A pilot investigation of differential neuroendocrine associations with fronto-limbic activation during semantically-cued list learning in mood disorders.

BACKGROUND: Decreased volume and disrupted function in neural structures essential for memory formation (e.g. medial temporal lobe and prefrontal cortex) are common among individuals with depression. Hypothalamic-pituitary-axis function, as reflected by measurement of cortisol levels, is linked to neural activity during memory encoding in healthy people. However, it is not as well understood whether cortisol is associated with alterations in fronto-temporal recruitment during memory encoding in depression. METHODS: In this pilot study, we evaluated associations between cortisol and neural activation during memory encoding in 62 adults (18-65 years) with mood disorders (MD; n = 39, 66.7% female), including major depression (n = 28) and bipolar I disorder (n = 11), and healthy controls (HC; n = 23, 43.5% female). Participants provided salivary cortisol samples before and after completing a semantically-cued list-learning task during 3-Tesla fMRI. Links between pre-scan cortisol (and cortisol change) and activation during encoding were evaluated using block and event-related models. RESULTS: Overall, pre-scan cortisol level was positively associated with greater engagement of fronto-limbic activation during the encoding block. However, in MD, pre-scan cortisol was associated with attenuated activation during encoding in medial frontal, superior and middle temporal gyri, insula, lingual gyrus, and claustrum relative to HCs. Cortisol-related attenuation of activation in MD was also observed during encoding of words subsequently recalled in the ventral anterior cingulate, hypothalamus, and middle temporal gyrus. By and large, cortisol change (pre/post scan) predicted the same pattern of findings in both block and event-related contrasts. LIMITATIONS: Although analyses accounted for variations in scanner time of day, circadian alterations in cortisol may have introduced variability into the results. CONCLUSIONS: Pre-scan cortisol may selectively interfere with recruitment of important fronto-temporal memory circuitry in mood disorders. The inverted associations between cortisol and neural function in MD relative to HC also elucidate potentially unique pathophysiological markers of mood disorders.

Considering sex differences clarifies the effects of depression on facial emotion processing during fMRI.

BACKGROUND: Sex differences in emotion processing may play a role in women's increased risk for Major Depressive Disorder (MDD). However, studies of sex differences in brain mechanisms involved in emotion processing in MDD (or interactions of sex and diagnosis) are sparse. METHODS: We conducted an event-related fMRI study examining the interactive and distinct effects of sex and MDD on neural activity during a facial emotion perception task. To minimize effects of current affective state and cumulative disease burden, we studied participants with remitted MDD (rMDD) who were early in the course of the illness. In total, 88 individuals aged 18-23 participated, including 48 with rMDD (32 female) and 40 healthy controls (HC; 25 female). RESULTS: fMRI revealed an interaction between sex and diagnosis for sad and neutral facial expressions in the superior frontal gyrus and left middle temporal gyrus. Results also revealed an interaction of sex with diagnosis in the amygdala. LIMITATIONS: Data was from two sites, which might increase variability, but it also increases power to examine sex by diagnosis interactions. CONCLUSIONS: This study demonstrates the importance of taking sex differences into account when examining potential trait (or scar) mechanisms that could be useful in identifying individuals at-risk for MDD as well as for evaluating potential therapeutic innovations.

Evaluation of clinical practice in perioperative patient blood management.

BACKGROUND: Several guidelines have been published to facilitate implementation of patient blood management (PBM). This study was performed to evaluate clinical practices in PBM. METHODS: An online survey based on the guidelines for the management of severe perioperative bleeding from the European Society of Anaesthesiology (ESA) was conducted among ESA members. We assessed characteristic data of participating physicians, preoperative assessment of bleeding risk and anaemia, intraoperative transfusion practices, specific pharmacologic treatment of significant bleeding, and clinical use of PBM algorithms. Data distributions for five European regions and the workplace and experience of physicians were analysed using a χ2 test. RESULTS: We received 706 fully completed surveys from physicians in 57 countries. Most (99%) respondents were anaesthetists or intensive care physicians, and 68% worked at university or university-affiliated hospitals. A standardised bleeding history before surgery is routinely obtained by 48% of physicians. When bleeding history is negative, 55% of physicians routinely order preoperative coagulation testing. Only 24% of physicians timely assess patients at risk of bleeding during surgery for anaemia before elective surgery. When anaemia is diagnosed, 38% of physicians routinely investigate its cause. The rate of routinely performed targeted haemostatic interventions with fibrinogen, vitamin K or prothrombin complex, and tranexamic acid was 60%, 52%, and 54%, respectively. Algorithms to guide PBM are used by 62% of physicians. Results varied between geographic regions. CONCLUSIONS: Major deficits exist in the use of recommended PBM among anaesthetists, indicating an opportunity to improve clinical standards.

