Too much of a good thing? Hand hygiene and the long-term course of contamination-related obsessive-compulsive symptoms.

Increased hygiene behavior may be a factor in the development of contamination-related obsessive-compulsive symptoms (C-OCS). We aimed at investigating (1) the course of C-OCS over 1 year after the start of the COVID-19 pandemic and (2) the effects of changes in hand hygiene (i.e., duration and frequency of handwashing) and related distress regulation on the long-term course of C-OCS. In a longitudinal study, we assessed 1,220 individuals from the German general population at the start of the COVID-19 pandemic (t1), 3 months later (t2), and 12 months later (t3). Pre-pandemic data were available in a subsample from 2014 (n = 430). A decrease in C-OCS over the first year of the pandemic emerged with a small effect size. Thirty-six percent of the participants scored above the clinical cut-off score at t1, 31% at t2, and 27% at t3. In 2014, only 11% scored above the clinical cut-off score. Hierarchical regression showed that C-OCS at t1 was the strongest predictor of a long-term increase in C-OCS. With small effect sizes, change in the duration (not frequency) of handwashing from t1 to t2, as well as the distress-reducing effect of handwashing served as additional predictors. Implications for information on hand hygiene guidelines are discussed.

Copeptin response to panic provocation with CO2 in healthy adults.

Repeated panic attacks are the core symptom of panic disorder and severely stressful for patients. Additional to the psychological response, the physiological symptoms are an important aspect of the experienced panic. However, data on the extent of hypothalamic-pituitary-adrenal (HPA)-axis activation during panic attacks is inconsistent. Therefore, in the present study, we aimed at investigating the stress-axis activity in more detail by including Copeptin (CoP) as a stable surrogate parameter for the vasopressinergic hypothalamic activity during experimentally induced panic attacks in healthy adults (N = 21). During a placebo-controlled panic challenge with 35% CO2 compared to normal air inhalation, we measured CoP and the peripheral effector hormones Adrenocorticotropic Releasing Hormone (ACTH) and cortisol in plasma along with the psychological response to panic anxiety. We analyzed hormonal secretion patterns, their correlations and individual panic ratings over time and explored differences between female and male participants. We found a significant CO2-induced increase of CoP plasma levels and psychological panic symptoms after CO2-administration, while no positive correlations of CoP levels with the peripheral HPA-axis hormones and with panic symptoms were present. No differences between female and male participants concerning their psychological response nor their baseline CoP levels, the release of CoP or its increase during the experiment were found. CoP could be a sensitive indicator for an organism's physiologic acute hypothalamic response during stress and panic attacks.

Expected increase in health competence improves over modules of an unguided internet-based cognitive-behavioural therapy for obsessive-compulsive disorder.

Internet-based cognitive-behavioural interventions (iCBT) are a valuable alternative to face-to-face psychotherapy. An unguided iCBT program has shown to be efficacious for patients with obsessive-compulsive disorder (OCD). However, the modules' mode of action is not well understood, which is the objective of the present study. Twenty-five patients with OCD who participated at the iCBT program for 8 weeks answered a questionnaire on their self-efficacy, motivation, expected increase in health competence and experiential avoidance before and after each module and were included in the present analyses. Linear mixed-effects models demonstrated that patients' expected increase in health competence improved over the course of the treatment. No within-module-specific effect was found. The iCBT program was able to improve patients' expected health competence. However, all other variables did not change. The iCBT program should be revised by focusing more strongly on the integration of the content to reduce experiential avoidance and to improve motivation.

Disentangling the roles of dopamine and noradrenaline in the exploration-exploitation tradeoff during human decision-making.

