Exploring neural mechanisms of the health benefits of gratitude in women: A randomized controlled trial.

BACKGROUND: Gratitude has received growing interest as an emotion that can bring greater happiness and health. However, little is known about the effects of gratitude on objective measures of physical health or the neural mechanisms that underlie these effects. Given strong links between gratitude and giving behavior, and giving and health, it is possible that gratitude may benefit health through the same mechanisms as giving to others. Thus, this study investigated whether gratitude activates a neural 'caregiving system' (e.g., ventral striatum (VS), septal area (SA)), which can downregulate threat responding (e.g., amygdala) and possibly cellular inflammatory responses linked to health. METHODS: A parallel group randomized controlled trial examined the effect of a six-week online gratitude (n = 31) vs. control (n = 30) writing intervention on neural activity and inflammatory outcomes. Pre- and post-intervention, healthy female participants (ages 35-50) reported on support-giving behavior and provided blood samples to assess circulating plasma levels and stimulated monocytic production of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)). Post-intervention, participants completed a gratitude task and a threat reactivity task in an fMRI scanner. RESULTS: There were no significant group differences (gratitude vs. control intervention) in neural responses (VS, SA, or amygdala) to the gratitude or threat tasks. However, across the entire sample, those who showed larger pre- to- post-intervention increases in self-reported support-giving showed larger reductions in amygdala reactivity following the gratitude task (vs. control task). Additionally, those who showed larger reductions in amygdala reactivity following the gratitude task showed larger pre-to-post reductions in the stimulated production of TNF-α and IL-6. Importantly, gratitude-related reductions in amygdala reactivity statistically mediated the relationship between increases in support-giving and decreases in stimulated TNF-α production. CONCLUSION: The observed relationships suggest that gratitude may benefit health (reducing inflammatory responses) through the threat-reducing effects of support-giving.

Feeling needed: Effects of a randomized generativity intervention on well-being and inflammation in older women.

Generativity, or concern for and contribution to the well-being of younger generations, plays an important role in successful aging. The purpose of this study was to develop a novel, writing-based intervention to increase feelings of generativity and test the effect of this intervention on well-being and inflammation in a sample of older women. Participants in this study (n = 73; mean age = 70.9 years, range 60-86 years) were randomly assigned to a 6-week generativity writing condition (writing about life experiences and sharing advice with others) or a control writing condition (neutral, descriptive writing). Self-reported measures of social well-being, mental health, and physical health, as well as objective measures of systemic and cellular levels of inflammation (plasma pro-inflammatory cytokines interleukin-6 and tumor necrosis factor-α; genome-wide RNA transcriptional profiling), were assessed pre- and post-intervention. The generativity intervention led to significant improvements across multiple domains, including increases in participation in social activities, decreases in psychological distress, more positive expectations regarding aging in the physical health domain, and decreases in pro-inflammatory gene expression. Thus, this study provides preliminary evidence for the ability of a novel, low-cost, low-effort intervention to favorably impact inflammation and well-being in older women.

Exposure to an inflammatory challenge enhances neural sensitivity to negative and positive social feedback.

Inflammation, part of the body's innate immune response, can lead to "sickness behaviors," as well as alterations in social and affective experiences. Elevated levels of pro-inflammatory cytokines have been associated with increased neural sensitivity to social rejection and social threat, but also decreased neural sensitivity to rewards. However, recent evidence suggests that inflammation may actually enhance sensitivity to certain social rewards, such as those that signal support and care. Despite a growing interest in how inflammation influences neural reactivity to positive and negative social experiences, no known studies have investigated these processes in the same participants, using a similar task. To examine this issue, 107 participants were randomly assigned to receive either placebo or low-dose endotoxin, which safely triggers an inflammatory response. When levels of pro-inflammatory cytokines were at their peak, participants were scanned using fMRI while they received positive, negative, and neutral feedback from an "evaluator" (actually a confederate) about how they came across in an audio-recorded interview. In response to negative feedback (vs. neutral), participants in the endotoxin condition showed heightened neural activity in a number of threat-related neural regions (i.e., bilateral amygdala, dorsal anterior cingulate cortex) and a key mentalizing-related region (i.e., dorsomedial PFC), compared to placebo participants. Interestingly, when receiving positive feedback (vs. neutral), endotoxin (vs. placebo) led to greater neural activity in the ventral striatum and ventromedial PFC, regions often implicated in processing reward, as well as greater activity in dorsomedial PFC. Together, these results reveal that individuals exposed to an inflammatory challenge are more "neurally sensitive" to both negative and positive social feedback, suggesting that inflammation may lead to a greater vigilance for both social threats and social rewards.