Decoupling of the amygdala to other salience network regions in adolescent-onset recurrent major depressive disorder.

BACKGROUND: Recent meta-analyses of resting-state networks in major depressive disorder (MDD) implicate network disruptions underlying cognitive and affective features of illness. Heterogeneity of findings to date may stem from the relative lack of data parsing clinical features of MDD such as phase of illness and the burden of multiple episodes. METHOD: Resting-state functional magnetic resonance imaging data were collected from 17 active MDD and 34 remitted MDD patients, and 26 healthy controls (HCs) across two sites. Participants were medication-free and further subdivided into those with single v. multiple episodes to examine disease burden. Seed-based connectivity using the posterior cingulate cortex (PCC) seed to probe the default mode network as well as the amygdala and subgenual anterior cingulate cortex (sgACC) seeds to probe the salience network (SN) were conducted. RESULTS: Young adults with remitted MDD demonstrated hyperconnectivity of the left PCC to the left inferior frontal gyrus and of the left sgACC to the right ventromedial prefrontal cortex (PFC) and left hippocampus compared with HCs. Episode-independent effects were observed between the left PCC and the right dorsolateral PFC, as well as between the left amygdala and right insula and caudate, whereas the burden of multiple episodes was associated with hypoconnectivity of the left PCC to multiple cognitive control regions as well as hypoconnectivity of the amygdala to large portions of the SN. CONCLUSIONS: This is the first study of a homogeneous sample of unmedicated young adults with a history of adolescent-onset MDD illustrating brain-based episodic features of illness.

It still hurts: altered endogenous opioid activity in the brain during social rejection and acceptance in major depressive disorder.

The µ-opioid receptor (MOR) system, well known for dampening physical pain, is also hypothesized to dampen 'social pain.' We used positron emission tomography scanning with the selective MOR radioligand [(11)C]carfentanil to test the hypothesis that MOR system activation (reflecting endogenous opioid release) in response to social rejection and acceptance is altered in medication-free patients diagnosed with current major depressive disorder (MDD, n=17) compared with healthy controls (HCs, n=18). During rejection, MDD patients showed reduced endogenous opioid release in brain regions regulating stress, mood and motivation, and slower emotional recovery compared with HCs. During acceptance, only HCs showed increased social motivation, which was positively correlated with endogenous opioid release in the nucleus accumbens, a reward structure. Altered endogenous opioid activity in MDD may hinder emotional recovery from negative social interactions and decrease pleasure derived from positive interactions. Both effects may reinforce depression, trigger relapse and contribute to poor treatment outcomes.

Smoking history, and not depression, is related to deficits in detection of happy and sad faces.

INTRODUCTION: Previous research has demonstrated that chronic cigarette smoking and major depressive disorder (MDD) are each associated with cognitive decrements. Further, these conditions co-occur commonly, though mechanisms in the comorbid condition are poorly understood. There may be distinct, additive, or overlapping factors underlying comorbid cigarette smoking and MDD. The present study investigated the impact of smoking and MDD on executive function and emotion processing. METHODS: Participants (N=198) were grouped by diagnostic category (MDD and healthy controls, HC) and smoking status (ever-smokers, ES and never-smokers, NS). Participants completed the Facial Emotion Perception Test (FEPT), a measure of emotional processing, and the parametric Go/No-go task (PGNG), a measure of executive function. RESULTS: FEPT performance was analyzed using ANCOVA with accuracy and reaction time as separate dependent variables. Repeated measures MANCOVA was conducted for PGNG with performance measure and task level as dependent variables. Analyses for each task included diagnostic and smoking group as independent variables, and gender was controlled for. Results for FEPT reveal that lower overall accuracy was found for ES relative to NS, though MDD did not differ from HC. Post-hoc analyses revealed that ES were poorer at identifying happy and sad, but not fearful or angry, faces. For PGNG, poorer performance was observed in MDD relative to HC in response time to Go targets, but there were no differences for ES and NS. Interaction of diagnosis and smoking group was not observed for performance on either task. CONCLUSIONS: The results of this study provide preliminary evidence for distinctive cognitive decrements in smokers and individuals with depression.

