Hartmut Schächinger

Calcitonin precursors are reliable markers of sepsis in a medical intensive care unit.

Objective: The diagnosis of infection in critically ill patients is challenging because traditional markers of infection are often misleading. For example, serum concentrations of calcitonin pre‐cursors are increased in patients with infections. However, their predictive accuracy for the diagnosis of sepsis in unselected patients in a medical intensive care unit (ICU) is unknown. Therefore, we compared the usefulness of serum concentrations of calcitonin precursors, C‐reactive protein, interleukin‐6, and lactate for the diagnosis of sepsis in consecutive patients suffering from a broad range of diseases with an anticipated stay of ≥ 24 hrs in a medical ICU. Design: Prospective cohort study. Setting: Medical intensive care unit in a university medical center. Patients: 101 consecutive critically ill patients. Intervention: None. Measurements and Main Results: Blood samples were collected at various time points during the course of the disease. Systemic inflammatory response syndrome, sepsis, severe sepsis, and septic shock were diagnosed according to standardized criteria, and patients were reclassified daily without prior knowledge of the serum concentrations of calcitonin precursors or interleukin‐6. At admission, 99% of the patients had systemic inflammatory response syndrome, 53% had sepsis, and 5% developed sepsis during their stay in the ICU. Calcitonin precursors, C‐reactive protein, interleukin‐6, and lactate levels increased with the severity of infection (p < .01, one‐way analysis of variance). In a receiver operating characteristic curve analysis, calcitonin precursors were found to be the most reliable laboratory variable for the diagnosis of sepsis as compared with C‐reactive protein, interleukin‐6, and lactate (p < .01, for each comparison). Calcitonin precursor concentrations of > 1 ng/mL had sensitivity of 89% and specificity of 94% for the diagnosis of sepsis. High serum concentrations of calcitonin precursors were associated with poor prognosis (p = .01). Conclusions: In a medical ICU, serum calcitonin precursor concentrations are more sensitive and are specific markers of sepsis as compared with serum C‐reactive protein, interleukin‐6, and lactate levels.

HPA axis activation by a socially evaluated cold-pressor test

The cold-pressor test (CPT) in which subjects immerse their hand in ice water is among the most commonly used laboratory stressors. While the CPT elicits strong sympathetic nervous system activation, cortisol elevations indicative for the reactivity of the hypothalamus-pituitary-adrenal (HPA) axis are moderate to low in response to the CPT. In the present study, we assessed whether cortisol responses to the CPT can be increased by adding social-evaluative elements. Therefore, 70 healthy young men immersed their hand in ice or warm water and were watched by a woman and videotaped during hand immersion or not. While the standard CPT and the socially evaluated cold-pressor test (SECPT) led to comparable increases in blood pressure and subjective stress ratings, saliva cortisol elevations and the proportion of subjects showing a saliva cortisol response (defined as increase >2nmol/l) were significantly higher after the SECPT. Social evaluation during hand immersion in warm water did not affect saliva cortisol levels suggesting that both social evaluation and a challenge are required for HPA axis activation. These findings indicate that the incorporation of social-evaluative elements increases HPA axis responses to the CPT. The SECPT can serve as a tool for future stress research.

Post-learning intranasal oxytocin modulates human memory for facial identity

The nanopeptide oxytocin has physiological functions during labour and lactation. In addition, oxytocin is known to modulate aggression, anxiety, social behaviour and cognition. Little is known about its effects on memory for emotional stimuli. In the present single-blind, placebo-controlled, randomised study we have investigated the short- and long-term effects of a single post-learning dose (20 IU) of intranasal oxytocin on memory for facial identity and expression in 36 healthy young females and males using a face portrait recognition test. In the acquisition phase of the test, 60 different male faces with happy, angry or neutral expressions were presented to the volunteers. Thirty minutes and 24h after oxytocin administration, recognition memory tests were performed using portraits with neutral facial expressions, only. Oxytocin improved identity recognition memory independently of participants gender, for neutral and angry faces, whereas this effect was not present for happy faces. Oxytocin-treated subjects had a lower bias to judge not previously seen faces as being previously seen. Oxytocin had no effect on facial expression memory. In conclusion, oxytocin has distinct effects on memory performance for facial identity and may contribute to the modulation of social behaviour.

