Endotoxin-Induced Physiological and Psychological Sickness Responses in Healthy Humans: Insights into the Post-Acute Phase.

INTRODUCTION: Experimental endotoxemia is a translational model of systemic inflammation that has contributed significantly to our current understanding of sickness behavior and inflammation-associated depression. Previous studies using this model revealed a strong association between cytokine levels, endocrine changes, and psychological sickness symptoms during the acute phase of inflammation. The objective of this randomized, double-blind, placebo-controlled crossover study was to gain insight into potential post-acute physiological and psychological consequences of endotoxin administration that may either persist or newly emerge between 24 and 72 h after injection. The main focus was on associations between serum levels of C-reactive protein (CRP) and affective symptoms as well as alterations in diurnal cortisol profile, the two key features of inflammation-associated depression. METHODS: Healthy male volunteers (N = 18) received an injection of either endotoxin (0.8 ng/kg) or placebo on two separate but otherwise identical study days, 7 days apart. Blood and saliva samples were collected during acute and post-acute phases after injection to measure blood inflammatory markers (interleukin [IL]-6, IL-1 receptor antagonist [ra], CRP) and salivary cortisol levels. In addition, participants completed a comprehensive battery of questionnaires to assess physical and psychological sickness symptoms. RESULTS: Endotoxin treatment induced a short-time rise in plasma IL-6 and a longer increase in IL-1ra. The increase in serum CRP was delayed compared to cytokines, peaking at 24 h and gradually decreasing until 72 h after injection. The inflammatory response was accompanied by bodily and psychological sickness symptoms which occurred only in the acute phase, whereas none of the symptoms persisted or recurred in the post-acute phase. Salivary cortisol levels were significantly increased during the acute phase and exhibited pronounced circadian changes. However, no significant differences in diurnal cortisol profiles were observed between placebo and endotoxin conditions on the days after treatment. CONCLUSION: Our findings suggest that CRP, which is elevated in patients with inflammation-associated depression, does not appear to be responsible for depressive symptomatology. Moreover, a single inflammatory episode is not sufficient to alter diurnal cortisol profiles, as observed in inflammation-associated depression. In addition, the absence of persistent lipopolysaccharide-induced psychological and physiological changes beyond the acute phase further supports the safety of endotoxin administration in humans.

Taste-immune associative learning amplifies immunopharmacological effects and attenuates disease progression in a rat glioblastoma model.

Mechanistic target of rapamycin (mTOR)-signaling is one key driver of glioblastoma (GBM), facilitating tumor growth by promoting the shift to an anti-inflammatory, pro-cancerogenic microenvironment. Even though mTOR inhibitors such as rapamycin (RAPA) have been shown to interfere with GBM disease progression, frequently chaperoned toxic drug side effects urge the need for developing alternative or supportive treatment strategies. Importantly, previous work document that taste-immune associative learning with RAPA may be utilized to induce learned pharmacological placebo responses in the immune system. Against this background, the current study aimed at investigating the potential efficacy of a taste-immune associative learning protocol with RAPA in a syngeneic GBM rat model. Following repeated pairings of a novel gustatory stimulus with injections of RAPA, learned immune-pharmacological effects could be retrieved in GBM-bearing animals when re-exposed to the gustatory stimulus together with administering 10 % amount of the initial drug dose (0.5 mg/kg). These inhibitory effects on tumor growth were accompanied by an up-regulation of central and peripheral pro-inflammatory markers, suggesting that taste-immune associative learning with RAPA promoted the development of a pro-inflammatory anti-tumor microenvironment that attenuated GBM tumor growth to an almost identical outcome as obtained after 100 % (5 mg/kg) RAPA treatment. Together, our results confirm the applicability of taste-immune associative learning with RAPA in animal disease models where mTOR overactivation is one key driver. This proof-of-concept study may also be taken as a role model for implementing learning protocols as alternative or supportive treatment strategy in clinical settings, allowing the reduction of required drug doses and side effects without losing treatment efficacy.

Pre-surgery optimization of patients' expectations to improve outcome in heart surgery: Study protocol of the randomized controlled multi-center PSY-HEART-II trial.