Coagulopathy induced by acidosis, hypothermia and hypocalcaemia in severe bleeding.

Acidosis, hypothermia and hypocalcaemia are determinants for morbidity and mortality during massive hemorrhages. However, precise pathological mechanisms of these environmental factors and their potential additive or synergistic anticoagulant and/or antiplatelet effects are not fully elucidated and are at least in part controversial. Best available evidences from experimental trials indicate that acidosis and hypothermia progressively impair platelet aggregability and clot formation. Considering the cell-based model of coagulation physiology, hypothermia predominantly prolongs the initiation phase, while acidosis prolongs the propagation phase of thrombin generation. Acidosis increases fibrinogen breakdown while hypothermia impairs its synthesis. Acidosis and hypothermia have additive effects. The effect of hypocalcaemia on coagulopathy is less investigated but it appears that below the cut-off of 0.9 mmol/L, several enzymatic steps in the plasmatic coagulation system are blocked while above that cut-off effects remain without clinical sequalae. The impact of environmental factor on hemostasis is underestimated in clinical practice due to our current practice of using routine coagulation laboratory tests such as partial thromboplastin time or prothrombin time, which are performed at standardized test temperature, after pH correction, and upon recalcification. Temperature-adjustments are feasible in viscoelastic point-of-care tests such as thrombelastography and thromboelastometry which may permit quantification of hypothermia-induced coagulopathy. Rewarming hypothermic bleeding patients is highly recommended because it improves patient outcome. Despite the absence of high-quality evidence, calcium supplementation is clinical routine in bleeding management. Buffer administration may not reverse acidosis-induced coagulopathy but may be essential for the efficacy of coagulation factor concentrates such as recombinant activated factor VII.

Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing.

Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.

Response of the µ-opioid system to social rejection and acceptance.

The endogenous opioid system, which alleviates physical pain, is also known to regulate social distress and reward in animal models. To test this hypothesis in humans (n=18), we used an µ-opioid receptor (MOR) radiotracer to measure changes in MOR availability in vivo with positron emission tomography during social rejection (not being liked by others) and acceptance (being liked by others). Social rejection significantly activated the MOR system (i.e., reduced receptor availability relative to baseline) in the ventral striatum, amygdala, midline thalamus and periaqueductal gray (PAG). This pattern of activation is consistent with the hypothesis that the endogenous opioids have a role in reducing the experience of social pain. Greater trait resiliency was positively correlated with MOR activation during rejection in the amygdala, PAG and subgenual anterior cingulate cortex (sgACC), suggesting that MOR activation in these areas is protective or adaptive. In addition, MOR activation in the pregenual ACC was correlated with reduced negative affect during rejection. In contrast, social acceptance resulted in MOR activation in the amygdala and anterior insula, and MOR deactivation in the midline thalamus and sgACC. In the left ventral striatum, MOR activation during acceptance predicted a greater desire for social interaction, suggesting a role for the MOR system in social reward. The ventral striatum, amygdala, midline thalamus, PAG, anterior insula and ACC are rich in MORs and comprise a pathway by which social cues may influence mood and motivation. MOR regulation of this pathway may preserve and promote emotional well being in the social environment.

Shifted inferior frontal laterality in women with major depressive disorder is related to emotion-processing deficits.