Corticosteroids operate as a switch between memory systems

Stress and corticosteroid hormones are known to affect learning and memory processes. In this study, we examined whether stress and corticosteroids are capable of facilitating the switch between multiple memory systems in mice. For this purpose, we designed a task that allowed measurement of nucleus caudate-based stimulus–response and hippocampus-based spatial learning strategies. Naive mice used spatial strategies to locate an exit hole on a circular hole board at a fixed location flagged by a proximal stimulus. When the mice were either stressed or administered corticosterone before the task, 30–50% of the mice switched to a stimulus–response strategy. This switch between learning strategies was accompanied by a rescue of performance, whereas performance declined in the stressed mice that kept using the spatial strategy. Pretreatment with a mineralocorticoid receptor antagonist prevented the switch toward the stimulus–response strategy but led to deterioration of hippocampus-dependent performance. These findings (i) show that corticosteroids promote the transition from spatial to stimulus–response memory systems, (ii) provide evidence that the mineralocorticoid receptor underlies this corticosteroid-mediated switch, and (iii) suggest that a stress-induced switch from hippocampus-based to nucleus caudate-based memory systems can rescue performance.

Effects of pre-learning stress on memory for neutral, positive and negative words : Different roles of cortisol and autonomic arousal

Stress can have enhancing or impairing effects on memory. Here, we addressed the effect of pre-learning stress on subsequent memory and asked whether neutral and emotionally valent information are differentially affected by specific stress components, autonomic arousal and stress-induced cortisol. Ninety-six healthy men and women underwent either a stressor (modified cold pressor test) or a control warm water exposure. During stress, participants showed comparable autonomic arousal (heart rate, blood pressure), while 60 percent showed an increase of cortisol (responders vs. 40 percent non-responders). Ten minutes after the cold pressor test neutral, positive and negative words were presented. Free recall was tested 1 and 24h later. Overall, positive and negative words were better recalled than neutral words. Stress enhanced the recall of neutral words independently of cortisol response. In contrast, the free recall of negative words was enhanced in cortisol responders in the 1-h but not 24-h test which might suggest different effects of cortisol on consolidation and reconsolidation processes. Recall for positive words was unaffected by stress-induced cortisol. To summarize, (i) pre-learning stress can enhance memory for neutral words independently of cortisol and (ii) stress effects on memory for negative words appear to rely on stress-induced cortisol elevations, the absence of this effect for positive words might be at least partly due to differences in arousal evoked by positive vs. negative words.

Cardiovascular indices of peripheral and central sympathetic activation.

Objective A number of sympathetic nervous system (SNS) parameters have been used in cardiovascular psychophysiology. This study aimed to describe the pattern and redundancy of a set of SNS parameters during peripherally induced changes of cardiac sympathetic activation and reflex modulation of central SNS control. Preejection period (PEP) was assessed as a marker of peripheral sympathetic activation. Low-frequency blood pressure variability (BPV) was assessed as an estimate of central SNS control. Methods Peripheral &bgr;-sympathetic stimulation and blockade were achieved with epinephrine and esmolol hydrochloride (&bgr;1-blockade), respectively. Changes in central SNS output were induced by loading and unloading arterial baroreceptors with norepinephrine and nitroprusside sodium, respectively. This single-blinded, crossover study in 24 healthy men also included two placebo control periods. PEP was derived from impedance cardiography and adjusted individually for heart rate. BPV was calculated by power spectral analyses of beat-to-beat heart rate and systolic blood pressure (Finapres system) data. Results PEP decreased during epinephrine infusion (−40.1 ± 3.8 ms, p < .0001) and increased during esmolol infusion (+6.6 ± 3.5 ms, p = .05). PEP was shortened after central SNS activation by nitroprusside (−16.8 ± 2.9 ms, p < 0.0001). Systolic BPV in the low-frequency range (0.07–0.14 Hz, Mayer waves) increased during nitroprusside infusion (+0.44 ± 0.19 ln mm Hg2, p = .03) and decreased during norepinephrine infusion (−0.67 ± 0.13 ln mm Hg2, p < 0.0001). Low-frequency BPV did not change significantly during epinephrine or esmolol infusion. Conclusions Our data provide empirical evidence of separable peripheral and central sympathetic response components. The combined report of low-frequency BPV and PEP gives distinct information on both central SNS control and the level of sympathetic cardiac activation achieved.