Balancing the exploration of new options and the exploitation of known options is a fundamental challenge in decision-making, yet the mechanisms involved in this balance are not fully understood. Here, we aimed to elucidate the distinct roles of dopamine and noradrenaline in the exploration-exploitation tradeoff during human choice. To this end, we used a double-blind, placebo-controlled design in which participants received either a placebo, 400 mg of the D2/D3 receptor antagonist amisulpride, or 40 mg of the ß-adrenergic receptor antagonist propranolol before they completed a virtual patch-foraging task probing exploration and exploitation. We systematically varied the rewards associated with choice options, the rate by which rewards decreased over time, and the opportunity costs it took to switch to the next option to disentangle the contributions of dopamine and noradrenaline to specific choice aspects. Our data show that amisulpride increased the sensitivity to all of these three critical choice features, whereas propranolol was associated with a reduced tendency to use value information. Our findings provide novel insights into the specific roles of dopamine and noradrenaline in the regulation of human choice behavior, suggesting a critical involvement of dopamine in directed exploration and a role of noradrenaline in more random exploration.

The influence of opioid blockage on the sexual response cycle: A randomized placebo-controlled experiment with relevance for the treatment of Compulsive Sexual Behavior Disorder (CSBD).

The use of opioid antagonists is discussed as a feasible and tolerable treatment of Compulsive Sexual Behavior Disorder (CSBD). However, little is known about the influence of opioid blockage on relevant physiological functions such as sexual arousal, pain perception as well as disgust sensitivity during the sexual response cycle (SRC). Healthy participants (N = 64, n = 32 women) were invited to the laboratory twice using a double-blind, randomized cross-over design, with an interval of four weeks between sessions. Participants were randomly subjected to an SRC condition (including an erotic audio play and masturbation to orgasm) and a control condition. Participants received either naltrexone (50 mg, n = 32) or placebo at both sessions. Self-reported sexual arousal and physiological measures of arousal as well as pain perception, odor disgust sensitivity, and prolactin levels were assessed along the SRC. Naltrexone increased prolactin levels and blunted the orgasm-induced prolactin rise. Naltrexone also reduced self-reported sexual arousal throughout the sexual response cycle and blunted respiration rate during masturbation. However, naltrexone did not affect other markers of physiological arousal, pressure pain ratings and odor disgust sensitivity. These findings suggest that naltrexone has an acute negative effect on sexual arousal. Since prolactin levels mediate sexual satiation, we propose that a prolactin-induced increase in sexual satiation could explain the positive effects reported for naltrexone in the treatment of CSBD.

Acute stress leaves fear generalization in healthy individuals intact.

Because threatening situations often occur in a similar manner, the generalization of fear to similar situations is adaptive and can avoid harm to the organism. However, the overgeneralization of fear to harmless stimuli is maladaptive and assumed to contribute to anxiety disorders. Thus, elucidating factors that may modulate fear (over)generalization is important. Based on the known effects of acute stress on learning, which are at least partly due to noradrenergic arousal, we investigated whether stress may promote fear overgeneralization and whether we could counteract this effect by reducing noradrenergic arousal. In a placebo-controlled, double-blind, between-subjects design, 120 healthy participants underwent a fear-conditioning procedure on Day 1. Approximately 24 hours later, participants received orally either a placebo or the beta-adrenergic receptor antagonist propranolol and were exposed to a stress or control manipulation before they completed a test of fear generalization. Skin conductance responses as well as explicit rating data showed a successful acquisition of conditioned fear on Day 1 and a pronounced fear generalization 24 hours later. Although physiological data confirmed the successful stress manipulation and reduction of noradrenergic arousal, the extent of fear generalization remained unaffected by stress and propranolol. The absence of a stress effect on fear generalization was confirmed by a second study and a Bayesian analysis across both data sets. Our findings suggest that acute stress leaves fear generalization processes intact, at least in a sample of healthy, young individuals.

Noradrenergic stimulation increases fear memory expression.