The PSY-HEART-I trial indicated that a brief expectation-focused intervention prior to heart surgery improves disability and quality of life 6 months after coronary artery bypass graft surgery (CABG). However, to investigate the clinical utility of such an intervention, a large multi-center trial is needed to generalize the results and their implications for the health care system. The PSY-HEART-II study aims to examine whether a preoperative psychological intervention targeting patients' expectations (EXPECT) can improve outcomes 6 months after CABG (with or without heart valve replacement). EXPECT will be compared to Standard of Care (SOC) and an intervention providing emotional support without targeting expectations (SUPPORT). In a 3-arm multi-center randomized, controlled, prospective trial (RCT), N = 567 patients scheduled for CABG surgery will be randomized to either SOC alone or SOC and EXPECT or SOC and SUPPORT. Patients will be randomized with a fixed unbalanced ratio of 3:3:1 (EXPECT: SUPPORT: SOC) to compare EXPECT to SOC and EXPECT to SUPPORT. Both psychological interventions consist of 2 in-person sessions (à 50 minute), 2 phone consultations (à 20 minute) during the week prior to surgery, and 1 booster phone consultation post-surgery 6 weeks later. Assessment will occur at baseline approx. 3-10 days before surgery, preoperatively the day before surgery, 4-6 days later, and 6 months after surgery. The study's primary end point will be patients' illness-related disability 6 months after surgery. Secondary outcomes will be patients' expectations, subjective illness beliefs, quality of life, length of hospital stay and blood sample parameters (eg, inflammatory parameters such as IL-6, IL-8, CRP). This large multi-center trial has the potential to corroborate and generalize the promising results of the PSY-HEART-I trial for routine care of cardiac surgery patients, and to stimulate revisions of treatment guidelines in heart surgery.

Targeting the Meningeal Compartment to Resolve Chemobrain and Neuropathy via Nasal Delivery of Functionalized Mitochondria.

Cognitive deficits (chemobrain) and peripheral neuropathy occur in ∼75% of patients treated for cancer with chemotherapy and persist long-term in >30% of survivors. Without preventive or curative interventions and with increasing survivorship rates, the population debilitated by these neurotoxicities is rising. Platinum-based chemotherapeutics, including cisplatin, induce neuronal mitochondrial defects leading to chemobrain and neuropathic pain. This study investigates the capacity of nasally administered mesenchymal stem cell-derived mitochondria coated with dextran-triphenylphosphonium polymer (coated mitochondria) to reverse these neurotoxicities. Nasally administered coated mitochondria are rapidly detectable in macrophages in the brain meninges but do not reach the brain parenchyma. The coated mitochondria change expression of >2400 genes regulating immune, neuronal, endocrine and vascular pathways in the meninges of mice treated with cisplatin. Nasal administration of coated mitochondria reverses cisplatin-induced cognitive deficits and resolves neuropathic pain at a >55-times lower dose compared to uncoated mitochondria. Reversal of these neuropathologies is associated with resolution of cisplatin-induced deficits in myelination, synaptosomal mitochondrial integrity and neurogenesis. These findings demonstrate that nasally administered coated mitochondria promote resolution of chemobrain and peripheral neuropathy, thereby identifying a novel facile strategy for clinical application of mitochondrial donation and treating central and peripheral nervous system pathologies by targeting the brain meninges.

Glioma: molecular signature and crossroads with tumor microenvironment.

In patients with glioblastoma, the average survival time with current treatments is short, mainly due to recurrences and resistance to therapy. This insufficient treatment success is, in large parts, due to the tremendous molecular heterogeneity of gliomas, which affects the overall prognosis and response to therapies and plays a vital role in gliomas' grading. In addition, the tumor microenvironment is a major player for glioma development and resistance to therapy. Active communication between glioma cells and local or neighboring healthy cells and the immune environment promotes the cancerogenic processes and contributes to establishing glioma stem cells, which drives therapy resistance. Besides genetic alterations in the primary tumor, tumor-released factors, cytokines, proteins, extracellular vesicles, and environmental influences like hypoxia provide tumor cells the ability to evade host tumor surveillance machinery and promote disease progression. Moreover, there is increasing evidence that these players affect the molecular biological properties of gliomas and enable inter-cell communication that supports pro-cancerogenic cell properties. Identifying and characterizing these complex mechanisms are inevitably necessary to adapt therapeutic strategies and to develop novel measures. Here we provide an update about these junctions where constant traffic of biomolecules adds complexity in the management of glioblastoma.

