Christopher P. Fagundes

Stressful early life experiences and immune dysregulation across the lifespan

There is considerable evidence that stressful early life events influence a variety of physical health problems later in life. Childhood adversity has been linked to elevated rates of morbidity and mortality from a number of chronic diseases. Immune dysregulation may be one potential pathway that explains this link. In this mini-review, we summarize human studies demonstrating that severe early life stressors have lasting immune consequences. We propose a model outlining potential biobehavioral pathways that explain how early life stressors leave people vulnerable to these maladaptive outcomes. Finally, we suggest ideas for future work to test different aspects of this model.

Inflammation: Depression Fans the Flames and Feasts on the Heat

Depression and inflammation fuel one another. Inflammation plays a key role in depressions pathogenesis for a subset of depressed individuals; depression also primes larger cytokine responses to stressors and pathogens that do not appear to habituate. Accordingly, treatment decisions may be informed by attention to questions of how (pathways) and for whom (predispositions) these links exist, which are the focus of this article. When combined with predisposing factors (moderators such as childhood adversity and obesity), stressors and pathogens can lead to exaggerated or prolonged inflammatory responses. The resulting sickness behaviors (e.g., pain, disturbed sleep), depressive symptoms, and negative health behaviors (e.g., poor diet, a sedentary lifestyle) may act as mediating pathways that lead to further, unrestrained inflammation and depression. Depression, childhood adversity, stressors, and diet can all influence the gut microbiome and promote intestinal permeability, another pathway to enhanced inflammatory responses. Larger, more frequent, or more prolonged inflammatory responses could have negative mental and physical health consequences. In clinical practice, inflammation provides a guide to potential targets for symptom management by signaling responsiveness to certain therapeutic strategies. For example, a theme across research with cytokine antagonists, omega-3 fatty acids, celecoxib, and exercise is that anti-inflammatory interventions have a substantially greater impact on mood in individuals with heightened inflammation. Thus, when inflammation and depression co-occur, treating them in tandem may enhance recovery and reduce the risk of recurrence. The bidirectional links between depression, inflammation, and disease suggest that effective depression treatments could have a far-reaching impact on mood, inflammation, and health.

Loneliness predicts pain, depression, and fatigue: understanding the role of immune dysregulation.

OBJECTIVE The pain, depression, and fatigue symptom cluster is an important health concern. Loneliness is a common risk factor for these symptoms. Little is known about the physiological mechanisms linking loneliness to the symptom cluster; immune dysregulation is a promising candidate. Latent herpesvirus reactivation, which is reflected by elevated herpesvirus antibody titers, provides a window into immune dysregulation. Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are two common herpesviruses. METHODS Participants were 200 breast cancer survivors who were 2 months to 3 years post-treatment at the time of the study. They completed questionnaires and provided a blood sample that was assayed for CMV and EBV antibody titers. RESULTS Lonelier participants experienced more pain, depression, and fatigue than those who felt more socially connected. Lonelier participants also had higher CMV antibody titers which, in turn, were associated with higher levels of the pain, depression, and fatigue symptom cluster. Contrary to expectations, EBV antibody titers were not associated with either loneliness or the symptom cluster. CONCLUSIONS The pain, depression, and fatigue symptom cluster is a notable clinical problem, especially among cancer survivors. Accordingly, understanding the risk factors for these symptoms is important. The current study suggests that loneliness enhances risk for immune dysregulation and the pain, depression, and fatigue symptom cluster. The present data also provide a glimpse into the pathways through which loneliness may impact health.

Loneliness Promotes Inflammation During Acute Stress

Although evidence suggests that loneliness may increase risk for health problems, the mechanisms responsible are not well understood. Immune dysregulation is one potential pathway: Elevated proinflammatory cytokines such as interleukin-6 (IL-6) increase risk for health problems. In our first study (N = 134), lonelier healthy adults exposed to acute stress exhibited greater synthesis of tumor necrosis factor-alpha (TNF-α) and IL-6 by peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharide (LPS) than their less lonely counterparts. Similarly, in the second study (N = 144), lonelier posttreatment breast-cancer survivors exposed to acute stress exhibited greater synthesis of IL-6 and interleukin-1 beta (IL-1β) by LPS-stimulated PBMCs than their counterparts who felt more socially connected. However, loneliness was unrelated to TNF-α in Study 2, although the result was in the expected direction. Thus, two different populations demonstrated that lonelier participants had more stimulated cytokine production in response to stress than less lonely participants, which reflects a proinflammatory phenotype. These data provide a glimpse into the pathways through which loneliness may affect health.

Depressive symptoms enhance stress-induced inflammatory responses.

Depression is a risk factor for morbidity and mortality, and immune dysregulation may be partially responsible for this link. Proinflammatory cytokines such as interleukin 6 (IL-6) are reliable predictors of quality of life, morbidity, and many causes of mortality. The current study evaluated relationships between depressive symptoms, as assessed by the CES-D, and stress-induced inflammation. The participants, 138 healthy adults, were evaluated at rest, and after a standardized laboratory speech and mental arithmetic stressor. Compared with individuals with fewer depressive symptoms, those with more depressive symptoms produced more IL-6 in response to the stressor, as well as significantly higher levels of IL-6 both 45 min and 2 h after the stressor. These findings add to our emerging understanding of the complex interactions among stress, depression, and immune dysregulation, and provide one potential pathway to explain relationships between depressive symptoms and disease.

