Back morphology and walking patterns mean 13.8 years after surgery for lumbar disk herniation in adolescents.

Introduction: In many pain conditions, there is lingering pain despite healed tissue damage. Our previous study shows that individuals who underwent surgery for lumbar disk herniation (LDH) during adolescence have worse health, more pain, and increased disk degeneration mean 13 years after surgery compared with controls. It is unclear if walking patterns segregate surgically treated LDH adolescents and controls at mean 13-year follow-up. Objectives: Here, we analyzed the relationship between gait, back morphology and other health outcomes in a cohort of individuals treated surgically because of lumbar disk herniation compared with controls. Methods: We analyzed gait during a walking paradigm, back morphology at the site of surgery, and standardized health outcomes, among individuals who received surgery for LDH as adolescents, "cases" (n = 23), compared with "controls" (n = 23). Results: There were gait differences in head (P = 0.021) and trunk angle (P = 0.021) between cases and controls in a direction where cases exhibited a posture associated with sickness. The gait variance was explained by subjective pain and exercise habits rather than objective disk degeneration. Conclusion: Over a decade after surgery for LDH during adolescence, health among cases is worse compared with controls. The head and trunk angles differ between cases and controls, indicating that the residual pain lingers and may cause changes in movement patterns long after a painful episode in early life. Gait may be a useful target for understanding maintenance of pain and disability among individuals treated surgically for LDH during adolescence.

Assessing sickness behavior in the French: Validation of the French translation of the sickness questionnaire (SicknessQ) in a non-clinical French population.

The Sickness Questionnaire (SicknessQ) is a questionnaire developed to assess symptoms of sickness behavior, including somatic, behavioral, and affective dimensions. To promote cross-cultural assessments of sickness behavior, we aim to expand the use of this questionnaire to other populations and languages. The aim of the present study was to evaluate the French translation of SicknessQ in a French-speaking general population during the COVID-19 pandemic. One hundred and thirty-nine individuals completed the SicknessQ online, along with the construct criteria measures of self-rated health, state anxiety (STAI-S), and depressive symptoms (PHQ-9). The principal component analyses revealed two components: the first component included seven items concerning mood, motivation and experiences of fatigue and pain; the second component included three items concerning somatic sickness symptoms. Higher scores on the total scale and the two component subscales were associated with poorer self-rated health and higher STAI-S and PHQ-9 scores. Since the associations with construct criteria variables were relatively similar between the single- and the two-dimensional solutions, both the total scale and the subscales of the two components of the French SicknessQ can be used in future studies to measure sickness behavior in French-speaking populations.

Olfactory Cues of Naturally Occurring Systemic Inflammation: A Pilot Study of Seasonal Allergy.

INTRODUCTION: In an attempt to avoid contact with infectious individuals, humans likely respond to generalized rather than specific markers of disease. Humans may thus perceive a noninfectious individual as socially less attractive if they look (e.g., have facial discolouration), move (e.g., have a slower walking pace), or sound (e.g., sneeze) sick. This pilot study tested whether humans are averse to the body odour of noninfectious individuals with a low-grade systemic inflammation. METHODS: We collected the axillary body odour of individuals with severe seasonal allergy (N = 14) and healthy controls (N = 10) during and outside the allergy season and measured serum levels of two inflammatory cytokines (tumour necrosis factor-α and interleukin-5). Independent participants (N = 67) then sampled and rated these odours on intensity and pleasantness. RESULTS: While individuals with seasonal allergy had nominally more unpleasant and intense body odours during the allergy season, relative to outside the allergy season and to healthy controls, these effects were not significant. When examining immune markers, the change in perceived pleasantness of an individual's body odour (from out-to-inside pollen season) was significantly related to the change in their interleukin-5 levels but not to tumour necrosis factor-α. DISCUSSION: Our findings tentatively suggest that the human olfactory system could be sensitive to inflammation as present in a noncommunicable condition. Larger replications are required to determine the role of olfaction in the perception of infectious and noninfectious (e.g., chronic diseases) conditions.

Beyond the symptom: the biology of fatigue.

A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.

Lipopolysaccharide-induced changes in the kynurenine pathway and symptoms of sickness behavior in humans.

