Associations between sickness behavior, but not inflammatory cytokines, and psychiatric comorbidity in chronic pain.

OBJECTIVES: Approximately one in five adults experiences chronic pain, often in co-occurrence with depression, insomnia, anxiety, and lower self-rated health. Elevated levels of cytokines, e.g. tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), interleukin 8 (IL-8), and interleukin 10 (IL-10), have been identified in patients with chronic pain. Depression, insufficient sleep, poor self-rated health, and pain intensity have also been associated with inflammatory biomarkers. This study aimed to investigate the interrelationships between inflammatory biomarkers and depression, insomnia, anxiety, self-rated health, sickness behavior, and pain intensity in patients with chronic pain. METHODS: Self-report questionnaires and blood samples analyzed for plasma levels of inflammatory biomarkers were collected from 80 adult patients with chronic pain. Associations between inflammatory biomarkers (TNF-α, IL-6, IL-8, IL-10, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) and depression, insomnia, anxiety, self-rated health, sickness behavior, and pain intensity, were analyzed using bivariate Spearman rank correlation coefficients and regression analyses. RESULTS: Participants were mainly women (72.5 %), with a mean age of 50.8 years, and a reported mean pain duration of 16.7 years. There were significant correlations between insomnia and CRP (rs =.26, p <.05); sex and ESR (rs =.29, p <.05); age and IL-6 (rs =.29, p <.05) and IL-8 (rs =.30, p <.05); BMI and IL-6 (rs =.50, p <.001), CRP (rs =.63, p <.001) and ESR (rs =.42, p <.001). Ratings of depression were positively and significantly related to ratings of sickness behavior and anxiety (ß =.32 and ß =.40, respectively), explaining 49 % of the total variance in depression ratings. Insomnia was positively and significantly related to sickness behavior (ß =.37) explaining 31 % of the total variance in insomnia ratings. Inflammatory biomarkers, however, did not contribute significantly to the models. CONCLUSIONS: Participants reported high levels of symptoms, yet the associations between these ratings and the inflammatory biomarkers were either absent or weak. Also, despite high levels of self-reported sickness behavior, overall the inflammatory status remained within the normal range. Ratings of sickness behavior contributed more than inflammatory markers in explaining ratings of depression and insomnia. The present results point to the complexity of chronic pain, and the challenges of identifying biomarkers that explain symptomatology.

Illness acceptance and its relationship to health-behaviors among patients with type 2 diabetes: A mediating role of self-hardiness.

OBJECTIVES: The current study aims to assess the level of acceptance of their illness in patients diagnosed with type 2 diabetes mellitus, determine whether the self-hardiness of patients with type 2 diabetes mellitus can serve as a predictive factor for their illness acceptance and health-behaviors, and Explore variations in illness acceptance, health-behaviors, and self-hardiness in relation to socio-demographic factors among patients with type 2 diabetes mellitus. METHODOLOGY: A descriptive correlational study was carried out at Al-Rifia Teaching Hospital, and and Imam Al-Qiam Health Center. the study was started from 15th October, 2023 to 3th March, 2024. Purposive sample (non-probability) of 200 patients with type 2 diabetes (male and female). by the used of questionnaire and interviews techniques, data are collected from those who diagnosed with diabetes mellitus. the study instrument consisted of four parts: part one the sociodemographic sheet, part two concerned illness acceptance which composed of 22 items, part three health behaviors which composed of 22 items, and part four concerned self-hardiness which composed of 25 items. RESULTS: The study results revealed that the who participated in this study their age 55-64 years old and constituted 64 (32.0%), more than half of participants were male patients with type 2 diabetes mellitus 109 (54.5%), where revealed (79.5%) exhibited that the neutral acceptance level as described by mean score (±SD) = 2.075, health-behaviors among patients with type 2 diabetes, findings illustrated that the (51.0%) of patients with type 2 diabetes mellitus exhibited that they follow good health-behaviors level, and good Self-Hardiness among Patients with Type 2 diabetes, in addition, there is a high significant relationship between illness acceptance, health behaviors and patients self-hardness at p-value (< 0.005). RECOMMENDATIONS: should support people with educational initiatives and assist them in accepting their sickness and taking an active role in managing it, Psychological support to resolve disease-related problems, cope with difficulties and develop positive attitudes towards the disease.

Hide-and-sick: How bacteria manipulate a neural circuit that makes you sick.