Rodent Models to Analyze the Glioma Microenvironment.

Animal models are still indispensable for understanding the basic principles of glioma development and invasion. Preclinical approaches aim to analyze the treatment efficacy of new drugs before translation into clinical trials is possible. Various animal disease models are available, but not every approach is useful for addressing specific questions. In recent years, it has become increasingly evident that the tumor microenvironment plays a key role in the nature of glioma. In addition to providing an overview, this review evaluates available rodent models in terms of usability for research on the glioma microenvironment.

Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits.

Up to seventy-five percent of patients treated for cancer suffer from cognitive deficits which can persist for months to decades, severely impairing quality of life. Although the number of cancer survivors is increasing tremendously, no efficacious interventions exist. Cisplatin, most commonly employed for solid tumors, leads to cognitive impairment including deficits in memory and executive functioning. We recently proposed deficient neuronal mitochondrial function as its underlying mechanism. We hypothesized nasal administration of mitochondria isolated from human mesenchymal stem cells to mice, can reverse cisplatin-induced cognitive deficits. Methods: Puzzle box, novel object place recognition and Y-maze tests were used to assess the cognitive function of mice. Immunofluorescence and high-resolution confocal microscopy were employed to trace the nasally delivered mitochondria and evaluate their effect on synaptic loss. Black Gold II immunostaining was used to determine myelin integrity. Transmission electron microscopy helped determine mitochondrial and membrane integrity of brain synaptosomes. RNA-sequencing was performed to analyse the hippocampal transcriptome. Results: Two nasal administrations of mitochondria isolated from human mesenchymal stem cells to mice, restored executive functioning, working and spatial memory. Confocal imaging revealed nasally delivered mitochondria rapidly arrived in the meninges where they were readily internalized by macrophages. The administered mitochondria also accessed the rostral migratory stream and various other brain regions including the hippocampus where they colocalized with GFAP+ cells. The restoration of cognitive function was associated with structural repair of myelin in the cingulate cortex and synaptic loss in the hippocampus. Nasal mitochondrial donation also reversed the underlying synaptosomal mitochondrial defects. Moreover, transcriptome analysis by RNA-sequencing showed reversal of cisplatin-induced changes in the expression of about seven hundred genes in the hippocampus. Pathway analysis identified Nrf2-mediated response as the top canonical pathway. Conclusion: Our results provide key evidence on the therapeutic potential of isolated mitochondria - restoring both brain structure and function, their capability to enter brain meninges and parenchyma upon nasal delivery and undergo rapid cellular internalization and alter the hippocampal transcriptome. Our data identify nasal administration of mitochondria as an effective strategy for reversing chemotherapy-induced cognitive deficits and restoring brain health, providing promise for the growing population of both adult and pediatric cancer survivors.

Neurobehavioral effects in rats with experimentally induced glioblastoma after treatment with the mTOR-inhibitor rapamycin.

Psychiatric symptoms as seen in affective and anxiety disorders frequently appear during glioblastoma (GBM) treatment and disease progression, additionally deteriorate patient's daily life routine. These central comorbidities are difficult to recognize and the causes for these effects are unknown. Since overactivation of mechanistic target of rapamycin (mTOR)- signaling is one key driver in GBM growth, the present study aimed at examining in rats with experimentally induced GBM, neurobehavioral consequences during disease progression and therapy. Male Fisher 344 rats were implanted with syngeneic RG2 tumor cells in the right striatum and treated with the mTOR inhibitor rapamycin (3 mg/kg; once daily, for eight days) before behavioral performance, brain protein expression, and blood samples were analyzed. We could show that treatment with rapamycin diminished GBM tumor growth, confirming mTOR-signaling as one key driver for tumor growth. Importantly, in GBM animals' anxiety-like behavior was observed but only after treatment with rapamycin. These behavioral alterations were moreover accompanied by aberrant glucocorticoid receptor, phosphorylated p70 ribosomal S6 kinase alpha (p-p70s6k), and brain derived neurotrophic factor protein expression in the hippocampus and amygdala in the non-tumor-infiltrated hemisphere of the brain. Despite the beneficial effects on GBM tumor growth, our findings indicate that therapy with rapamycin impaired neurobehavioral functioning. This experimental approach has a high translational value. For one, it emphasizes aberrant mTOR functioning as a central feature mechanistically linking complex brain diseases and behavioral disturbances. For another, it highlights the importance of elaborating the cause of unwanted central effects of immunosuppressive and antiproliferative drugs used in transplantation medicine, immunotherapy, and oncology.

