I am a Psychoneuroimmunologist aiming at better understanding how inflammation influences behavior and what factors underlie the inter-individual differences in the vulnerability to the behavioral effects of cytokines. My work includes basic science research using clinical and experimental models in humans, which characterize in details the overt and subjective behavioral changes induced by inflammation in humans, investigate the adaptive relevance of sickness behavior, analyze the psychological and biological factors that interact with cytokines to affect the brain and behavior, and the underlying mechanisms. My research highlights the complex motivational changes that occur during inflammation by demonstrating that sickness behavior is not only driven by immune signals, but that top-down processes can shape the behavioral effects of pro-inflammatory cytokines. I also investigate how overt changes in behavior during inflammatory sickness affect the relationship with others and the care one receives, and how this in turn modulates health outcomes.
I am part of the steering committee and webmaster of the newly developed European Psychoneuroimmunology Network (https://pnieurope.se). I have received the PNIRS Ader New Investigator Award 2021. This prestigious award is presented to an outstanding new research scientist who has made exciting basic science or clinical contributions to the field of Psychoneuroimmunology. The award honors Dr. Ader’s innovation and creativity as a scientist and recognizes his contributions to the instantiation of PNI as a meaningful endeavor dedicated to the betterment of health and the prevention of disease.
Stress and sleep: from bench to bedside. PSMT64
A selection from Stockholm University publication database
Anterior insula morphology and vulnerability to psychopathology-related symptoms in response to acute inflammation
2022. Kristoffer N. T. Månsson (et al.). Brain, behavior, and immunity 99, 9-16Article
Introduction: The role of inflammation in common psychiatric diseases is now well acknowledged. However, the factors and mechanisms underlying inter-individual variability in the vulnerability to develop psychopathology related symptoms in response to inflammation are not well characterized. Herein, we aimed at investigating morphological brain regions central for interoception and emotion regulation, and if these are associated with acute inflammation-induced sickness and anxiety responses.
Methods: Systemic inflammation was induced using an intravenous injection of lipopolysaccharide (LPS) at a dose of 0.6 ng/kg body weight in 28 healthy individuals, while 21 individuals received an injection of saline (placebo). Individuals' gray matter volume was investigated by automated voxel-based morphometry technique on T1-weighted anatomical images derived from magnetic resonance imaging (MRI). Plasma concentrations of TNF alpha and IL-6, sickness symptoms (SicknessQ), and state anxiety (STAI-S) were measured before and after the injection.
Results: A stronger sickness response to LPS was significantly associated with a larger anterior insula gray matter volume, independently from increases in cytokine concentrations, age, sex and body mass index (R-2 = 65.6%). Similarly, a greater LPS-induced state anxiety response was related to a larger anterior insula gray matter volume, and also by a stronger increase in plasma TNF-alpha concentrations (R-2 = 40.4%).
Discussion: Anterior insula morphology appears central in the sensitivity to develop symptoms of sickness and anxiety in response to inflammation, and could thus be one risk factor in inflammation-related psychopathologies. Because of the limited sample size, the current results need to be replicated.
Acute Systemic Experimental Inflammation Does Not Reduce Human Odor Identification Performance
2021. Arnaud Tognetti (et al.). Chemical Senses 46Article
Olfactory dysfunction is a common symptom of various diseases, but the underlying pathophysiology has not been fully understood. Evidence from both animal and human studies suggests that local inflammation of the olfactory epithelium is linked to olfactory dysfunction. However, whether systemic inflammation causes olfactory dysfunction is yet to be determined. In the present behavioral study, we set out to test whether acute systemic inflammation impairs olfactory identification performance by inducing a transient and controlled state of systemic inflammation using an experimental endotoxemia model. We treated young healthy participants (N = 20) with a relatively high dose (2.0 ng/kg) of lipopolysaccharide (LPS) and a placebo treatment in a double-blind within-subject design, and assessed participants' ability to identify odors using the MONEX-40, a reliable method for experimental assessment of odor identification ability in healthy and young individuals. Our results show that olfactory identification performance was not affected by the acute systemic inflammation triggered by the injection of LPS. Moreover, odor identification performance following the LPS injection was not associated with levels of circulating proinflammatory cytokines (interleukin-6, interleukin-8, and tumor necrosis factor-alpha). Because experimental LPS-induced systemic inflammation does not affect olfactory identification performance, our findings suggest that chronic, rather than transient, systemic inflammation is a more likely mechanism to explore in order to explain the olfactory deficits observed in inflammatory diseases.