Inflammation impairs social cognitive processing: A randomized controlled trial of endotoxin.

UNLABELLED: Neuropsychiatric disorders (e.g., autism, schizophrenia) are partially characterized by social cognitive deficits, including impairments in the ability to perceive others' emotional states, which is an aspect of social cognition known as theory of mind (ToM). There is also evidence that inflammation may be implicated in the etiology of these disorders, but experimental data linking inflammation to deficits in social cognition is sparse. Thus, we examined whether exposure to an experimental inflammatory challenge led to changes in ToM. One hundred and fifteen (n=115) healthy participants were randomly assigned to receive either endotoxin, which is an inflammatory challenge, or placebo. Participants completed a social cognition task, the Reading the Mind in the Eyes (RME) test, at baseline and at the peak of the inflammatory response for the endotoxin group. The RME test, a validated measure of ToM, evaluates how accurately participants can identify the emotional state of another person by looking only at their eyes. We found that endotoxin (vs. placebo) led to decreases in performance on the RME test from baseline to the peak of inflammatory response, indicating that acute inflammation can lead to decreases in the ability to accurately and reliably comprehend emotional information from others. Given that deficits in ToM are implicated in neuropsychiatric disorders, including those which may have an inflammatory basis, these results may have implications for understanding the links between inflammation, social cognition, and neuropsychiatric disorders. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT01671150.

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.

Yoga for youth in pain: the UCLA pediatric pain program model.

Children, adolescents, and young adults do not typically feature in clinics, studies, and mainstream notions of chronic pain. Yet many young people experience debilitating pain for extended periods of time. Chronic pain in these formative years may be especially important to treat in order for young patients to maintain life tasks and to prevent protracted disability. The Pediatric Pain Program at the University of California, Los Angeles, is a multidisciplinary treatment program designed for young people with chronic pain and their families. We offer both conventional and complementary medicine to treat the whole individual. This article describes the work undertaken in the clinic and our newly developed Yoga for Youth Research Program. The clinical and research programs fill a critical need to provide service to youth with chronic pain and to scientifically study one of the more popular complementary treatments we offer, Iyengar yoga.

Frontostriatal functional connectivity underlies self-enhancement during social evaluation.

Self-enhancement, the tendency to view oneself positively, is a pervasive social motive widely investigated in the psychological sciences. Relatively little is known about the neurocognitive mechanisms underlying this motive, specifically in social-evaluative situations. To investigate whether positive emotion regulation circuitry, circuitry involved in modulating positive affect, relates to the self-enhancement motive in social contexts, we conducted an functional magnetic resonance imaging (fMRI) study in a healthy young adult sample. We hypothesized that self-enhancement indices (state and trait self-esteem) would relate to greater functional connectivity between right ventrolateral prefrontal cortex (RVLPFC), a region implicated in emotion regulation, and the ventral striatum (VS), a region associated with reward-related affect, during a social feedback task. Following social evaluation, participants experienced stable or decreased state self-esteem. Results showed that stable state self-esteem from pre- to post-scan and higher trait self-esteem related to greater RVLPFC-VS connectivity during positive evaluation. Stable-state self-esteem also related to greater RVLPFC-VS connectivity during negative evaluation. Moreover, RVLPFC activation during all types of feedback processing and left VS activation during negative feedback processing was greater for participants with stable-state self-esteem. These findings implicate neurocognitive mechanisms underlying emotion regulation in the self-enhancement motive and highlight a pathway through which self-enhancement may restore feelings of self-worth during threatening situations.

Generativity and Social Well-Being in Older Women: Expectations Regarding Aging Matter.