IL-8 and CRP moderate the effects of preoperative psychological interventions on postoperative long-term outcomes 6 months after CABG surgery - The randomized controlled PSY-HEART trial.

INTRODUCTION: Inflammation has been related to several somatic and psychological disorders and may moderate effects of psychological interventions. In the PSY-HEART trial patients benefitted from preoperative psychological interventions before undergoing coronary artery bypass graft surgery (CABG) and, if necessary, concomitant valvular surgery, compared to standard medical care. In this study we examined whether patients' baseline inflammatory status moderated the intervention effects. MATERIAL AND METHODS: In a prospective three-arm randomized clinical trial with 6-months follow-up, 124 patients scheduled for CABG surgery alone or concomitant with valvular surgery were randomized to (i) standard medical care only (SMC) or two preoperative psychological interventions: (ii) CBT-based optimizing expectations (EXPECT) and an (iii) an active control group focusing on emotional support (SUPPORT). Available baseline CRP- (n = 79), IL-6- (n = 78), IL-8- (n = 78) and TNF-alpha-(n = 80) parameters were considered as potential moderators (CRP as a categorical and continuous moderator). Linear mixed model analyses were calculated to test whether baseline inflammatory levels moderated intervention effects on disability, mental and physical quality of life at 6 months after surgery. RESULTS: IL-8 moderated intervention effects on patients' disability and categorical CRP moderated intervention effects on mental quality of life. Follow-up tests indicated that EXPECT (and in part SUPPORT) led to lower postoperative disability and higher mental quality of life compared to SMC in patients with low baseline inflammatory markers. EXPECT indicated higher mental quality of life compared to SUPPORT in the high CRP subgroup. Patients in the SMC group had higher mental quality of life in the high CRP subgroup compared to the low CRP subgroup. CONCLUSION: Especially for patients with a lower inflammatory baseline status preoperative psychological interventions might be helpful to optimize long-term CABG surgery outcomes.

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.

Dose-Dependent Acute Effects of Everolimus Administration on Immunological, Neuroendocrine and Psychological Parameters in Healthy Men.

The rapamycin analogue everolimus (EVR) is a potent inhibitor of the mammalian target of rapamycin (mTOR) and clinically used to prevent allograft rejections as well as tumor growth. The pharmacokinetic and immunosuppressive efficacy of EVR have been extensively reported in patient populations and in vitro studies. However, dose-dependent ex vivo effects upon acute EVR administration in healthy volunteers are rare. Moreover, immunosuppressive drugs are associated with neuroendocrine changes and psychological disturbances. It is largely unknown so far whether and to what extend EVR affects neuroendocrine functions, mood, and anxiety in healthy individuals. Thus, in the present study, we analyzed the effects of three different clinically applied EVR doses (1.5, 2.25, and 3 mg) orally administered 4 times in a 12-hour cycle to healthy male volunteers on immunological, neuroendocrine, and psychological parameters. We observed that oral intake of medium (2.25 mg) and high doses (3 mg) of EVR efficiently suppressed T cell proliferation as well as IL-10 cytokine production in ex vivo mitogen-stimulated peripheral blood mononuclear cell. Further, acute low (1.5 mg) and medium (2.25 mg) EVR administration increased state anxiety levels accompanied by significantly elevated noradrenaline (NA) concentrations. In contrast, high-dose EVR significantly reduced plasma and saliva cortisol as well as NA levels and perceived state anxiety. Hence, these data confirm the acute immunosuppressive effects of the mTOR inhibitor EVR and provide evidence for EVR-induced alterations in neuroendocrine parameters and behavior under physiological conditions in healthy volunteers.