Pain, Depression, and Fatigue: Loneliness as a Longitudinal Risk Factor

OBJECTIVE Pain, depression, and fatigue function as a symptom cluster and thus may share common risk factors. Interpersonal relationships clearly influence health, suggesting that loneliness may promote the development of the pain, depression, and fatigue symptom cluster. We hypothesized that loneliness would be related to concurrent symptom cluster levels and increases in symptom cluster levels over time. METHOD We utilized two observational studies with distinct longitudinal samples. Study 1 was a sample of cancer survivors and benign controls (N = 115) assessed annually for 2 years. Study 2 was a sample of older adults caring for a spouse with dementia (caregivers) and non-caregiver controls (N = 229) assessed annually for 4 years. Participants completed annual measures assessing loneliness, pain, depression, and fatigue. RESULTS Across both samples, lonelier participants experienced more concurrent pain, depression, and fatigue and larger increases in symptom cluster levels from one year to the next than less lonely participants. Sleep quality did not mediate the results in either study. All analyses were adjusted for relevant demographic and health variables. CONCLUSIONS Two longitudinal studies with different populations demonstrated that loneliness was a risk factor for the development of the pain, depression, and fatigue symptom cluster over time. The current research helps identify people most at risk for pain, depression, and fatigue, and lays the groundwork for research about their diagnosis and treatment. These data also highlight the health risks of loneliness; pain, depression, and fatigue often accompany serious illness and place people at risk for poor health and mortality.

Sympathetic and parasympathetic activity in cancer-related fatigue: More evidence for a physiological substrate in cancer survivors

Fatigue is a notable clinical problem in cancer survivors, and understanding its pathophysiology is important. This study evaluated relationships between fatigue and both sympathetic and parasympathetic nervous system activity in breast cancer survivors. Norepinephrine and heart rate variability (HRV) were evaluated at rest, as well as during and after a standardized laboratory speech and mental arithmetic stressor. The participants, 109 women who had completed treatment for stage 0-IIIA breast cancer within the past two years, were at least two months post surgery, radiation or chemotherapy, whichever occurred last. Women who reported more fatigue had significantly higher norepinephrine and lower HRV before and after the stressor than their less fatigued counterparts. Fatigue was not related to treatment or disease variables including treatment type, cancer stage, time since diagnosis, and time since treatment. Importantly, the relationship between HRV and cancer-related fatigue was sizeable. Based on research that has demonstrated characteristic age-related HRV decrements, our findings suggest a 20-year difference between fatigued and non-fatigued cancer survivors, raising the possibility that fatigue may signify accelerated aging. Furthermore, lower HRV and elevated norepinephrine have been associated with a number of adverse health outcomes; accordingly, fatigue may also signal the need for increased vigilance to other health threats.

Psychobiological research on attachment

Over the past decade, psychobiological research on adult attachment has increased dramatically. We review recent findings regarding associations between attachment style and patterns of reactivity in the hypothalamic—pituitary—adrenocortical axis and the autonomic nervous system. The overall pattern of results suggests that both anxiety and avoidance are associated with heightened hypothalamic—pituitary—adrenocortical and autonomic nervous system reactivity to stress, consistent with the notion that attachment insecurity is associated with deficits in emotion regulation. The finding of heightened physiological reactivity among avoidant individuals is particularly notable, given that avoidant individuals typically report dampened levels of subjective distress. Key directions for future study include greater investigation into profiles of physiological functioning across multiple systems and contexts and greater consideration of the relative importance of childhood versus adult patterns of attachment insecurity for adult physiological functioning.

Lower subjective social status exaggerates interleukin-6 responses to a laboratory stressor.

Growing evidence suggests that lower subjective social status (SSS), which reflects where a person positions himself on a social ladder in relation to others, is independently related to poor health. People who rate themselves lower in status also experience more frequent stressors and report higher stress than those who rate themselves higher in status, and chronic stress can enhance an individuals response to subsequent stressors. To address whether SSS predicted stress-induced interleukin-6 (IL-6) changes, we assessed 138 healthy adults at rest and following the Trier Social Stress Test (TSST). Participants completed the TSST at two study visits, separated by 4 months. People who placed themselves lower on the social ladder had larger IL-6 responses from baseline to 45 min post-stressor (p=0.01) and from baseline to 2h post-stressor (p=0.03) than those who placed themselves higher on the social ladder. Based on a ratio of subjective threat and coping ratings of the stress task, participants who viewed themselves as lower in status also tended to rate the speech task as more threatening and less manageable than those who viewed themselves as higher in status (p=0.05). These data suggest that people with lower perceived status experience greater physiological and psychological burden from brief stressors compared to those with higher perceived status. Accordingly, responses to stressors may be a possible mechanistic link among SSS, stress, and health.

Child maltreatment and breast cancer survivors: Social support makes a difference for quality of life, fatigue and cancer stress

PURPOSE To identify how child maltreatment is associated with quality of life (QOL) among breast cancer survivors. PATIENTS AND METHODS One hundred and thirty two women who had completed treatment for stage 0-IIIA breast cancer within the past 2 years (except for tamoxifen/aromatase inhibitors) and were at least 2 months post surgery, radiation, or chemotherapy completed questionnaires including the Childhood Trauma Questionnaire, the Impact of Events Scale, the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) and the Fact-B breast cancer quality of life questionnaire. RESULTS Women who were abused or neglected as children reported more cancer-related psychological distress, more fatigue and poorer physical, emotional, functional and breast cancer-specific well-being after treatment. These relations were partially explained by the fact that breast cancer survivors reported receiving less support as adults. CONCLUSION The findings suggest that child maltreatment is an important predictor of QOL among breast cancer survivors. One reason why this association exists is because those who are maltreated as children report less support as adults. A better understanding of how child maltreatment contributes to breast cancer survivor QOL will help in tailoring and, therefore, enhancing the efficacy of interventions aimed at improving QOL.