OBJECTIVES: Beliefs about aging can contribute to health and well-being in older adults. Feeling generative, or that one is caring for and contributing to the well-being of others, can also impact health and well-being. In this study, we hypothesized that those with more positive expectations regarding aging (ERA) in the mental health domain would report greater levels of perceived social support (PSS) and lower levels of loneliness in response to a generativity intervention (vs control condition). METHOD: Participants in this study (n = 73, 100% female) were randomly assigned to a 6-week generativity condition, which involved writing about life experiences and sharing advice with others, or to a control condition, which involved writing about neutral topics. Pre- and postintervention, PSS, and feelings of loneliness were measured. RESULTS: Those in the generativity condition with more positive ERA in the mental health domain reported greater PSS and lower loneliness postintervention. DISCUSSION: These results highlight the importance of psychological factors, such as ERA, in moderating the efficacy of interventions to promote social well-being in older adults.

Sex Differences in the Effect of Inflammation on Subjective Social Status: A Randomized Controlled Trial of Endotoxin in Healthy Young Adults.

It has been established that inflammation leads to a variety of changes in social experience, but one area of social experience that has been overlooked is subjective social status. Furthermore, given sex differences in the relationship between inflammation and social status, males may be more sensitive to inflammation-induced changes in social status. However, no previous studies in humans have examined this possibility. In the present study, healthy young participants (n = 115) were randomly assigned to receive either endotoxin, an experimental inflammatory challenge, or placebo. Participants reported their subjective social status at baseline (prior to injection), and approximately 2 h later (time of peak inflammatory response for the endotoxin group). Results, using ANCOVA analyses, indicated that males exposed to endotoxin, but not females, reported lower levels of subjective social status at the peak of inflammatory response (vs. placebo). These results suggest that males may be more sensitive to the effects of inflammation in certain social domains, such as perceived social status. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01671150.

Moderators for depressed mood and systemic and transcriptional inflammatory responses: a randomized controlled trial of endotoxin.

Activation of the innate immune system is thought to contribute to depression. Multiple social and behavioral factors are also known to instigate depression. Whether these socio-behavioral factors interact with inflammatory stimuli to alter proinflammatory responses and depressed mood is not known. In 115 healthy adults, social, emotional, and behavioral factors were assessed at baseline. A single infusion of endotoxin (Escherichia coli; 0.8 ng/kg of body weight) or placebo (0.9% saline) was administered with hourly assessment of depressed mood and proinflammatory cytokines (interleukin-6 (IL-6); tumor necrosis factor-α (TNF)). Inflammatory gene expression was examined at 30 min after infusion, prior to increase of inflammatory cytokines. As compared to placebo, endotoxin-induced increases of depressed mood were moderated by baseline levels of perceived stress, trait sensitivity to social disconnection, and severity of symptoms of anxiety and depression (all Ps < 0.05) but not early life stress, social status, social support, neuroticism, or sleep disturbance. Anxiety symptoms remained significant in multivariable analyses (P < 0.01). None of these socio-behavioral factors were related to increases in proinflammatory cytokines. Transcriptome profiling analyses indicated that perceived stress, sensitivity to social disconnection, and depressive symptoms were associated with increased activation of pro-inflammatory transcription control pathways (i.e., activator protein-1, nuclear factor-κB) in response to endotoxin (all Ps < 0.05). These results indicate that an array of socio-behavioral factors, which are associated with depression risk, modify vulnerability to inflammation-induced depressed mood. Together, these observations may be used to help target therapeutic interventions to mitigate occurrence of the inflammatory biotype of depression.

Sex Differences in the Relationship Between Inflammation and Reward Sensitivity: A Randomized Controlled Trial of Endotoxin.

BACKGROUND: There are robust sex differences in the prevalence of depression. Inflammation and anhedonia may play a role in understanding these sex differences. Indeed, sex differences in inflammation-induced neural responses to reward may provide insight into the sex gaps in depression, but no study has examined this question. METHODS: As such, the current study examined whether there were sex differences in reward-related neural activity (i.e., ventral striatum [VS] activity) in response to an experimental inflammatory challenge. Human participants (N = 115; 69 female) were randomly assigned to receive either placebo or low-dose endotoxin, which increases inflammation in a safe, time-limited manner. Two hours after receiving placebo or endotoxin (the height of the inflammatory response to endotoxin), participants completed a task in which they anticipated monetary reward in a functional magnetic resonance imaging scanner. RESULTS: Results demonstrated that endotoxin (vs. placebo) led to reduced VS activity in anticipation of reward and that there were sex differences in this effect. Specifically, in female participants, endotoxin (vs. placebo) led to decreased VS activity in anticipation of reward, but this effect was not present in male participants. In addition, within the endotoxin condition, decreases in VS activity in anticipation of reward were related to increases in inflammation for female but not male participants. CONCLUSIONS: These findings may have implications for understanding how inflammation may contribute to sex differences in rates of depression.