Salivary cortisol levels and anxiety in melanoma patients undergoing sentinel lymph node excision under local anesthesia versus general anesthesia: a prospective study.

BACKGROUND: Sentinel lymph node excision (SLNE) can be performed in tumescent local anesthesia (TLA) or general anesthesia (GA). Perioperative cortisol level changes and anxiety are common in surgical interventions and might be influenced by the type of anesthesia. In this study, we intended to determine whether the type of anesthesia impacts the patients' perioperative levels of salivary cortisol (primary outcome) and the feeling of anxiety evaluated by psychological questionnaires (secondary outcome). METHODS: All melanoma patients of age undergoing SLNE at the University Hospital Essen, Germany, could be included in the study. Exclusion criteria were patients' intake of glucocorticoids or psychotropic medication during the former 6 months, pregnancy, age under 18 years, and BMI ≥ 30 as salivary cortisol levels were reported to be significantly impacted by obesity and might confound results. RESULTS: In total, 111 melanoma patients undergoing SLNE were included in our prospective study between May 2011 and April 2017 and could choose between TLA or GA. Salivary cortisol levels were measured three times intraoperatively, twice on the third and second preoperative day and twice on the second postoperative day. To assess anxiety, patients completed questionnaires (Hospital Anxiety and Depression Scale (HADS), State-Trait Anxiety Inventory (STAI)) perioperatively. Patients of both groups exhibited comparable baseline levels of cortisol and perioperative anxiety levels. Independent of the type of anesthesia, all patients showed significantly increasing salivary cortisol level from baseline to 30 min before surgery (T3) (TLA: t = 5.07, p < 0.001; GA: t = 3.09, p = 0.006). Post hoc independent t tests showed that the TLA group exhibited significantly higher cortisol concentrations at the beginning of surgery (T4; t = 3.29, p = 0.002) as well as 20 min after incision (T5; t = 277, p = 0.008) compared to the GA group. CONCLUSIONS: The type of anesthesia chosen for SLNE surgery significantly affects intraoperative cortisol levels in melanoma patients. Further studies are mandatory to evaluate the relevance of endogenous perioperative cortisol levels on the postoperative clinical course. TRIAL REGISTRATION: German Clinical Trials Register DRKS00003076, registered 1 May 2011.

Acute inflammation and psychomotor slowing: Experimental assessment using lipopolysaccharide administration in healthy humans.

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 â€‹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 â€‹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.

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.

Behavioral conditioning of anti-proliferative and immunosuppressive properties of the mTOR inhibitor rapamycin.

Suppression of immune functions can be elicited by behavioral conditioning using drugs such as cyclosporine A, cyclophosphamide, or opioids. Nevertheless, little is known regarding the conditioned actions of clinically approved immunosuppressive drugs with distinct cell signaling pathways. The present study tested the assumption to condition immunopharmacological properties of rapamycin (sirolimus), a small-molecule drug widely used as anti-tumor medication and to prevent graft rejection. For this purpose, a conditioned taste avoidance (CTA) paradigm was used, pairing the presentation of a novel taste (saccharin) as conditioned stimulus (CS) with injections of rapamycin as unconditioned stimulus (US). Subsequent re-exposure to the CS at a later time revealed that conditioning with rapamycin induced an only moderate CTA. However, pronounced conditioned immunopharmacological effects were observed, reflected by significantly reduced levels of IL-10 cytokine production and diminished proliferation of splenic CD4+ and CD8+ T cells in Dark Agouti and Fischer 344 rats. For one, these findings support earlier observations revealing that not a pronounced CTA but rather re-exposure to the CS or taste itself is essential for conditioned immunosuppression. Moreover, our results provide first evidence that the phenomenon of learned immune responses generalizes across many, if not all, small-molecule drugs with immunosuppressive properties, thereby providing the basis for employing learned immunopharmacological strategies in clinical contexts such as supportive therapy.

Can a brief psychological expectancy intervention improve postoperative pain? A randomized, controlled trial in patients with breast cancer.