Infections frequently cause behavioral changes, known as sickness behavior. In a recent study,1 Yipp and collaborators discovered a sensory circuit that is activated by a bacterial lipopolysaccharide during lung infection and drives sickness behaviors independent of inflammation. Biofilm-producing bacteria, however, avoid activating this lung-brain circuit, resulting in infection without sickness behavior.

Perception of unfamiliar caregivers during sickness - Using the new Caregiver Perception Task (CgPT) during experimental endotoxemia.

Social withdrawal is a well-established part of sickness behavior, but in some contexts sick animals might gain from keeping close instead of keeping away. For instance, sick individuals are more willing to be near known individuals who can provide care and safety (close others) compared to when healthy. Yet, interactions with some strangers might also be beneficial (i.e., healthcare professionals), but it is not known how sickness interplay with social behavior towards such individuals. Here, we assessed if sickness affects perception of caregivers, and developed a new task, the Caregiver Perception Task (CgPT). Twenty-six participants performed the CgPT, once after an injection of lipopolysaccharide (LPS, 0.8 ng/kg body weight, n = 24), and once after an injection of saline (n = 25), one hour and forty-five minutes post-injection. During the task, participants watched short video clips of three types of caregivers: a healthcare professional taking care of a sick individual, a healthcare professional not taking care of a sick individual, and a non-healthcare professional taking care of their sick adult child or partner. After each video clip, the likability, trustworthiness, professionalism, and willingness to interact with and receive care from the caregiver were rated on visual analogue scales. Results showed that participants injected with saline rated healthcare professionals who did not take care of a sick individual less positively on all aspects compared to healthcare professionals who took care of a sick individual. Moreover, compared to saline, LPS increased the participants' willingness to receive care from healthcare professionals and non-healthcare professionals providing care, but not from healthcare professionals not providing care. Thus, our results indicate that sick individuals may approach unknown individuals with potential to provide care and support.

Acute experimental inflammation in healthy women attenuates empathy for psychological pain.

Administration of low-dose lipopolysaccharide (LPS) to healthy humans is a translational approach to analyze the effects of acute systemic inflammation and sickness behavior. Although studies documented that LPS-induced inflammation can alter social behavior, its impact on empathy remains poorly understood. In this double-blind, placebo-controlled study, 52 healthy female volunteers received an intravenous injection of either LPS (0.4 ng/kg body weight) or placebo and completed the Social Interaction Empathy Task (SIET) two hours after injection. Physiological responses (blood pressure, heart rate, body temperature, cytokines, cortisol) were analyzed along with sickness symptoms and mood before and after LPS or placebo administration. LPS application led to significant increases in plasma cytokines and sickness symptoms as well as low mood. Moreover, volunteers receiving LPS showed significantly less empathy for other's psychological pain than those who received placebo. Furthermore, LPS-injected volunteers with more severe sickness symptoms displayed higher pain ratings in the first-person perspective. Thus, low-grade inflammation reduces empathy for other's psychological pain which might reflect an adaptive strategy to save energy by not responding empathetically when sick oneself.

Neuromodulator hydrogen sulfide attenuates sickness behavior induced by lipopolysaccharide.

Sickness behavior reflects a state of altered physiology and central nervous system function that occurs during systemic infection or inflammation, serving as an adaptive response to illness. This study aims to elucidate the role of hydrogen sulfide (H2S) in regulating sickness behavior and neuroinflammatory responses in a rat model of systemic inflammation. Adult male Wistar rats were treated with lipopolysaccharide (LPS) to induce sickness behavior. Intracerebroventricular (i.c.v.) pretreatments included aminooxyacetic acid (AOAA), an inhibitor of H2S synthesis, and sodium sulfide (NaHS), an H2S donor. Behavioral assays were conducted, along with the assessment of astrocyte activation, as indicated by GFAP expression in the hypothalamus. Pretreatment with NaHS mitigated LPS-induced behavioral changes, including hypophagia, social and exploratory deficits, without affecting peripheral cytokine levels, indicating a central modulatory effect. AOAA, conversely, accentuated certain behavioral responses, suggesting a complex role of endogenous H2S in sickness behavior. These findings were reinforced by a lack of effect on plasma interleukin levels but significant reduction in GFAP expression. Our findings support the central role of H2S in modulating neuroinflammation and sickness behavior, highlighting the therapeutic potential of targeting H2S signaling in neuroinflammatory conditions.

Involvement of NLRP3 inflammasome pathway in the protective mechanisms of ferulic acid and p-coumaric acid in LPS-induced sickness behavior and neuroinflammation in mice.