Back to the future of psychoneuroimmunology
2021. Julie Lasselin. Brain, Behavior, & Immunity - Health 18Article
What do we know about sickness behavior? In this article, I guide you through some of the complexity of sickness behavior occurring after an immune challenge. I highlight the many features of behavioral and affective changes induced during experimental endotoxemia in humans, and describe how little we know about many of these features. I argue that we need to dismantle the components of inflammation-induced sickness behavior, and study each component in detail. I also point out the large inter-individual differences in inflammation-induced behavioral and affective changes, and the fact that psychosocial factors likely interact with inflammation to shape inflammation-induced sickness behavior. PNI clearly lacks investigations of the vulnerability and resilient factors underlying the inter-individual variability in sickness behavior. Throughout the article, I base my argument on my published articles, and provide concrete examples from my experience and the data that I have collected over the past 10 years. Given the relevance of inflammation-induced sickness behavior for inflammation-associated depression and for how people react to infections, I encourage current and future psychoneuroimmunologists to return towards basic science of sickness behavior.
Editorial: The Different Faces of Sickness
2021. Lena Rademacher (et al.). Frontiers in Psychiatry 12Article
Sickness not only includes symptoms that classically define an infection (e.g., fever, nausea, headache), but also comes along with profound neurobehavioral consequences for the infected individual. These include anhedonia, anorexia, pain, lethargy, fatigue, sleepiness, and social withdrawal, and are collectively called “sickness behavior”. Sickness behavior in the infected individual is triggered by mediators of the activated immune system that signal to the brain, thus linking the immunological (inflammatory) response with the psychological (behavioral) response to a pathogen. These inflammatory mediators include cytokines (e.g., interleukins, IL; tumor necrosis factor, TNF) that can be assessed in the circulation in addition to clinical markers of inflammation (e.g., C-reactive protein, CRP). Inflammation and sickness behavior are paralleled by neuroendocrine changes including activation of the autonomic nervous system and the hypothalamus-pituitary-adrenal (HPA) axis, which are both critical for the feedback regulation of the immune response.
Human sickness detection is not dependent on cultural experience
2021. Artin Arshamian (et al.). Proceedings of the Royal Society of London. Biological Sciences 288 (1954)Article
Animals across phyla can detect early cues of infection in conspecifics, thereby reducing the risk of contamination. It is unknown, however, if humans can detect cues of sickness in people belonging to communities with whom they have limited or no experience. To test this, we presented Western faces photographed 2 h after the experimental induction of an acute immune response to one Western and five non-Western communities, including small-scale hunter-gatherer and large urban-dwelling communities. All communities could detect sick individuals. There were group differences in performance but Western participants, who observed faces from their own community, were not systematically better than all non-Western participants. At odds with the common belief that sickness detection of an out-group member should be biased to err on the side of caution, the majority of non-Western communities were unbiased. Our results show that subtle cues of a general immune response are recognized across cultures and may aid in detecting infectious threats.