Exploring the role of gratitude and support-giving on inflammatory outcomes.

Although there has been much interest in understanding the effect of gratitude on health-related outcomes, this remains an understudied area of research, particularly regarding mechanisms and measurement of biological outcomes. The present study explored whether a gratitude intervention could reduce inflammatory outcomes and whether this occurred through increased support-giving. Healthy women (n = 76) were randomly assigned to a 6-week gratitude intervention (i.e., writing on topics intended to induce gratitude) or a control condition (i.e., neutral writing). Support-giving and markers of inflammation were measured pre- and postintervention. Those in the gratitude intervention (vs. control) reported higher postintervention levels of support-giving. Moreover, those with lower levels of psychological distress gave more support as a function of the gratitude intervention. Regarding inflammatory outcomes, although there was no effect of the gratitude intervention on postintervention inflammatory markers, increases in support-giving across the entire sample were related to decreases in inflammatory markers. These results, along with a scarcity of work in this area, suggest that further work is needed to more fully understand the relationships between gratitude and biological markers relevant to health. Finally, these novel findings linking support-giving and decreases in inflammation also indicate that the mammalian caregiving system, associated with enhanced support-giving and reduced physiological stress responding, is a mechanism worth further examination to elucidate the links between social support and health. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Effects of inflammation on social processes and implications for health.

Although at first glance inflammation and social behavior may appear unrelated, research points to an important role for inflammation in shaping social processes. This review summarizes findings in this field, specifically highlighting work that provides support for the idea that inflammation can lead to (1) increases in sensitivity to negative, threatening social experiences and (2) increases in sensitivity to positive, socially rewarding experiences. These diverging sensitivities in response to inflammation may depend on context and be adaptive for recuperation and recovery from illness. This review also discusses the implications of these findings for health and future research, including implications for depression, loneliness, and inflammatory disorders.

In Sickness and in Health: The Co-Regulation of Inflammation and Social Behavior.

Although it has commonly been assumed that the immune system and the processes that govern social behavior are separate, non-communicating entities, research over the past several decades suggests otherwise. Considerable evidence now shows that inflammatory processes and social behavior are actually powerful regulators of one another. This review first summarizes evidence that inflammatory processes regulate social behavior, leading to characteristic changes that may help an individual navigate the social environment during times of sickness. Specifically, this review shows that inflammation: (1) increases threat-related neural sensitivity to negative social experiences (eg, rejection, negative social feedback), presumably to enhance sensitivity to threats to well-being or safety in order to avoid them and (2) enhances reward-related neural sensitivity to positive social experiences (eg, viewing close others and receiving positive social feedback), presumably to increase approach-related motivation towards others who might provide support and care during sickness. Next, this review summarizes evidence showing that social behavior also regulates aspects of inflammatory activity, preparing the body for situations in which wounding and infection may be more likely (social isolation). Here, we review research showing: (1) that exposure to social stressors increases proinflammatory activity, (2) that individuals who are more socially isolated (ie, lonely) show increased proinflammatory activity, and (3) that individuals who are more socially isolated show increased proinflammatory activity in response to an inflammatory challenge or social stressor. The implications of the co-regulation of inflammation and social behavior are discussed.

Correction: A Pilot Study Examining Physical and Social Warmth: Higher (Non-Febrile) Oral Temperature Is Associated with Greater Feelings of Social Connection.

[This corrects the article DOI: 10.1371/journal.pone.0156873.].

A Pilot Study Examining Physical and Social Warmth: Higher (Non-Febrile) Oral Temperature Is Associated with Greater Feelings of Social Connection.

An emerging literature suggests that experiences of physical warmth contribute to social warmth-the experience of feeling connected to others. Thus, thermoregulatory systems, which help maintain our relatively warm internal body temperatures, may also support feelings of social connection. However, the association between internal body temperature and feelings of connection has not been examined. Furthermore, the origins of the link between physical and social warmth, via learning during early experiences with a caregiver or via innate, co-evolved mechanisms, remain unclear. The current study examined the relationship between oral temperature and feelings of social connection as well as whether early caregiver experiences moderated this relationship. Extending the existing literature, higher oral temperature readings were associated with greater feelings of social connection. Moreover, early caregiver experiences did not moderate this association, suggesting that the physical-social warmth overlap may not be altered by early social experience. Results provide additional support for the link between experiences of physical warmth and social warmth and add to existing theories that highlight social connection as a basic need on its own.