Ferulic acid (FA) and p-coumaric acid (PCA) are abundantly present in commonly consumed food and beverages. Being polyphenolic compounds, they have been explored for their antioxidant and anti-inflammatory properties. Based on our previous study, we selected these two compounds to further investigate their potential in lipopolysaccharide (LPS)-induced sickness behavior and the ensuing neuroinflammation by specifically focusing on the NLRP3 inflammasome pathway. Male Swiss albino mice were divided into nine groups (n = 6) consisting of Normal Control, LPS, fluoxetine (FLX), FA40, FA160, FA640, PCA40, PCA160, and PCA640 respectively. Each group received respective FA or PCA treatment except Normal Control and LPS, which received the vehicle, carboxymethylcellulose 0.25% w/v. All groups were challenged with LPS 1.5 mg/kg, intraperitoneally except the Normal Control group, which received saline. Behavioral assessments were performed between 1-2 h, and the whole brains were collected at 3 h post-LPS administration. LPS-induced sickness behavior was characterized by significantly reduced spontaneous activity and high immobility time. The expression of NLRP3, ASC, caspase-1 and IL-1ß was significantly increased, along with the levels of brain IL-1ß suggesting the assembly and activation of NLRP3 inflammasome pathway. Furthermore, the major cytokines involved in sickness behavior, IL-6 and TNF-α were also significantly elevated with the accompanied lipid peroxidation. The results of this study emphasize that within the employed dose ranges of both FA and PCA, both the compounds were effective at blocking the activation of the NLRP3 inflammasome pathway and thereby reducing the release of IL-1ß and the sickness behavior symptoms. There was a prominent effect on cytokine levels and lipid peroxidation as well.

Illness identity and well-being in congenital heart disease: Directionality of effects and developmental trajectories.

OBJECTIVE: This longitudinal study explores the relationship between illness identity and well-being in emerging adults with congenital heart disease (CHD), aiming to understand the factors contributing to well-being in individuals with CHD. METHOD: Dutch-speaking emerging adults with CHD (N = 254, age range = 24-28 years) participated in a three-wave study, which is part of the I-DETACH 2 project. Cross-lagged analyses examined the directionality of effects between illness identity and well-being. Multivariate latent class growth analysis identified developmental trajectory classes of illness identity. Multigroup latent growth curve modeling investigated differences in the development of well-being among these classes. RESULTS: Bidirectional associations were uncovered between illness identity and well-being. For instance, acceptance predicted better quality of life and less depressive symptoms over time. Three trajectory classes of illness identity were identified: high (i.e., as compared to the sample mean) acceptance and enrichment with low rejection and engulfment (Class 1), high rejection with low levels in the other dimensions (Class 2), and high rejection and engulfment along with high enrichment and low acceptance (Class 3). Individuals in Class 3 experienced the worse well-being. In addition, individuals with complex heart defects were strongly represented in this class. CONCLUSIONS: This study demonstrates the significance of illness identity in understanding individual differences in well-being among emerging adults with CHD. Additionally, this study provided valuable insight in the development of illness identity and its longitudinal relationship with well-being. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

TNFR1 signaling converging on FGF14 controls neuronal hyperactivity and sickness behavior in experimental cerebral malaria.

BACKGROUND: Excess tumor necrosis factor (TNF) is implicated in the pathogenesis of hyperinflammatory experimental cerebral malaria (eCM), including gliosis, increased levels of fibrin(ogen) in the brain, behavioral changes, and mortality. However, the role of TNF in eCM within the brain parenchyma, particularly directly on neurons, remains underdefined. Here, we investigate electrophysiological consequences of eCM on neuronal excitability and cell signaling mechanisms that contribute to observed phenotypes. METHODS: The split-luciferase complementation assay (LCA) was used to investigate cell signaling mechanisms downstream of tumor necrosis factor receptor 1 (TNFR1) that could contribute to changes in neuronal excitability in eCM. Whole-cell patch-clamp electrophysiology was performed in brain slices from eCM mice to elucidate consequences of infection on CA1 pyramidal neuron excitability and cell signaling mechanisms that contribute to observed phenotypes. Involvement of identified signaling molecules in mediating behavioral changes and sickness behavior observed in eCM were investigated in vivo using genetic silencing. RESULTS: Exploring signaling mechanisms that underlie TNF-induced effects on neuronal excitability, we found that the complex assembly of fibroblast growth factor 14 (FGF14) and the voltage-gated Na+ (Nav) channel 1.6 (Nav1.6) is increased upon tumor necrosis factor receptor 1 (TNFR1) stimulation via Janus Kinase 2 (JAK2). On account of the dependency of hyperinflammatory experimental cerebral malaria (eCM) on TNF, we performed patch-clamp studies in slices from eCM mice and showed that Plasmodium chabaudi infection augments Nav1.6 channel conductance of CA1 pyramidal neurons through the TNFR1-JAK2-FGF14-Nav1.6 signaling network, which leads to hyperexcitability. Hyperexcitability of CA1 pyramidal neurons caused by infection was mitigated via an anti-TNF antibody and genetic silencing of FGF14 in CA1. Furthermore, knockdown of FGF14 in CA1 reduced sickness behavior caused by infection. CONCLUSIONS: FGF14 may represent a therapeutic target for mitigating consequences of TNF-mediated neuroinflammation.