Regulation of emotions during experimental endotoxemia
2021. Lina S. Hansson (et al.). Brain, behavior, and immunity 93, 420-424Article
Even though dysfunctional emotion regulation is prominent in depression and a link between depression and inflammation is well established, there is little knowledge about how inflammation affects the regulation of emotions. The aim of this pilot study was to explore the effect of experimentally induced inflammation on the cognitive reappraisal of emotions, and to assess domain specificity by comparing success in regulation of emotions towards two unpleasant stimuli classes (general negative stimuli and disgust stimuli). In a between-subject design, ten healthy participants were injected with an intravenous injection of lipopolysaccharide (2 ng/kg body weight) and eleven were injected with saline. Participants performed a cognitive reappraisal task, in which they had to down-regulate or up-regulate their emotions towards general negative stimuli and disgust stimuli, 5–6 h post-injection. Contrary to our hypotheses, participants injected with lipopolysaccharide reported greater success in down-regulating emotional responses towards unpleasant stimuli as compared to the saline group. In addition, both groups were poorer at down-regulating emotions towards disgust stimuli as compared to general negative stimuli. The current pilot study indicates that cognitive reappraisal of emotions is affected during experimental endotoxemia, and suggests that disgust stimuli might be difficult to reappraise.
Sick for science
2020. Julie Lasselin (et al.). Molecular PsychiatryArticle
Depression is one of the global leading causes of disability, but treatments remain limited and classical antidepressants were found to be ineffective in a substantial proportion of patients. Thus, novel effective therapies for the treatment of depression are urgently needed. Given the emerging role of inflammation in the etiology and pathophysiology of affective disorders, we herein illustrate how experimental endotoxemia, a translational model of systemic inflammation, could be used as a tool to develop and test new therapeutic options against depression. Our concept is based on the striking overlap of inflammatory, neural, and affective characteristics in patients with inflammation-associated depression and in endotoxin-challenged healthy subjects. Experimental administration of endotoxin in healthy volunteers is safe, well-tolerated, and without known long-term health risks. It offers a highly standardized translational approach to characterize potential targets of therapies against inflammation-associated depression, as well as to identify characteristics of patients that would benefit from these interventions, and, therefore, could contribute to improve personalization of treatment and to increase the overall rate of responders.
Comparison of bacterial lipopolysaccharide-induced sickness behavior in rodents and humans
2020. Julie Lasselin (et al.). Neuroscience and Biobehavioral Reviews 115, 15-24Article
Increasing evidence from animal and human studies suggests that inflammation may be involved in mood disorders. Sickness behavior and emotional changes induced by experimental inflammatory stimuli have been extensively studied in humans and rodents to better understand the mechanisms underlying inflammationdriven mood alterations. However, research in animals and humans have remained compartmentalized and a comprehensive comparison of inflammation-induced sickness and depressive-like behavior between rodents and humans is lacking. Thus, here, we highlight similarities and differences in the effects of bacterial lipopolysaccharide administration on the physiological (fever and cytokines), behavioral and emotional components of the sickness response in rodents and humans, and discuss the translational challenges involved. We also emphasize the differences between observable sickness behavior and subjective sickness reports, and advocate for the need to obtain both subjective reports and objective measurements of sickness behavior in humans. We aim to provide complementary insights for translational clinical and experimental research on inflammation-induced behavioral and emotional changes, and their relevance for mood disorders such as depression.
Biological motion during inflammation in humans
2020. Julie Lasselin (et al.). Brain, behavior, and immunity 84, 147-153Article
Biological motion is a powerful perceptual cue that can reveal important information about the inner state of an individual. Activation of inflammatory processes likely leads to changes in gait, posture, and mobility patterns, but the specific characteristics of inflammation-related biological motion have not been characterized. The aim of this study was to determine the effect of inflammation on gait and motion in humans. Systemic inflammation was induced in 19 healthy volunteers with an intravenous injection of lipopolysaccharide (2 ng/kg body weight). Biological motion parameters (walking speed, stride length and time, arm, leg, head, and shoulder angles) were assessed during a walking paradigm and the timed-up-and-go test. Cytokine concentrations, body temperature, and sickness symptoms were measured. During inflammation, compared to placebo, participants exhibited shorter, slower, and wider strides, less arm extension, less knee flexion, and a more downward-tilting head while walking. They were also slower and took a shorter First step in the timed-up-and-go test. Higher interleukin-6 concentrations, stronger sickness symptoms, and lower body temperature predicted the inflammation-related alterations in biological motion. These findings show that biological motion contains clear information about the inflammatory status of an individual, and may be used by peers or artificial intelligence to recognize that someone is sick or contagious.
