Lena Brydon

Inflammation Causes Mood Changes Through Alterations in Subgenual Cingulate Activity and Mesolimbic Connectivity

Background Inflammatory cytokines are implicated in the pathophysiology of depression. In rodents, systemically administered inflammatory cytokines induce depression-like behavior. Similarly in humans, therapeutic interferon-α induces clinical depression in a third of patients. Conversely, patients with depression also show elevated pro-inflammatory cytokines. Objectives To determine the neural mechanisms underlying inflammation-associated mood change and modulatory effects on circuits involved in mood homeostasis and affective processing. Methods In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Mood questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed an implicit emotional face perception task during functional magnetic resonance imaging. Analyses focused on neurobiological correlates of inflammation-associated mood change and affective processing within regions responsive to emotional expressions and implicated in the etiology of depression. Results Typhoid but not placebo injection produced an inflammatory response indexed by increased circulating interleukin-6 and significant mood reduction at 3 hours. Inflammation-associated mood deterioration correlated with enhanced activity within subgenual anterior cingulate cortex (sACC) (a region implicated in the etiology of depression) during emotional face processing. Furthermore, inflammation-associated mood change reduced connectivity of sACC to amygdala, medial prefrontal cortex, nucleus accumbens, and superior temporal sulcus, which was modulated by peripheral interleukin-6. Conclusions Inflammation-associated mood deterioration is reflected in changes in sACC activity and functional connectivity during evoked responses to emotional stimuli. Peripheral cytokines modulate this mood-dependent sACC connectivity, suggesting a common pathophysiological basis for major depressive disorder and sickness-associated mood change and depression.

Loneliness and neuroendocrine, cardiovascular, and inflammatory stress responses in middle-aged men and women

Loneliness is a psychological experience related to social isolation and perceived lack of companionship, and may be relevant to health risk. The revised UCLA loneliness scale was completed by 240 working men and women aged 47-59 years, and related to affective state and neuroendocrine, cardiovascular, and inflammatory responses. Loneliness scores were not associated with gender, age or socioeconomic position, but were lower in married than single or divorced participants, and were positively related to social isolation, low emotional support, ratings of depression, hopelessness and low self-esteem, and to reported sleep problems. Diastolic blood pressure reactions to acute mental stress were positively correlated with loneliness in women but not men, independently of age, socioeconomic status, smoking, body mass and marital status (p = 0.014). Lonely individuals also displayed significantly greater fibrinogen (p = 0.038) and natural killer cell responses (p = 0.042) to stress, independently of covariates. The cortisol response over the first 30 min following waking was positively associated with loneliness after adjusting for waking cortisol value, sex, socioeconomic status, smoking, time of waking, and body mass (p = 0.046). We conclude that loneliness is a psychological experience with potentially adverse effects on biological stress processes that may be relevant to health.

Peripheral Inflammation is Associated with Altered Substantia Nigra Activity and Psychomotor Slowing in Humans

Background Systemic infections commonly cause sickness symptoms including psychomotor retardation. Inflammatory cytokines released during the innate immune response are implicated in the communication of peripheral inflammatory signals to the brain. Methods We used functional magnetic resonance brain imaging (fMRI) to investigate neural effects of peripheral inflammation following typhoid vaccination in 16 healthy men, using a double-blind, randomized, crossover-controlled design. Results Vaccination had no global effect on neurovascular coupling but markedly perturbed neural reactivity within substantia nigra during low-level visual stimulation. During a cognitive task, individuals in whom typhoid vaccination engendered higher levels of circulating interleukin-6 had significantly slower reaction time responses. Prolonged reaction times and larger interleukin-6 responses were associated with evoked neural activity within substantia nigra. Conclusions Our findings provide mechanistic insights into the interaction between inflammation and neurocognitive performance, specifically implicating circulating cytokines and midbrain dopaminergic nuclei in mediating the psychomotor consequences of systemic infection.

Neural origins of human sickness in interoceptive responses to inflammation.