Yearning for connection? Loneliness is associated with increased ventral striatum activity to close others.

Loneliness is a distressing state indicating that one's basic need for social connection is not being met. In an effort to satisfy the need for social connection, loneliness may increase the processing of social cues and desire to connect with others. Yet the neural substrates that contribute to the drive for increased connection in response to loneliness are not known. The ventral striatum (VS), previously shown to increase in response to craving food and other rewarding stimuli, may contribute to "social craving" when one is lonely. That is, the VS may track one's 'hunger' for reconnection much as it tracks hunger for food. To examine this, participants reported on their feelings of loneliness before undergoing an fMRI scan where they viewed cues of potential social reconnection (images of a close other). Consistent with the hypothesis that loneliness stems from an unmet need for connection, loneliness was associated with reduced feelings of connection with the close other. Furthermore, greater reported loneliness was associated with increased VS activity to viewing a close other (vs stranger). Results extend the current literature by showing that lonely individuals show increased activity in reward-related regions to their closest loved ones, possibly reflecting an increased desire for social connection.

Sex differences in depressive and socioemotional responses to an inflammatory challenge: implications for sex differences in depression.

Substantial evidence demonstrates that inflammatory processes may underlie depression for a subset of patients, including work showing that healthy subjects exposed to an inflammatory challenge show increases in depressed mood and feelings of social disconnection. However, despite the fact that depression is two times as likely to occur in females than males, the vast majority of this work has been carried out in males. Thus, the objective of this study was to determine whether females (vs males) would show greater increases in proinflammatory cytokines, depressed mood, and social disconnection in response to an inflammatory challenge. One hundred and fifteen healthy participants (69 female) completed this double-blind, placebo-controlled, randomized clinical trial in which participants were randomly assigned to receive either a single infusion of low-dose endotoxin (derived from Escherichia coli; 0.8 ng/kg of body weight) or placebo (same volume of 0.9% saline). Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), depressed mood, and feelings of social disconnection were assessed hourly. Results showed that endotoxin (vs placebo) led to increases in proinflammatory cytokines (TNF-α, IL-6), depressed mood, and feelings of social disconnection. Females exposed to endotoxin showed greater increases in depressed mood and feelings of social disconnection. Furthermore, increases in TNF-α and IL-6 were correlated with increases in social disconnection for females but not for males. These sex differences in the relationships between inflammatory and socioemotional responses to an inflammatory challenge may be particularly important for understanding why females are two times as likely as males to develop depressive disorders.

Trait sensitivity to social disconnection enhances pro-inflammatory responses to a randomized controlled trial of endotoxin.

UNLABELLED: One proposed mechanism for the association between social isolation and poor health outcomes is inflammation. Lonely or socially disconnected individuals show greater inflammatory responses, including up-regulation of pro-inflammatory gene expression, and people who are sensitive to cues of social disconnection (e.g., high levels of anxious attachment) exhibit greater inflammation in response to psychological stress. However, no studies have examined how sensitivity to social disconnection may influence pro-inflammatory responses to an inflammatory challenge. In the present study, we investigated the impact of sensitivity to social disconnection (a composite score comprised of loneliness, anxious attachment, fear of negative evaluation, and rejection sensitivity) on pro-inflammatory cytokines and gene expression in response to endotoxin, an inflammatory challenge, vs. placebo in a sample of one hundred and fifteen (n=115) healthy participants. Results showed that those who are more sensitive to social disconnection show increased pro-inflammatory responses (i.e., increased levels of tumor necrosis factor-alpha and interleukin-6) to endotoxin, as well as up-regulation of multiple genes related to inflammation. Furthermore, bioinformatics analyses revealed that those in the endotoxin group who are more sensitive to social disconnection exhibited a conserved transcriptional response to adversity (CTRA) regulatory profile, involving up-regulation of beta-adrenergic and pro-inflammatory transcription control pathways and down-regulation of antiviral transcription factors in response to endotoxin. These results may ultimately have implications for understanding the links between social isolation, inflammation, and health. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov NCT01671150.