BACKGROUND: Facial emotion perception (FEP) is a critical human skill for successful social interaction, and a substantial body of literature suggests that explicit FEP is disrupted in major depressive disorder (MDD). Prior research suggests that weakness in FEP may be an important phenomenon underlying patterns of emotion-processing challenges in MDD and the disproportionate frequency of MDD in women. Method Women with (n = 24) and without (n = 22) MDD, equivalent in age and education, completed a FEP task during functional magnetic resonance imaging. RESULTS: The MDD group exhibited greater extents of frontal, parietal and subcortical activation compared with the control group during FEP. Activation in the inferior frontal gyrus (IFG) appeared shifted from a left >right pattern observed in healthy women to a bilateral pattern in MDD women. The ratio of left to right suprathreshold IFG voxels in healthy controls was nearly 3:1, whereas in the MDD group, there was a greater percentage of suprathreshold IFG voxels bilaterally, with no leftward bias. In MDD, relatively greater activation in right IFG compared with left IFG (ratio score) was present and predicted FEP accuracy (r = 0.56, p < 0.004), with an inverse relationship observed between FEP and subgenual cingulate activation (r = - 0.46, p = 0.02). CONCLUSIONS: This study links, for the first time, disrupted IFG activation laterality and increased subgenual cingulate activation with deficient FEP in women with MDD, providing an avenue for imaging-to-assessment translational applications in MDD.

Abnormal anterior cingulate cortical activity during emotional n-back task performance distinguishes bipolar from unipolar depressed females.

BACKGROUND: Depression in the context of bipolar disorder (BDd) is often misdiagnosed as unipolar disorder depression (UDd) leading to poor clinical outcomes for many bipolar sufferers. We examined neural circuitry supporting emotion regulation in females with either BDd or UDd as a first stage toward identifying biomarkers that may differentiate BDd from UDd. METHOD: Fifty-seven females aged 18-45 years participated in this study: 23 with UDd, 18 with bipolar disorder type I depression (BDId) and 16 healthy females. During 3-T functional magnetic resonance imaging (fMRI), the participants performed an emotional face n-back (EFNBACK) task, that is an n-back task with high (2-back) and low (0-back) memory load conditions flanked by two positive, negative or neutral face distracters. This paradigm examines executive control with emotional distracters-emotion regulation. RESULTS: High memory load with neutral face distracters elicited greater bilateral and left dorsal anterior midcingulate cortex (dAMCC) activity in UDd than in healthy and BDId females respectively, and greater bilateral putamen activity in both depressed groups versus healthy females. High memory load with happy face distracters elicited greater left putamen activity in UDd than in healthy females. Psychotropic medication was associated with greater putamen activity to these contrasts in UDd females. CONCLUSIONS: During high memory load with neutral face distracters, elevated dAMCC activity in UDd suggests abnormal recruitment of attentional control circuitry to maintain task performance, whereas elevated putamen activity unrelated to psychotropic medication in BDId females may suggest an attentional bias toward ambiguous neutral face distracters. Differential patterns of functional abnormalities in neural circuitry supporting attentional control during emotion regulation, especially in the dAMCC, is a promising neuroimaging measure to distinguish UDd from BDId in females.

Mild and moderate hypothermia increases platelet aggregation induced by various agonists: a whole blood in vitro study.

The mechanisms causing temperature-dependent bleeding, especially in hypothermic patients, warrant clarification. Therefore the aim of this study was to investigate platelet aggregation at the clinically important temperature range of 30-34 degrees C. After obtaining informed consent citrated whole blood was drawn from 12 healthy adult male volunteers, who had not taken any medication in the previous 14 days. After venipuncture blood samples were incubated at 37 degrees C until platelet testing. Platelet aggregation was performed in whole blood using the impedance aggregometer Multiplate at five different test temperatures between 30 degrees C and 34 degrees C. Aggregation responses at 37 degrees C served as controls. At temperatures of mild and moderate hypothermia (30-34 degrees C), overall platelet aggregation was increased compared to 37 degrees C. Increases were recorded in response to collagen, thrombin receptor activating peptide and ristocetin between 31 degrees C and 34 degrees C and in response to adenosine diphosphate between 30 degrees C and 34 degrees C. Overall platelet aggregation is increased at mild and moderate hypothermia down to 30 degrees C. These results indicate that bleeding complications reported in mildly hypothermic patients are not due to hypothermia-induced platelet inhibition. The pathomechanism of the overall increased platelet aggregation between 30 degrees C and 34 degrees C requires further detailed study.