Background Inflammation is associated with psychological, emotional, and behavioral disturbance, known as sickness behavior. Inflammatory cytokines are implicated in coordinating this central motivational reorientation accompanying peripheral immunologic responses to pathogens. Studies in rodents suggest an afferent interoceptive neural mechanism, although comparable data in humans are lacking. Methods In a double-blind, randomized crossover study, 16 healthy male volunteers received typhoid vaccination or saline (placebo) injection in two experimental sessions. Profile of Mood State questionnaires were completed at baseline and at 2 and 3 hours. Two hours after injection, participants performed a high-demand color word Stroop task during functional magnetic resonance imaging. Blood samples were performed at baseline and immediately after scanning. Results Typhoid but not placebo injection produced a robust inflammatory response indexed by increased circulating interleukin-6 accompanied by a significant increase in fatigue, confusion, and impaired concentration at 3 hours. Performance of the Stroop task under inflammation activated brain regions encoding representations of internal bodily state. Spatial and temporal characteristics of this response are consistent with interoceptive information flow via afferent autonomic fibers. During performance of this task, activity within interoceptive brain regions also predicted individual differences in inflammation-associated but not placebo-associated fatigue and confusion. Maintenance of cognitive performance, despite inflammation-associated fatigue, led to recruitment of additional prefrontal cortical regions. Conclusions These findings suggest that peripheral infection selectively influences central nervous system function to generate core symptoms of sickness and reorient basic motivational states.

Socioeconomic status and stress-induced increases in interleukin-6.

Coronary artery disease (CAD) is more prevalent in people from a low socioeconomic background, and low socioeconomic status (SES) is associated with an increased exposure to psychological stress. The pro-inflammatory cytokine interleukin-6 (IL-6) plays a central role in CAD development. IL-6 is responsive to psychological stress and could potentially mediate the effect of psychosocial factors on CAD risk. Accordingly, we predicted that people of low SES would have greater and/or more sustained IL-6 responses to acute psychological stress. Based on previous findings, we also predicted that these people would have delayed post-stress cardiovascular recovery. Thirty-eight male civil servants were tested, with participants divided into high and low SES groups according to employment grade. There were no differences between the groups at baseline. However there were significant differences in IL-6 and heart rate responses to stress. Stress induced increases in plasma IL-6 in all participants. However, in the low SES group, IL-6 continued to increase between 75 min and 2h post-stress, whereas IL-6 levels stabilised at 75 min in the high SES group. Heart rate increased to the same extent following stress in both groups, however by 2h post-stress, it had returned to baseline in 75% of the high SES group compared with only 38.1% of the low SES group. These results suggest that low SES people are less able to adapt to stress than their high SES counterparts. Prolonged stress-induced increases in IL-6 in low SES groups represents a novel mechanism potentially linking socioeconomic position and heart disease.

Emotional triggering of cardiac events.

Psychological factors may contribute not only to the evolution of coronary atherosclerosis and long-term risk of coronary heart disease, but also to the triggering of acute cardiac events in patients with advanced atherosclerosis. Evidence for emotional triggering of cardiac events derives both from population-based studies of hospital admissions and sudden deaths following major traumas such as earthquakes and terrorist incidents, and from individually based interview studies with survivors of acute coronary syndromes (ACS). The latter indicate that acute anger, stress and depression or sadness may trigger ACS within a few hours in vulnerable individuals. The psychobiological processes underlying emotional triggering may include stress-induced haemodynamic responses, autonomic dysfunction and parasympathetic withdrawal, neuroendocrine activation, inflammatory responses involving cytokines and chemokines, and prothrombotic responses, notably platelet activation. These factors in turn promote coronary plaque disruption, myocardial ischaemia, cardiac dysrhythmia and thrombus formation. The implications of these findings for patient care and ACS prevention are outlined.

Synergistic effects of psychological and immune stressors on inflammatory cytokine and sickness responses in humans

Activation of the innate immune system is commonly accompanied by a set of behavioural, psychological and physiological changes known as ‘sickness behaviour’. In animals, infection-related sickness symptoms are significantly increased by exposure to psychosocial stress, suggesting that psychological and immune stressors may operate through similar pathways to induce sickness. We used a double-blind, randomised, placebo-controlled design to examine the effect of acute psychological stress on immune and subjective mood responses to typhoid vaccination in 59 men. Volunteers were assigned to one of four experimental conditions in which they were either injected with typhoid vaccine or saline placebo, and then either rested or completed two challenging behavioural tasks. Typhoid vaccine induced a significant rise in participants’ serum levels of interleukin-6 (IL-6) and this response was significantly larger in the stress versus rest conditions. Negative mood increased immediately post-tasks, an effect also more pronounced in the vaccine/stress condition. In the vaccine/stress group, participants with larger IL-6 responses had heightened systolic blood pressure responses to tasks and elevated post-stress salivary levels of the noradrenaline metabolite 3-methoxy-phenyl glycol (MHPG) and cortisol. Our findings suggest that, as seen in animals, psychological and immune stressors may act synergistically to promote inflammation and sickness behaviour in humans.