Acute inflammation and psychomotor slowing
2020. Analena Handke (et al.). Brain, Behavior, and Immunity - Health 8Article
Data from clinical and cross-sectional studies suggest that inflammation contributes to psychomotor slowing and attentional deficits found in depressive disorder. However, experimental evidence is still lacking. The aim of this study was to clarify the effect of inflammation on psychomotor slowing using an experimental and acute model of inflammation, in which twenty-two healthy volunteers received an intravenous injection of lipopolysaccharide (LPS, dose: 0.8 ng/kg body weight) and of placebo, in a randomized order following a double-blind within-subject crossover design. A reaction time test and a go/no-go test were conducted 3 h after the LPS/placebo injection and interleukin (IL)-6 and tumor necrosis factor (TNF)-α concentrations were assessed. No effect of experimental inflammation on reaction times or errors for either test was found. However, inflammation was related to worse self-rated performance and lower effort put in the tasks. Exploratory analyses indicated that reaction time fluctuated more over time during acute inflammation. These data indicate that acute inflammation has only modest effects on psychomotor speed and attention in healthy subjects objectively, but alters the subjective evaluation of test performance. Increased variability in reaction time might be the first objective sign of altered psychomotor ability and would merit further investigation.
Fatigue and sleepiness responses to experimental inflammation and exploratory analysis of the effect of baseline inflammation in healthy humans
2020. Julie Lasselin (et al.). Brain, behavior, and immunity 83, 309-314Article
Inflammation is believed to be a central mechanism in the pathophysiology of fatigue. While it is likely that dynamic of the fatigue response after an immune challenge relates to the corresponding cytokine release, this lacks evidence. Although both fatigue and sleepiness are strong signals to rest, they constitute distinct symptoms which are not necessarily associated, and sleepiness in relation to inflammation has been rarely investigated. Here, we have assessed the effect of an experimental immune challenge (administration of lipopolysaccharide, LPS) on the development of both fatigue and sleepiness, and the associations between increases in cytokine concentrations, fatigue and sleepiness, in healthy volunteers. In addition, because chronic-low grade inflammation may represent a risk factor for fatigue, we tested whether higher baseline levels of inflammation result in a more pronounced development of cytokine-induced fatigue and sleepiness. Data from four experimental studies was combined, giving a total of 120 subjects (LPS N = 79, 18 (23%) women; Placebo N = 69, 12 (17%) women). Administration of LPS resulted in a stronger increase in fatigue and sleepiness compared to the placebo condition, and the development of both fatigue and sleepiness closely paralleled the cytokine responses. Individuals with stronger increases in cytokine concentrations after LPS administration also suffered more from fatigue and sleepiness (N = 75), independent of gender. However, there was no support for the hypothesis that higher baseline inflammatory markers moderated the responses in fatigue or sleepiness after an inflammatory challenge. The results demonstrate a tight connection between the acute inflammatory response and development of both fatigue and sleepiness, and motivates further investigation of the involvement of inflammation in the pathophysiology of central fatigue.