Withdrawal forces of lumbar spinal catheters: no dependence on body position.

BACKGROUND: Spinal catheters, because of their smaller diameter, have lower tensile strength than epidural catheters. This study was designed to measure the withdrawal forces needed to remove lumbar spinal catheters and to determine whether patient position affects withdrawal forces. METHODS: Eighty-two patients with a 24-gauge spinal catheter placed midline at the lumbar L3/4 or L4/5 level were randomly assigned to catheter removal either in flexed lateral or sitting position. Withdrawal forces were measured using a tension spring balance. RESULTS: Mean withdrawal force was 0.91 N (95% CI: 0.73, 1.09) with extremes up to 5 N. Withdrawal force in the flexed lateral position was 1.04 N (95% CI: 0.73, 1.34) or in the sitting position was 0.78 N (95% CI: 0.59, 0.97). The 95% CI for the difference of the means was -0.62 N, 0.10 N. Thus, the absolute mean difference between the positions can be assumed to be smaller than 0.62 N. Neither the length of the spinal catheter under the skin or in the subarachnoid space, nor BMI influenced withdrawal force. CONCLUSION: Withdrawal force of spinal catheters is not influenced by body position during catheter removal, length of catheter under skin, or BMI.

[Direct thrombin inhibitors: pharmacology and application in cardiovascular anesthesia]. / Direkte Thrombininhibitoren: Pharmakologie und Anwendung in der kardiovaskulären Anästhesie.

The options for drug-controlled anticoagulation are becoming noticeably more manifold. In the area of anaesthesiology and intensive care, there are furthermore special disease patterns, such as heparin-induced thrombocytopenia (HIT) to be known, diagnosed and treated. This article gives a review of the substance groups of the direct thrombin inhibitors (DTI) as alternative anticoagulants for HIT in combination with cardiovascular diseases. For the administration of DTIs, experience and the correct dose are the keys to success and are the deciding factors for the two sides of haemostasis: thrombosis and haemorrhage.

[Preoperative evaluation of the bleeding history. Recommendations of the working group on perioperative coagulation of the Austrian Society for Anaesthesia, Resuscitation and Intensive Care]. / Präoperative Blutungsanamnese. Empfehlungen der Arbeitsgruppe perioperative Gerinnung der Osterreichischen Gesellschaft für Anästhesiologie, Reanimation und Intensivmedizin.

Unexpected bleeding in the perioperative period is largely caused by impaired inherited or drug-induced primary haemostasis. Standard tests for plasma coagulation are predominantly employed to gauge the risk of bleeding. In accordance with several reports the subcommittee for perioperative coagulation (AGPG) of the Austrian Society of Anaesthesia, Resuscitation and Intensive Care (OGARI) recommends the use of a standardised questionnaire to detect an increased risk of bleeding. Accordingly, healthy patients of the American Society of Anesthesiologists (ASA) grades I and II without any suspicion of impaired haemostasis who are scheduled for procedures without expected transfusion requirements, need no standard tests for coagulation. In all other patients (including patients taking medication affecting coagulation, or patients who are unable to provide adequate information) platelet count, platelet function, aPTT, PT, and fibrinogen levels should be assessed.

In vitro effects of gelatin solutions on platelet function: a comparison with hydroxyethyl starch solutions.

