Stress to inflammation and anhedonia: Mechanistic insights from preclinical and clinical models.

Anhedonia, as evidenced by impaired pleasurable response to reward, reduced reward motivation, and/or deficits in reward-related learning, is a common feature of depression. Such deficits in reward processing are also an important clinical target as a risk factor for depression onset. Unfortunately, reward-related deficits remain difficult to treat. To address this gap and inform the development of effective prevention and treatment strategies, it is critical to understand the mechanisms that drive impairments in reward function. Stress-induced inflammation is a plausible mechanism of reward deficits. The purpose of this paper is to review evidence for two components of this psychobiological pathway: 1) the effects of stress on reward function; and 2) the effects of inflammation on reward function. Within these two areas, we draw upon preclinical and clinical models, distinguish between acute and chronic effects of stress and inflammation, and address specific domains of reward dysregulation. By addressing these contextual factors, the review reveals a nuanced literature which might be targeted for additional scientific inquiry to inform the development of precise interventions.

The role of inflammation in acute psychosocial stress-induced modulation of reward processing in healthy female adults.

Background: Anhedonia, or loss of interest and pleasure, is a pernicious symptom of depression that involves deficits in reward processing. Stress-induced inflammation is a plausible biopsychosocial mechanism of reward deficits, but little is known whether stress-induced inflammation alters reward behavior. The present study (a secondary analysis of a completed randomized controlled trial) tested whether acute stress activated a key pro-inflammatory transcription control pathway, NF-κB, and whether this activation was associated with acute stress-induced modulation of reward processing. Methods: Healthy female adults (age 18-25) were randomized to undergo an acute psychosocial stressor (Trier Social Stress Test; n = 36) or a no-stress active control (n = 16). The Probabilistic Reward Task (PRT) (n = 30 stress; n = 12 control) was administered at baseline and at 90 min post-stress, coinciding with the peak of the stress-induced inflammatory response. Genome-wide expression profiling and bioinformatics analyses of NF-kB transcription factor activity were used to assess pro-inflammatory gene regulation. Results: Relative to the control condition, stress increased bioinformatic measures of NF-κB transcription factor activity (p = .01) and increased reward response bias scores on the PRT (p = .03). Within the stress condition, greater NF-κB activity was associated with greater increases in PRT scores (p = .01), whereas in the control condition greater NF-κB activity was associated with decreases in PRT scores (p = .002). Conclusions: Acute stress increases inflammatory signaling, and this effect is associated with increased reward processing. This demonstrates the reward system to be highly sensitive to inflammatory signaling, including the relatively mild alterations that occur following a single episode of acute psychosocial stress.

Neural responses to threat and reward and changes in inflammation following a mindfulness intervention.

OBJECTIVE: Mindfulness meditation has been shown to reduce distress and increase well-being among individuals with chronic disease, including breast cancer survivors. However, the neural correlates of these changes and their links with inflammatory biology are not yet known. The present study examined whether a mindfulness meditation intervention was associated with changes in neural responses to threat and reward from pre- to post-intervention, and whether those neural changes were associated with changes in markers of inflammation in breast cancer survivors. METHODS: This was a single-arm trial of a standardized, validated 6-week mindfulness meditation intervention. Participants were 20 women who had been diagnosed and treated for early-stage breast cancer. Participants provided peripheral blood samples and underwent a 90-minute neuroimaging scan before and after the intervention, with a focus on tasks known to elicit activity in threat- and reward-related neural regions. RESULTS: There were significant changes in neural responses to the two tasks of interest from pre to post-intervention (ps < 0.042). Participants showed significant reductions in amygdala activity in response to threatening images and significant increases in ventral striatum activity to rewarding images from pre- to post-intervention. Although changes in amygdala activity were not correlated with inflammatory markers, increases in ventral striatum activity were correlated with decreases in circulating concentrations of the proinflammatory cytokine IL-6 and the inflammatory marker CRP. CONCLUSIONS: These results, while preliminary, suggest that while a mindfulness meditation intervention can alter neural responses to both threat and nonsocial reward-related stimuli, changes in neural reward activity may be more closely linked to changes in circulating levels of inflammation.

Emotions in Social Relationships and Their Implications for Health and Disease: Introduction to the Special Issue of Psychosomatic Medicine.

Social relationships and emotions are important to health and disease, but research in this area has largely progressed along parallel and distinct historical paths. These areas are critically linked because relationships are among the most powerful elicitors of health-relevant emotions and emotions can in turn influence relationships for better or worse. Conceptually, relationships and emotions can have mediational, reciprocal, and interactive influences on health outcomes, associations that seem dependent on the broader sociocultural context. The articles in this issue of Psychosomatic Medicine are based on a joint meeting of the American Psychosomatic Society and the Society for Affective Science titled "Emotions in social relationships: implications for health and disease." Recent research and conceptual models that fall at the interface of relationships, emotions, and health are highlighted in this special issue. Future work that capitalizes on these links will be critical if this area is to fulfill its potential in terms of new scientific insights and intervention opportunities.