Bat behavioral immune responses in social contexts: current knowledge and future directions.

Animals often mount complex immune responses to infections. Aside from cellular and molecular defense mechanisms, animals can alter their behavior in response to infection by avoiding, resisting, or tolerating negative effects of pathogens. These behaviors are often connected to cellular and molecular immune responses. For instance, sickness behaviors are a set of behavioral changes triggered by the host inflammatory response (e.g., cytokines) and could aid in resisting or tolerating infection, as well as affect transmission dynamics if sick animals socially withdraw or are being avoided by others. To fully understand the group and population level transmission dynamics and consequences of pathogen infections in bats, it is not only important to consider cellular and molecular defense mechanisms, but also behavioral mechanisms, and how both interact. Although there has been increasing interest in bat immune responses due to their ability to successfully cope with viral infections, few studies have explored behavioral anti-pathogen defense mechanisms. My main objective is to explore the interaction of cellular and molecular defense mechanisms, and behavioral alterations that results from infection in bats, and to outline current knowledge and future research avenues in this field.

Revisiting geophagy: An evolved sickness behavior to microbiome-mediated gastrointestinal inflammation.

Geophagy, the consumption of clay or similar substances, is known as an evolved behavior that protects vulnerable populations, such as pregnant women and children, against gastrointestinal injury. However, perplexing questions remain, like the presence of geophagy in the absence of overt gastrointestinal infection and the potential causal relationship between geophagy and iron deficiency anemia. In this review, we hypothesize that geophagy is an inflammation-mediated sickness behavior regulated via the vagus nerve. We further hypothesize that the gut microbiome plays a critical role in mediating the relationship between inflammation and geophagy. By including inflammation and the microbiome within the existing protection hypothesis, we can explain how subclinical gastrointestinal states induce geophagy. Furthermore, we can explain how gastrointestinal inflammation is responsible for both geophagy and iron-deficiency anemia, explaining why the two phenomena frequently co-occur. Ultimately, defining geophagy as a sickness behavior allows us to integrate the gut-brain axis into geophagy research.

From mechanism to ecosystem: building bridges between ecoimmunology, psychoneuroimmunology and disease ecology.

Historically, the fields of ecoimmunology, psychoneuroimmunology and disease ecology have taken complementary yet disparate theoretical and experimental approaches, despite sharing critical common themes. Researchers in these areas have largely worked independently of one another to understand mechanistic immunological responses, organismal level immune performance, behavioral changes, and host and parasite/disease population dynamics, with few bridges across disciplines. Although efforts to strengthen and expand these bridges have been called for (and occasionally heeded) over the last decade, more integrative studies are only now beginning to emerge, with critical gaps remaining. Here, we briefly discuss the origins of these key fields, and their current state of integration, while highlighting several critical directions that we suggest will strengthen their connections into the future. Specifically, we highlight three key research areas that provide collaborative opportunities for integrative investigation across multiple levels of biological organization, from mechanisms to ecosystems: (1) parental effects of immunity, (2) microbiome and immune function and (3) sickness behaviors. By building new bridges among these fields, and strengthening existing ones, a truly integrative approach to understanding the role of host immunity on individual and community fitness is within our grasp.

Phoenix dactylifera (Ajwa Dates) Alleviate LPS-Induced Sickness Behaviour in Rats by Attenuating Proinflammatory Cytokines and Oxidative Stress in the Brain.