Pain after surgery remains a major health problem, calling for optimized treatment regimens to maximize the efficacy of pharmacological interventions. In this randomized controlled trial, we tested in a routine surgical treatment setting whether postoperative pain can be reduced by a brief preoperative intervention, ie, positive verbal suggestions in combination with sham acupuncture, designed to optimize treatment expectations. We hypothesized that the expectancy intervention as add-on to patient-controlled intravenous analgesia with morphine reduces patient-reported postoperative pain and improves satisfaction with analgesia. Ninety-six women undergoing breast cancer surgery were randomized at 2 stages: Before surgery, anesthesiologists delivered either positive or neutral verbal suggestions regarding the benefits of acupuncture needling on postoperative pain ("information condition"). Patients were then randomized to receive sham acupuncture or no sham acupuncture during postoperative care ("sham acupuncture condition"). Average pain during the 24-hour observation period after surgery as primary and satisfaction with analgesia as secondary outcome was assessed with standardized measures and analyzed with analysis of covariance accounting for morphine dose, surgery-related, and psychological parameters. Postoperative pain ratings were significantly reduced in patients who received positive treatment-related suggestions (F = 4.45, P = 0.038, main effect of information). Moreover, patients who received an intervention aimed at optimized treatment expectations reported significantly greater satisfaction with analgesia (F = 4.89, P = 0.030, interaction effect). Together, our proof-of-concept data support that optimizing treatment expectations through verbal suggestions may offer a promising approach to improve patient-reported outcomes. Future translational and clinical studies are needed to test such psychological strategies in different surgical interventions, patient groups, and pharmacological treatment regimens.

Altered temporal variance and functional connectivity of BOLD signal is associated with state anxiety during acute systemic inflammation.

Systemic inflammation is accompanied by complex behavioral changes and disturbed emotion regulation that have been related to the pathophysiology of mood disorders including depression and anxiety. However, the causal role of systemic inflammation on mood disorders is still unclear. We herein investigated neural resting state patterns of temporal variance of the amygdala and functional connectivity within the salience network underlying changes in state anxiety during experimentally-induced systemic inflammation. In this randomized, double-blind study, N = 43 healthy men received an intravenous injection of either low-dose lipopolysaccharide (LPS, 0.4 ng/kg body weight) or saline. Resting state functional magnetic resonance imaging was assessed before and 3.5 h after injection. State anxiety, assessed with a standardized questionnaire, and plasma cytokine concentrations were repeatedly measured. LPS administration induced a transient systemic inflammatory response reflected in increases in plasma Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-α concentration. Compared to placebo, state anxiety and temporal variance in the amygdala significantly increased while functional connectivity in the salience network decreased during LPS-induced systemic inflammation. Together, these data indicate that acute systemic inflammation alters temporal variance of the BOLD signal as well as functional connectivity in brain regions and networks implicated in emotion processing and regulation. These results are of translational importance to encourage further research on the role of inflammatory pathways in the pathophysiology of neuropsychiatric conditions including anxiety disorders.

Does Human Experimental Endotoxemia Impact Negative Cognitions Related to the Self?

A role of inflammatory processes in the pathophysiology of depression is increasingly recognized. Experimental endotoxemia offers an established model to induce transient systemic inflammation in healthy humans, and has been proposed as an experimental paradigm of depression. Indeed, different symptoms of depression can be observed during experimental endotoxemia, including negative mood or dysthymia as key symptoms of depression. Hopelessness and low self-esteem constitute common cognitive symptoms in depression, but have not been specifically assessed during endotoxemia. Thus, we pooled data from healthy volunteers who received low-dose endotoxin (i.e., 0.4 or 0.8 ng/kg lipopolysaccharide, LPS) or placebo in three randomized, controlled studies to investigate the effects of LPS on cognitive schemata related to depression. Validated questionnaires were used to assess self-esteem, hopelessness and the vulnerability factor intolerance of uncertainty after intravenous injection of LPS or placebo. Plasma tumor necrosis factor (TNF)-α and interleukin (IL)-6 were repeatedly assessed, along with self-reported mood. Because not all questionnaires were available from primary studies, data were analyzed in two separate data sets: In data set 1, self-esteem and intolerance of uncertainty were assessed in N = 87 healthy volunteers, who randomly received either 0.4 or 0.8 ng/kg LPS or placebo. In data set 2, hopelessness was measured in N = 59 volunteers who randomly received either LPS (0.8 ng/kg) or placebo. In both data sets, LPS-application led to significant increases in TNF-α and IL-6, reflecting systemic inflammation. Positive mood was significantly decreased in response to LPS, in line with inflammation-induced mood impairment. General self-esteem, intolerance of uncertainty and hopelessness did not differ between LPS- and placebo groups, suggesting that these negative cognitive schemata are not responsive to acute LPS-induced systemic inflammation. Interestingly, LPS-treated volunteers reported significantly lower body-related self-esteem, which was associated with increased TNF-α concentration. Thus, certain aspects of self-esteem related to physical attractiveness and sportiness were reduced. It is conceivable that this effect is primarily related to physical sickness symptoms and reduced physical ability during experimental endotoxemia. With respect to cognitive symptoms of depression, it is conceivable that LPS affects cognitive processes, but not negative cognitive schemata, which are rather based on learning and repeated experiences.