Changes in eudaimonic well-being and the conserved transcriptional response to adversity in younger breast cancer survivors.

BACKGROUND: The conserved transcriptional response to adversity (CTRA), characterized by increased expression of proinflammatory genes and decreased expression of antiviral and antibody-related genes, is upregulated in the context of chronic adversity and distress and has been linked to cancer progression. Several studies suggest that the CTRA may also be down-regulated in association with some positive psychological states, particularly eudaimonic well-being. However, it is not clear if the link between inter-individual differences in the CTRA and eudaimonic well-being can be extended to intra-individual change. Using a standardized mindfulness-based intervention, the current study tested whether mindfulness-related increases in eudaimonic well-being related to intra-individual reduction in the CTRA in a sample of younger breast cancer survivors. METHODS: Participants were 22 women who had been diagnosed and treated for early-stage breast cancer at or before age 50 (Mage = 46.6 years) and had no evidence of active disease. Women completed self-report questionnaires and provided peripheral blood samples before and after a 6-week mindfulness meditation intervention. Regression analyses were used to quantify associations between the magnitude of change in eudaimonic well-being and the magnitude of change in the global CTRA score. RESULTS: Women reported significant increases in eudaimonic well-being and showed decreased expression of the pro-inflammatory subcomponent of the CTRA from pre- to post-intervention. The magnitude of increase in eudaimonic well-being was associated with the magnitude of decrease in the composite CTRA score, and this relationship was driven primarily by increased expression of the antiviral/antibody-related CTRA subcomponent. While the intervention was also associated with reduced depressive symptoms, there was no association between change in depressive symptoms and change in the overall CTRA composite score or either of its subcomponents. CONCLUSIONS: Results are consistent with the hypothesis that eudaimonic well-being may be an important mechanism in interventions aimed at enhancing health in vulnerable groups, and contribute to our understanding of how psychological well-being may influence physical health in cancer patients.

When less is more: mindfulness predicts adaptive affective responding to rejection via reduced prefrontal recruitment.

Social rejection is a distressing and painful event that many people must cope with on a frequent basis. Mindfulness-defined here as a mental state of receptive attentiveness to internal and external stimuli as they arise, moment-to-moment-may buffer such social distress. However, little research indicates whether mindful individuals adaptively regulate the distress of rejection-or the neural mechanisms underlying this potential capacity. To fill these gaps in the literature, participants reported their trait mindfulness and then completed a social rejection paradigm (Cyberball) while undergoing functional magnetic resonance imaging. Approximately 1 hour after the rejection incident, participants reported their level of distress during rejection (i.e. social distress). Mindfulness was associated with less distress during rejection. This relation was mediated by lower activation in the left ventrolateral prefrontal cortex during the rejection incident, a brain region reliably associated with the inhibition of negative affect. Mindfulness was also correlated with less functional connectivity between the left ventrolateral prefrontal cortex and the bilateral amygdala and the dorsal anterior cingulate cortex, which play a critical role in the generation of social distress. Mindfulness may relate to effective coping with rejection by not over-activating top-down regulatory mechanisms, potentially resulting in more effective long-term emotion-regulation.

Dispositional mindfulness and depressive symptomatology: correlations with limbic and self-referential neural activity during rest.

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, whereas 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, whereas 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.

Neural correlates of dispositional mindfulness during affect labeling.

OBJECTIVE: Mindfulness is a process whereby one is aware and receptive to present moment experiences. Although mindfulness-enhancing interventions reduce pathological mental and physical health symptoms across a wide variety of conditions and diseases, the mechanisms underlying these effects remain unknown. Converging evidence from the mindfulness and neuroscience literature suggests that labeling affect may be one mechanism for these effects. METHODS: Participants (n = 27) indicated trait levels of mindfulness and then completed an affect labeling task while undergoing functional magnetic resonance imaging. The labeling task consisted of matching facial expressions to appropriate affect words (affect labeling) or to gender-appropriate names (gender labeling control task). RESULTS: After controlling for multiple individual difference measures, dispositional mindfulness was associated with greater widespread prefrontal cortical activation, and reduced bilateral amygdala activity during affect labeling, compared with the gender labeling control task. Further, strong negative associations were found between areas of prefrontal cortex and right amygdala responses in participants high in mindfulness but not in participants low in mindfulness. CONCLUSIONS: The present findings with a dispositional measure of mindfulness suggest one potential neurocognitive mechanism for understanding how mindfulness meditation interventions reduce negative affect and improve health outcomes, showing that mindfulness is associated with enhanced prefrontal cortical regulation of affect through labeling of negative affective stimuli.

Neural pathways link social support to attenuated neuroendocrine stress responses.

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 10-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.