Traditional medicine claims that various components of the Phoenix dactylifera (date plant) can be used to treat memory loss, fever, inflammation, loss of consciousness, and nerve disorders. The present study aims to evaluate the effectiveness of Phoenix dactylifera fruit extracts (PDF) against rat sickness behaviour caused by lipopolysaccharide (LPS) by assessing behavioural and biochemical parameters. PDF was prepared by extracting dry fruits of P. dactylifera with a methanol:water (4:1, v/v) mixture. The PDF was evaluated for phenolic and flavonoid content and HPLC analysis of quercetin estimation. Adult Wistar rats were treated with LPS, PDF + LPS and dexamethasone + LPS. Water and food intake, behavioural tests such as locomotor activity, tail suspension and forced swim tests were conducted. Furthermore, alanine transaminase (ALT) and aspartate transaminase (AST) were estimated in plasma and malondialdehyde (MDA), reduced glutathione (GSH), nitrite, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were estimated in the brain. PDF ameliorated LPS-induced sickness behaviour by reducing MDA, nitrite, IL-6, and TNF-α levels and improving GSH, behavioural alteration, water and food intake in the treated rats. In the plasma of the treated rats, PDF also decreased the levels of ALT and AST. The outcomes demonstrated the efficacy of PDF in reducing the sickness behaviour caused by LPS in rats. The authors believe that this study will provide the groundwork for future research to better understand the underlying mechanisms of action and therapeutic efficacy.

A brain cytokine-independent switch in cortical activity marks the onset of sickness behavior triggered by acute peripheral inflammation.

Systemic inflammation triggers protective as well as pro-inflammatory responses in the brain based on neuronal and/or cytokine signaling, and it associates with acutely and protractedly disrupted cognition. However, the multiple mechanisms underlying the peripheral-central inflammatory signaling are still not fully characterized. We used intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) in freely moving mice with chronically implanted electrodes for recording of local field potentials (LFP) and electrocorticography (ECoG) in the hippocampus and neocortex, respectively. We show here that a sudden switch in the mode of network activity occurred in both areas starting at 10-15 min after the LPS injection, simultaneously with a robust change from exploration to sickness behavior. This switch in cortical mode commenced before any elevations in pro-inflammatory cytokines IL-1ß, TNFα, CCL2 or IL-6 were detected in brain tissue. Thereafter, this mode dominated cortical activity for the recording period of 3 h, except for a partial and transient recovery around 40 min post-LPS. These effects were closely paralleled by changes in ECoG spectral entropy. Continuous recordings for up to 72 h showed a protracted attenuation in hippocampal activity, while neocortical activity recovered after 48 h. The acute sickness behavior recovered by 72 h post-LPS. Notably, urethane (1.3 mg/kg) administered prior to LPS blocked the early effect of LPS on cortical activity. However, experiments under urethane anesthesia which were started 24 h post-LPS (with neuroinflammation fully developed before application of urethane) showed that both theta-supratheta and fast gamma CA1 activity were reduced, DG delta activity was increased, and sharp-wave ripples were abolished. Finally, we observed that experimental compensation of inflammation-induced hypothermia 24-48 h post-LPS promoted seizures and status epilepticus; and that LPS decreased the threshold of kainate-provoked seizures beyond the duration of acute sickness behavior indicating post-acute inflammatory hyperexcitability. Taken together, the strikingly fast development and initial independence of brain cytokines of the LPS-induced cortical mode, its spectral characteristics and simultaneity in hippocampus and neocortex, as well as inhibition by pre-applied urethane, strongly suggest that the underlying mechanisms are based on activation of the afferent vagus nerve and its mainly cholinergic ascending projections to higher brain areas.

Lipopolysaccharide-induced sickness behavior is not altered in male Fmr1-deficient mice.

OBJECTIVES: Fragile X syndrome is the main monogenetic cause of intellectual disability and autism. Alterations in the immune system are commonly found in these developmental disorders. We and others have demonstrated that Fmr1 mutant mice present an altered response to immune stimuli. However, whether this altered immune response can influence the Fmr1 mutant behavioral outcomes in response to inflammation has not been fully investigated. MATERIALS AND METHODS: In the current study, we examine the behavioral sickness response of male wildtype and knockout  mice to the innate immune stimulus lipopolysaccharide (LPS) (0.1 mg/kg) to determine if Fmr1 mutants have altered sickness behavior. We used an enzyme-linked immunosorbent assay (ELISA) to measure changes in the cytokine interleukin-6 (IL-6) to determine that inflammation was induced in the mice. Sickness behavior was assessed in a wheel-running paradigm, and a tail suspension test was used to assess the depressive-like phenotype that follows sickness behavior in response to LPS. RESULTS: The ELISA using blood serum confirmed a significant increase in IL-6 in mice that were treated with LPS. Treated Fmr1 mutants exhibited decreased distance traveled in the wheel running after LPS administration, similar to treated controls. Another cohort of animals treated with LPS were tested in the tail suspension test and exhibited no alterations in immobility time in response to LPS. CONCLUSION: Together, our data suggest that Fmr1 mutant mice do not have altered sickness behavior in response to a low dose of LPS.