Metabolites of the kynurenine pathway are hypothesized to be implicated in inflammation-associated depression, but there is a lack of experimental studies in humans assessing the kinetics of kynurenine metabolites in relation to experimentally-induced sickness. The aim of the present study was to assess changes in the kynurenine pathway and to explore its relation to symptoms of sickness behavior during an acute experimental immune challenge. This double-blind placebo-controlled randomized cross-over study included 22 healthy human participants (n = 21 both sessions, Mage = 23.4, SD = 3.6, nine women) who received an intravenous injection of 2.0 ng/kg lipopolysaccharide (LPS) and saline (placebo) on two different occasions in a randomized order. Blood samples (0 h, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 7 h post-injection) were analyzed for kynurenine metabolites and inflammatory cytokines. The intensity of symptoms of sickness behavior was assessed using the 10-item Sickness Questionnaire at 0 h, 1.5 h, 3 h, 5 h, and 7 h post-injection. LPS induced significantly lower concentrations of plasma tryptophan (at 2 h, 4 h, 5 h, and 7 h post-injection), kynurenine (at 2 h, 3 h, 4 h, and 5 h post-injection), nicotinamide (at 4 h, 5 h, and 7 h post-injection), and higher levels for quinolinic acid at 5 h post-injection as compared to placebo. LPS did not affect kynurenic acid, 3-hydroxykynurenine, and picolinic acid. The development of the sickness symptoms was largely similar across items, with the highest levels around 1.5-3 h post-injection. Changes in plasma levels of kynurenine metabolites seem to coincide rather than precede or follow changes in subjective sickness. Exploratory analyses indicate that higher Sickness Questionnaire total scores at 1.5-5 h post-injection were correlated with lower kynurenic acid and nicotinamide levels. These results lend further support for LPS-induced changes in the kynurenine pathway, but may not, as interpreted from blood levels, causally link to LPS-induced acute symptoms of sickness behavior. Future research may consider a larger sample to further scrutinize the role of the kynurenine pathway in the sickness response.

Family still matters: Human social motivation across 42 countries during a global pandemic.

The COVID-19 pandemic caused drastic social changes for many people, including separation from friends and coworkers, enforced close contact with family, and reductions in mobility. Here we assess the extent to which people's evolutionarily-relevant basic motivations and goals-fundamental social motives such as Affiliation and Kin Care-might have been affected. To address this question, we gathered data on fundamental social motives in 42 countries (N = 15,915) across two waves, including 19 countries (N = 10,907) for which data were gathered both before and during the pandemic (pre-pandemic wave: 32 countries, N = 8998; 3302 male, 5585 female; M age  = 24.43, SD = 7.91; mid-pandemic wave: 29 countries, N = 6917; 2249 male, 4218 female; M age  = 28.59, SD = 11.31). Samples include data collected online (e.g., Prolific, MTurk), at universities, and via community sampling. We found that Disease Avoidance motivation was substantially higher during the pandemic, and that most of the other fundamental social motives showed small, yet significant, differences across waves. Most sensibly, concern with caring for one's children was higher during the pandemic, and concerns with Mate Seeking and Status were lower. Earlier findings showing the prioritization of family motives over mating motives (and even over Disease Avoidance motives) were replicated during the pandemic. Finally, well-being remained positively associated with family-related motives and negatively associated with mating motives during the pandemic, as in the pre-pandemic samples. Our results provide further evidence for the robust primacy of family-related motivations even during this unique disruption of social life.

Fundamental social motives measured across forty-two cultures in two waves.

How does psychology vary across human societies? The fundamental social motives framework adopts an evolutionary approach to capture the broad range of human social goals within a taxonomy of ancestrally recurring threats and opportunities. These motives-self-protection, disease avoidance, affiliation, status, mate acquisition, mate retention, and kin care-are high in fitness relevance and everyday salience, yet understudied cross-culturally. Here, we gathered data on these motives in 42 countries (N = 15,915) in two cross-sectional waves, including 19 countries (N = 10,907) for which data were gathered in both waves. Wave 1 was collected from mid-2016 through late 2019 (32 countries, N = 8,998; 3,302 male, 5,585 female; Mage = 24.43, SD = 7.91). Wave 2 was collected from April through November 2020, during the COVID-19 pandemic (29 countries, N = 6,917; 2,249 male, 4,218 female; Mage = 28.59, SD = 11.31). These data can be used to assess differences and similarities in people's fundamental social motives both across and within cultures, at different time points, and in relation to other commonly studied cultural indicators and outcomes.

Anterior insula morphology and vulnerability to psychopathology-related symptoms in response to acute inflammation.

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-α 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 (R2 = 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-α concentrations (R2 = 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.

Back to the future of psychoneuroimmunology: Studying inflammation-induced sickness behavior.

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.

Human sickness detection is not dependent on cultural experience.

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.

Acute Systemic Experimental Inflammation Does Not Reduce Human Odor Identification Performance.

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-α). 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.

Regulation of emotions during experimental endotoxemia: A pilot study.

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: experimental endotoxemia as a translational tool to develop and test new therapies for inflammation-associated depression.

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.

Immunological and behavioral responses to in vivo lipopolysaccharide administration in young and healthy obese and normal-weight humans.

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-α, 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.

Olfactory Communication of Sickness Cues in Respiratory Infection.

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.

Comparison of bacterial lipopolysaccharide-induced sickness behavior in rodents and humans: Relevance for symptoms of anxiety and depression.

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 inflammation-driven 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.