Learned immunosuppressive placebo responses in renal transplant patients.

Patients after organ transplantation or with chronic, inflammatory autoimmune diseases require lifelong treatment with immunosuppressive drugs, which have toxic adverse effects. Recent insight into the neurobiology of placebo responses shows that associative conditioning procedures can be employed as placebo-induced dose reduction strategies in an immunopharmacological regimen. However, it is unclear whether learned immune responses can be produced in patient populations already receiving an immunosuppressive regimen. Thus, 30 renal transplant patients underwent a taste-immune conditioning paradigm, in which immunosuppressive drugs (unconditioned stimulus) were paired with a gustatory stimulus [conditioned stimulus (CS)] during the learning phase. During evocation phase, after patients were reexposed to the CS, T cell proliferative capacity was significantly reduced in comparison with the baseline kinetics of T cell functions under routine drug intake (ƞp2 = 0.34). These data demonstrate, proof-of-concept, that learned immunosuppressive placebo responses can be used as a supportive, placebo-based, dose-reduction strategy to improve treatment efficacy in an ongoing immunopharmacological regimen.

Effects of Preoperative Psychological Interventions on Catecholamine and Cortisol Levels After Surgery in Coronary Artery Bypass Graft Patients: The Randomized Controlled PSY-HEART Trial.

OBJECTIVE: The aim of the study was to examine whether preoperative psychological interventions targeting patients' expectations are capable of influencing the biological stress response after coronary artery bypass graft (CABG) surgery and could thus improve recovery after heart surgery. METHODS: Randomized controlled trial with assessments 10 days before surgery, after psychological intervention (day of hospital admission, but before surgery), postoperative (6-8 days later), and at follow-up (6 months after surgery). Eligible patients (N = 124) scheduled for elective on-pump CABG or CABG with valve replacement surgery were approached before hospital admission. Standard medical care (SMC) was compared with two additional preoperative psychological interventions: (a) an expectation manipulation intervention to optimize patients' expectations about course and outcomes or (b) supportive therapy, containing the same amount of therapeutic attention, but without specifically focusing on expectations. Postoperative plasma adrenaline, noradrenaline, and cortisol levels were a secondary outcome of our study (primary outcome patients' disability 6 months after surgery and other secondary patient-reported or clinical outcomes were reported elsewhere). RESULTS: Expectation manipulation intervention (3.68 ln pg/mL, 95% confidence interval = 3.38-3.98, p = .015) and supportive therapy (3.70 ln pg/mL, 95% confidence interval = 3.38-4.01, p = .026) led to significantly lower postoperative adrenaline levels compared with SMC (4.26 ln pg/mL, 95% confidence interval = 3.99-4.53) only. There were no treatment effects of the preoperative intervention for noradrenaline (p = .90) or cortisol (p = .30). Higher postoperative adrenaline levels predicted disability 6 months after surgery (r = .258, p = .018). CONCLUSIONS: In addition to SMC, preoperative psychological interventions seem to buffer psychobiological stress responses and could thus facilitate recovery from CABG surgery. Patients' postoperative stress responses could be an important factor for explaining trajectories of long-term outcomes. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov(NCT01407055).