Neural Processing of Auditory Looming in the Human Brain

Acoustic intensity change, along with interaural, spectral, and reverberation information, is an important cue for the perception of auditory motion. Approaching sound sources produce increases in intensity, and receding sound sources produce corresponding decreases. Human listeners typically overestimate increasing compared to equivalent decreasing sound intensity and underestimate the time to contact of approaching sound sources. These characteristics could provide a selective advantage by increasing the margin of safety for response to looming objects. Here, we used dynamic intensity and functional magnetic resonance imaging to examine the neural underpinnings of the perceptual priority for rising intensity. We found that, consistent with activation by horizontal and vertical auditory apparent motion paradigms, rising and falling intensity activated the right temporal plane more than constant intensity. Rising compared to falling intensity activated a distributed neural network subserving space recognition, auditory motion perception, and attention and comprising the superior temporal sulci and the middle temporal gyri, the right temporoparietal junction, the right motor and premotor cortices, the left cerebellar cortex, and a circumscribed region in the midbrain. This anisotropic processing of acoustic intensity change may reflect the salience of rising intensity produced by looming sources in natural environments.

Relevance of Stress and Female Sex Hormones for Emotion and Cognition

There are clear sex differences in incidence and onset of stress-related and other psychiatric disorders in humans. Yet, rodent models for psychiatric disorders are predominantly based on male animals. The strongest argument for not using female rodents is their estrous cycle and the fluctuating sex hormones per phase which multiplies the number of animals to be tested. Here, we will discuss studies focused on sex differences in emotionality and cognitive abilities in experimental conditions with and without stress. First, female sex hormones such as estrogens and progesterone affect emotions and cognition, contributing to sex differences in behavior. Second, females respond differently to stress than males which might be related to the phase of the estrous cycle. For example, female rats and mice express less anxiety than males in a novel environment. Proestrus females are less anxious than females in the other estrous phases. Third, males perform in spatial tasks superior to females. However, while stress impairs spatial memory in males, females improve their spatial abilities, depending on the task and kind of stressor. We conclude that the differences in emotion, cognition and responses to stress between males and females over the different phases of the estrous cycle should be used in animal models for stress-related psychiatric disorders.

Disordered calcium homeostasis of sepsis: association with calcitonin precursors

Hypocalcemia and increased serum levels of calcitonin precursors are common in critically ill patients, especially in those with sepsis. We investigated calcium homeostasis in such patients.

For whom the bell (curve) tolls: Cortisol rapidly affects memory retrieval by an inverted U-shaped dose–response relationship

Stress and cortisol are generally considered to impair declarative memory retrieval, although opposite results have also been reported. Dose-dependent effects and differences between genomic and non-genomic cortisol effects are possible reasons for these discrepancies. The aim of the current experiment was to assess the non-genomic effects of escalating doses of intravenous cortisol on cued recall of socially relevant information in humans. 40 participants (age range 20-30 years; 20 females) learned associations between male faces with a neutral facial expression and descriptions of either positive or negative social behaviors and were tested one week later in a cued recall paradigm. Escalating doses of cortisol (0, 3, 6, 12, 24 mg) were administered 8 min before testing according to a between-subjects design. An inverted U-shaped dose-response relationship between salivary cortisol levels and recall performance was observed, with moderate elevation of salivary cortisol resulting in the best recall performance. This is the first study in humans demonstrating that cortisol rapidly modulates declarative memory retrieval via a dose-dependent, non-genomic mechanism that follows an inverted U-shaped curve. Our result further emphasizes the importance of fast cortisol effects for human cognition.