Immunological and behavioral responses to in vivo lipopolysaccharide administration in young and healthy obese and normal-weight humans
2020. Julie Lasselin (et al.). Brain, behavior, and immunity 88, 283-293Article
Obesity is associated with an increase prevalence of neuropsychiatric symptoms and diseases, such as depression. Based on the facts that pro-inflammatory cytokines are able to modulate behavior, and that obesity is characterized by a chronic low-grade inflammatory state, inflammation has been hypothesized to contribute to the neuropsychiatric comorbidity in obese individuals. However, a causal link between inflammation and the development of neuropsychiatric symptoms is hard to establish in humans. Here, we used an inflammatory stimulus, i.e. the intravenous injection of lipopolysaccharide (LPS), in a double-blind placebo-controlled design, to determine the vulnerability of obese individuals to inflammation-induced behavioral changes. The hypothesis was that obese individuals would show heightened behavioral response compared to normal-weight subjects for the same inflammatory stimulus, reflecting an increased sensitivity to the behavioral effects of pro-inflammatory cytokines. LPS (dose 0.8 ng/kg body weight, adjusted for estimated blood volume in obese subjects) and placebo (saline) were intravenously injected in 14 obese healthy subjects and 23 normal-weight healthy subjects in a within-subject, randomized, crossover design. LPS administration induced, in both groups, an acute increase in blood concentrations of cytokines (interleukin-6, tumor necrosis factor-alpha, and IL-10), as well as in body temperature, cortisol, norepinephrine, sickness symptoms, fatigue, negative mood, and state anxiety. There were little differences in the immune and behavioral responses to LPS between obese and normal-weight subjects, but the cortisol response to LPS was strongly attenuated in obese individuals. Higher percentage of body fat was related to a lower cortisol response to LPS. Taken together, the population of young and healthy obese individuals in this study did not exhibit an increased behavioral sensitivity to cytokines, but an attenuated cortisol response to the immune challenge. Future studies will need to determine whether additional physiological and psychological factors interact with the state of obesity to increase the risk for inflammation-induced neuropsychiatric symptoms.
Is inflammation-associated depression atypical depression?
2020. Julie Lasselin. Brain, behavior, and immunity 87, 193-194Article
Major depressive disorder (MDD) remains today a challenge to treat and to prevent, mostly because of the highly heterogeneous features and multifactorial processes underlying the disease. During the last two decades, some hope have emerged from clinical and experimental evidence revealing the role of inflammation in the pathophysiology of depression (Miller and Raison, 2016). This research provides support for the use of anti-inflammatory treatments in depressed patients. However, it is estimated that only about 30% of depressed patients exhibit signs of inflammation and would benefit from anti-inflammatory treatments (Chamberlain et al., 2018). Therefore, it has become clear that the solution to better treatments against major depression is to develop therapies tailored to match subpopulations of patients. To this aim, it is crucial to define and characterize these subpopulations, such as proposed by Cosgrove et al. (2020) in their recent article published in Brain, Behavior, and Immunity.
Olfactory Communication of Sickness Cues in Respiratory Infection
2020. Georgia Sarolidou (et al.). Frontiers in Psychology 11Article
Animals detect sick conspecifics by way of body odor that enables the receiver to avoid potential infectious transmission. Human observational studies also indicate that different types of disease are associated with more or less aversive smells. In addition, body odors from otherwise healthy human individuals smell more aversive as a function of experimentally induced systemic inflammation. To investigate if naturally occurring immune activation also gives rise to perceivable olfactory changes, we collected body odor samples during two nights from individuals with a respiratory infection as well as when they were healthy. We hypothesized that independent raters would rate the body odor originating from sick individuals as smelling more aversive than when the same individuals were healthy. Even though body odor samples from sick individuals nominally smelled more intense, more disgusting, and less pleasant and healthy than the body odor from the same individuals when healthy, these effects were not statistically significant. Moreover, raters filled out three questionnaires, Perceived Vulnerability to Disease, Disgust Scale, and Health Anxiety, to assess potential associations between sickness-related personality traits and body odor perception. No such association was found. Since experimentally induced inflammation have made body odors more aversive in previous studies, we discuss whether this difference between studies is due to the level of sickness or to the type of trigger of the sickness response.
Prolonged elevation of plasma HMGB1 is associated with cognitive impairment in intensive care unit survivors
2020. Emily Brück (et al.). Intensive Care Medicine 46, 811-812Article