Changes in Financial Strain Over Three Years, Ambulatory Blood Pressure, and Cortisol Responses to Awakening

Objective: Chronic psychosocial stress has been associated cross-sectionally with ambulatory blood pressure and with salivary cortisol, but there have been few longitudinal studies of the effects of changes in chronic stress. We assessed the influence of changes in financial strain on ambulatory blood pressure and salivary cortisol. Methods: Data were analyzed from 160 men and women age 47 to 59 years at the first assessment (T1) who repeated ambulatory monitoring 3 years later (T2). We analyzed change in financial strain as a continuous variable, and specifically compared people who did and did not report an improvement in financial strain. Results: Change in financial strain was associated with change in ambulatory systolic pressure after controlling for T1 ambulatory systolic pressure, gender, socioeconomic position, age, smoking, body mass index, and T1 financial strain (p = .041). Systolic pressure at T2 was lower in the improved financial strain (121.7 ± 11.2 mm Hg) than in the worse/no change group (125.5 ± 11.5 mm Hg; p = .029). The corresponding diastolic pressures averaged 78.5 ± 7.1 mm Hg and 80.7 ± 7.9 mm Hg, respectively (p = .061). The cortisol awakening response (difference between waking and 30 minutes later) was lower (p = .048) in men who reported improved financial strain, controlling for T1 cortisol response, socioeconomic position, age, smoking, time of waking, and T1 financial strain. There were no differences in the slope of cortisol decline over the day or in evening values. Conclusion: These longitudinal data extend cross-sectional findings in showing associations between favorable changes in chronic stress and reduced cardiovascular and neuroendocrine activation in everyday life. CAR = cortisol awakening response; BMI = body mass index; SEP = socioeconomic position; CHD = coronary heart disease; CI = confidence interval.

Psychological stress activates interleukin-1β gene expression in human mononuclear cells

The pathophysiological mechanisms underlying the association between psychological stress and cardiovascular disease are unclear. Interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) are inflammatory cytokines playing a pivotal role in atherosclerosis. IL-1beta activates IL-6, and both cytokines are produced by peripheral blood mononuclear cells. One mechanism through which stress could promote atherosclerosis is by regulating mononuclear cell cytokine gene expression. We studied cardiovascular and cytokine responses in 32 healthy men participating in two 5-min mental tasks and in 10 controls. Blood pressure and heart rate, assessed using a Portapres-2, increased significantly following tasks in all participants. Plasma IL-6 levels, determined by ELISA, also increased following tasks, with maximum levels detected 2h post-stress. Quantitative RT-PCR analysis showed that mononuclear cell IL-1beta gene expression rose significantly at 30 min post-stress and remained elevated at 75 and 120 min. Increases in IL-1beta gene expression correlated positively with plasma IL-6 responses, cardiovascular responses, subjective stress ratings, and anxiety symptoms. No changes were detected in controls. Stress-induced activation of mononuclear IL-1beta is a novel mechanism potentially linking stress and heart disease. This mechanism could also play a role in other inflammatory diseases exacerbated by stress.

Platelets, coronary heart disease, and stress

Coronary heart disease is the leading cause of death in Western society, and its development is associated with chronic stress and other psychosocial factors. Atherosclerosis, the disorder underlying this disease, is an inflammatory process in which leukocytes interact with structurally intact but dysfunctional endothelium of the arteries. Platelets play a key role in this process by binding to leukocytes and promoting their recruitment to the endothelium. Platelet-leukocyte interactions also stimulate the release of pro-inflammatory and pro-thrombotic factors which promote atherosclerosis. Elevated circulating levels of platelet-leukocyte aggregates have been reported in cardiac patients and in individuals of low socioeconomic status, a factor associated with chronic psychological stress. Increased platelet activation has also been observed in individuals prone to depression or hostility, and in people subject to high levels of work stress. Acute psychological stress increases circulating platelet-leukocyte aggregates in healthy individuals and this effect is prolonged in cardiac patients. Platelet activation may be a mechanism linking psychosocial stress with increased coronary risk, and may also play a role in the emotional triggering of acute coronary syndromes in patients with advanced coronary disease.