Evaluation of a Behavioral Test for Sickness Behavior Associated with Fusarium Mycotoxin Ingestion in Female Beagle Dogs (Canis familiaris).

Animals exhibit behavioral changes during illness, including lethargy, anorexia, fever, adipsia, and anhedonia, which are believed to comprise an adaptive evolutionary strategy. Exploratory and social behaviors generally decrease during illness, but behavioral changes of dogs during illness have not been described. The objective of this study was to evaluate a novel canine behavior test during subclinical illness induced by dietary Fusarium mycotoxin. Twelve mature female beagle dogs received 3 treatment diets: a control diet (control), a diet formulated with grains contaminated with Fusarium mycotoxin (toxin), and the toxin diet together with a toxin binding agent (binder). All dogs received each diets for 14 d in a Latin square design with a 7-d washout period between diet trials. The test consisted of individually releasing dogs into the center aisle of the housing room for 4 min per day, during which interactions with familiar dogs in adjacent kennels were recorded by an observer outside the room who was blind to treatment groups. Total interactions, orientation, and attempted physical contact with other dogs were less frequent during the toxin and binder diet treatments. Conversely, frequencies of physical proximity and olfactory contact with familiar dogs in adjacent kennels were not associated with diet. In conclusion, induction of subclinical gastrointestinal illness influenced aspects of social interactions in beagle dogs. A clinical assessment sheet integrating these findings was developed to aid in early identification of subclinical illness in research dogs based on behavior.

Brain-Based Predictions of Psychiatric Illness-Linked Behaviors Across the Sexes.

BACKGROUND: Individual differences in functional brain connectivity can be used to predict both the presence of psychiatric illness and variability in associated behaviors. However, despite evidence for sex differences in functional network connectivity and in the prevalence, presentation, and trajectory of psychiatric illnesses, the extent to which disorder-relevant aspects of network connectivity are shared or unique across the sexes remains to be determined. METHODS: In this work, we used predictive modeling approaches to evaluate whether shared or unique functional connectivity correlates underlie the expression of psychiatric illness-linked behaviors in males and females in data from the Adolescent Brain Cognitive Development Study (N = 5260; 2571 females). RESULTS: We demonstrate that functional connectivity profiles predict individual differences in externalizing behaviors in males and females but predict internalizing behaviors only in females. Furthermore, models trained to predict externalizing behaviors in males generalize to predict internalizing behaviors in females, and models trained to predict internalizing behaviors in females generalize to predict externalizing behaviors in males. Finally, the neurobiological correlates of many behaviors are largely shared within and across sexes: functional connections within and between heteromodal association networks, including default, limbic, control, and dorsal attention networks, are associated with internalizing and externalizing behaviors. CONCLUSIONS: Taken together, these findings suggest that shared neurobiological patterns may manifest as distinct behaviors across the sexes. Based on these results, we recommend that both clinicians and researchers carefully consider how sex may influence the presentation of psychiatric illnesses, especially those along the internalizing-externalizing spectrum.

Sickness behaviour and depression: An updated model of peripheral-central immunity interactions.

Current research into mood disorders indicates that circulating immune mediators participating in the pathophysiology of chronic somatic disorders have potent influences on brain function. This paradigm has brought to the fore the use of anti-inflammatory therapies as adjunctive to standard antidepressant therapy to improve treatment efficacy, particularly in subjects that do not respond to standard medication. Such new practice requires biomarkers to tailor these new therapies to those most likely to benefit but also validated mechanisms of action describing the interaction between peripheral immunity and brain function to optimize target intervention. These mechanisms are generally studied in preclinical models that try to recapitulate the human disease, MDD, through peripherally induced sickness behaviour. In this proposal paper, after an appraisal of the data in rodent models and their adherence to the data in clinical cohorts, we put forward a modified model of periphery-brain interactions that goes beyond the currently established view of microglia cells as the drivers of depression. Instead, we suggest that, for most patients with mild levels of peripheral inflammation, brain barriers are the primary actors in the pathophysiology of the disease and in treatment resistance. We then highlight data gaps in this proposal and suggest novel lines of research.