivity to both social threat and social reward, as well as desire to socially engage with others. Participants will also have blood drawn to assess inflammation. It is hypothesized that naproxen (vs. placebo) will lead to decreases in feelings of loneliness via dampening of social threat and social reward systems. Furthermore, it is hypothesized that naproxen will lead to increased interest in social re-engagement. We will also explore whether these effects are mediated by changes in inflammatory pathways as well as whether these changes persist past the end of the intervention. The present study will aid in our understanding of the relationship between loneliness and inflammation, particularly in middle-aged adults where this relationship is understudied and could be especially impactful. Moreover, it will provide insight into how we can target biological processes such as inflammation in order to improve loneliness, an important psychosocial factor with far-reaching effects on heath outcomes.

In response to COVID-19, people across the United States have experienced extreme and abrupt shifts in their level of daily contact with others, forcing many people into a state of social isolation. This project examines whether the experience of social isolation amplifies the development of harmful and persistent fears in humans. The research further tests if social isolation reduces the ability to eliminate those fears once learned. This study utilizes a unique situational event (social isolation due to COVID-19), which cannot be replicated in the laboratory, to provide rare insight into how social isolation heightens the development of fear and if experiences of social connection can reverse these effects. This research will contribute to the growing understanding of the effects of social isolation on increasing fears and influencing the developmental course of trauma; it may also provide simple strategies to mitigate those effects.

Research suggests that social isolation may influence long-term trauma by directly influencing fear learning processes. Socially isolated animals exhibit increases in fear responses that persist even when a threat is no longer present, are more likely to develop PTSD-like symptoms following trauma. Similarly, research suggests that socially isolated humans are at a greater risk of developing PTSD. To date, however, no work has directly examined the impact of extreme social isolation on fear learning in humans. Preliminary data suggests that feeling socially isolated appears to lead to persistent fears and poorer fear extinction, although these effects may be eliminated when individuals are reminded of their social support during fear extinction. This project will evaluate these hypotheses by sampling people from across the U.S. living in places where some form of ?Stay at Home? order is in place. The research examines whether the extreme situational social isolation brought about by COVID-19 leads to increased development of fear associations for neutral images paired with negative affective stimuli. The study also examines whether a two-week social connection intervention, during which individuals will be asked to do positive things for others to promote feelings of connectedness, improves fear extinction and decreases the development of fear associations in those most severely isolated. The findings of this work have the potential to shed light on how social isolation influences the course of trauma and reveal simple, low-cost, and accessible interventions to reduce this trauma that can be used immediately and in the future to ease the harmful side effects of necessary measures to address COVID-19 and similar events.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Project Summary/Abstract It is estimated that roughly one third of adults in the US will be affected by a fear-related disorder over the course of their lifetime. These disorders, including diagnoses such as generalized anxiety disorder, social anxiety disorder, or post-traumatic stress disorder, are marked by disruptive fears that can interfere with daily life and have harmful long-term consequences on health and well-being. Yet, even the most successful treatment to date, exposure therapy (a set of procedures that employs fear extinction processes to reduce fear) has limited effects, with discomfort during therapy leading to drop-out and relapse remaining a common occurrence. Thus, investigation of methods to augment exposure therapy treatments and improve fear reduction strategies is critical for improving the well-being of individuals with fear-related disorders. Recent work has revealed that social support may represent one such method, demonstrating that social support reminders enhance the extinction of fear and reduce the acquisition of fear in healthy adults. These findings are unexpected, as they are in direct contrast with current views that all safety signals, including social support figures, are harmful during fear-reduction interventions. Thus, while current views would suggest that these cues reduce extinction and enhance acquisition, social support reminders in fact enhance extinction and reduce acquisition. This divergence may be explained by the crucial role of social support in human survival; specifically, the neurobiological mechanisms that have evolved to reinforce social bonds appear to overlap with the systems that support fear learning, making social support uniquely poised to reduce fear. These previous findings hint at the exciting possibility that social support may play an important role in improving outcomes for individuals with fear-related disorders. In particular, the presence of social support reminders (e.g., pictures) may augment exposure therapy treatments, enhancing extinction outcomes, and enrich strategies to prevent fear acquisition in individuals at risk for developing disruptive fears. However, while the fear-reducing effects of social support have been demonstrated in healthy adults, these effects have never been tested in adults with fear-related disorders. Thus, the proposed studies will be the first to explore whether social support 1) enhances fear extinction and 2) reduces fear acquisition in adults with social anxiety disorder (SAD) and healthy controls. In the first study, we will test whether the presence of a social support image (vs. smiling stranger image) leads to enhanced extinction in participants diagnosed with SAD (n=60, 30 females) and healthy controls (n=60, 30 females). In the second study, we will test whether the presence of a social support image (vs. smiling stranger image) reduces acquisition in participants with SAD (n=60, 30 females) and healthy controls (n=60, 30 females). This work will establish whether the fear-reducing effects of social support extend beyond healthy adults to those with fear-related disorders, potentially shedding light on simple, inexpensive ways to augment current fear reduction treatments and attenuate the formation of new fears.