The aim of this study was to investigate the effects of various gelatin and hydroxyethyl starch solutions on platelet reactivity. Citrated whole blood was obtained from 20 healthy volunteers. Expression of glycoprotein (GP) IIb-IIIa and p-selectin were determined using whole blood flow cytometry on both resting and agonist-activated platelets before and after in vitro haemodilution (20% and 40%) using oxypolygelatin, modified gelatin, urea-linked gelatin, hydroxyethyl starch (HES) 130 (mean molecular weight in kDa), HES 200, HES 450 and HES 550. High degrees of haemodilution using oxypolygelatin had no significant effect, similar to HES 130, whereas modified gelatin inhibited GP IIb-IIIa expression, similar to HES 200 and HES 450. Urea-linked gelatin significantly increased the expression of GP IIb-IIIa, similar to HES 550. p-selectin expression remained unchanged in all samples. The present in vitro study indicates that chemical characteristics of colloidal solutions modulate their influence on platelet reactivity.

[Locoregional anesthesia and coagulation inhibitors. Recommendations of the Task Force on Perioperative Coagulation of the Austrian Society for Anesthesiology and Intensive Care Medicine]. / Lokoregionalanästhesien unter gerinnungshemmender Medikation. Empfehlungen der Arbeitsgruppe Perioperative Gerinnung (AGPG) der Osterreichischen Gesellschaft für Anästhesiologie und Intensivmedizin (OGARI).

More efficacious anticoagulant and antiplatelet agents have been introduced in vascular medicine and in the prevention of perioperative venous thromboembolisms. Patient management should be guided by familiarity with the pharmacology of coagulation-altering drugs and by consensus statements. The present paper reviews recommendations from the Austrian Task Force for Perioperative Coagulation which are based on thorough evaluation of the available pharmacological information and case reports. The consensus statement focuses on neuraxial and peripheral techniques and is designed to encourage safe and quality patient care.

[Locoregional anesthesia and blood coagulation: impact of new antiplatelet drugs]. / Lokoregionalanästhesie und Blutgerinnung. Behandlung mit Thrombozytenfunktionshemmern.

New antiplatelet drugs such as glycoprotein IIb/IIIa receptor antagonists, thienopyridines (adenosine diphosphate receptor antagonists), inhibitors of cyclooxygenase and phosphodiesterase, and antiaggregatory prostaglandins have been introduced in vascular medicine. This paper reviews the pharmacokinetics, mechanisms of action, indications, and side effects of platelet-inhibiting agents as well as methods for coagulation monitoring. Updated guidelines for the management of locoregional anesthesia in patients receiving new antiplatelet drugs are discussed. In this clinical situation, the decision for or against locoregional anesthesia must be preceded by a risk-benefit analysis based on history of bleeding, physical examination, and coagulation monitoring. Blockade should be performed as atraumatically as possible and specific time intervals must be maintained between the last administration of antiplatelet agents and the performance of the blockade or withdrawal of a catheter in all elective patients.

The effects of hydroxyethyl starch solutions on thromboelastography in preoperative male patients.

BACKGROUND: Hydroxyethyl starches (HES) have been shown to decrease clot strength and to increase coagulation times assessed by thromboelastography (TEG). HES with minimal anticoagulant side-effects is beneficial for plasma volume expansion in the perioperative setting. A comparison of the in vivo effects of high, middle and low molecular weight HES solutions on TEG variables has not been performed so far. METHODS: Blood was obtained before and after intravenous infusion (10 ml kg-1) of either saline, HES 70/0.5/4 (molecular weight in kDa/degree of substitution/C2:C6 ratio), HES 130/0.4/9, HES 200/0.6/9.4, or HES 450/0.7/4.6 in 50 otherwise healthy patients. Thromboelastography was performed in 360 micro l of 1% celite activated citrated whole blood after recalcification. RESULTS: HES 450/0.7/4.6 prolonged reaction time indicating impairment of the plasmatic coagulation system. TEG parameters indicative for platelet function, including angle alpha, maximum amplitude and coagulation time, deteriorated after infusion of HES 450/0.7/4.6 and HES 70/0.5/4. HES 200/0.6/9.4 and HES 130/0.4/9 impaired platelet contribution to hemostasis only partially, decreasing two or one TEG platelet parameters, respectively. CONCLUSION: Infusion of HES 450/0.7/4.6 compromises TEG parameters more than the other solutions tested, whereas HES 130/0.4/9 has the smallest effect. Further outcome-related studies are needed in order to assess the clinical relevance of our findings.