Fear responses are typically not limited to the actual threatening stimulus but generalize to other stimuli resembling the threatening stimulus. Although this fear generalization is generally adaptive, fear overgeneralization is maladaptive and assumed to contribute to anxiety disorders. Despite the clinical relevance of fear (over)generalization, how the extent of fear generalization is modulated remains not well understood. Based on the known effects of stress on learning and memory, we tested here the impact of major stress mediators, glucocorticoids and noradrenergic arousal, on fear generalization. In a laboratory-based, placebo-controlled, double-blind, between-subject design, 125 healthy participants first underwent a fear conditioning procedure. About 24 h later, participants received orally either a placebo, hydrocortisone, the α2-adrenoceptor antagonist yohimbine, leading to increased noradrenergic stimulation, or both drugs before a test of fear generalization. Skin conductance responses as well as explicit rating data revealed that yohimbine intake led to enhanced fear memory expression, i.e. an enhanced responding to the CS+ but not to stimuli resembling the CS+. Moreover, neither enhanced safety learning nor a mere enhancement of perceptual discrimination ability could explain this result. In contrast to yohimbine, hydrocortisone had no significant effect on fear memory. These findings suggest that noradrenergic arousal strengthens fear memory expression and have important implications for mental disorders in which the overgeneralization of conditioned fear is prominent.

Stress-induced modulation of multiple memory systems during retrieval requires noradrenergic arousal.

Stress has been shown to favor dorsal striatum-dependent 'habit' memory over hippocampus-dependent 'cognitive' memory during learning. Here, we investigated whether stress may modulate the engagement of these 'cognitive' and 'habit' systems also during memory retrieval and if so, whether such a stress-induced shift in the control of memory retrieval depends on noradrenergic activation. To this end, participants acquired a probabilistic classification learning (PCL) task that can be solved by both the 'cognitive' and the 'habit' system, reflected in the distinct behavioral strategies. Twenty-four hours later, participants received either the beta-adrenergic receptor antagonist propranolol or a placebo before they underwent a psychosocial stressor or a non-stressful control manipulation, followed by a retrieval version of the PCL task. Overall, participants showed a practice-dependent shift from 'cognitive' to 'habit' memory. Stressed participants that had received a placebo fell back to a 'cognitive' strategy during retrieval, which was linked to an impairment in retrieval performance. Propranolol blocked this stress-induced shift towards the less efficient strategy. Moreover, our results showed that salivary cortisol was related to the retrieval strategy only when paralleled by increased autonomic arousal. Together, these results indicate that stress effects on the modulation of multiple memory system during retrieval necessitate noradrenergic arousal, with relevant implications for retrieval performance under stress.

(Lack of) Effects of noradrenergic stimulation on human working memory performance.

RATIONALE: Working memory depends on prefrontal cortex functioning, which is particularly sensitive to levels of noradrenaline. Studies in non-human primates have shown that modest levels of noradrenaline improve working memory, and that higher levels of noradrenaline impair working memory performance. However, research in humans provided inconsistent findings concerning noradrenergic effects on working memory. OBJECTIVE: The present study aimed at assessing dose-dependent effects of yohimbine, an alpha-2 adrenoceptor antagonist, on working memory performance in healthy humans. We further aimed to explore a potential interactive effect between noradrenergic arousal and lack of control over aversive events on working memory performance. METHODS: We used a double-blind, fully crossed, placebo-controlled, between-subject design. Participants (N = 121) performed an adaptive n-back task before and after oral administration of either a placebo, 20 mg, or 40 mg yohimbine and a manipulation of controllability, during which participants could either learn to avoid electric shocks (controllability groups), had no instrumental control over shock administration (uncontrollability groups), or did not receive any shocks (no-shock control group). RESULTS: While no significant results of noradrenergic stimulation through yohimbine were obtained using conventional frequentist analyses, additional Bayesian analyses provided strong evidence for the absence of an association between pharmacological treatment and working memory performance. We further observed no effect of controllability and no interaction between noradrenergic stimulation and the manipulation of controllability. CONCLUSIONS: Our results suggest that noradrenergic stimulation through yohimbine does not affect (non-spatial) working memory in healthy human participants.

Glucocorticoids, Noradrenergic Arousal, and the Control of Memory Retrieval.

Glucocorticoids and noradrenaline can enhance memory consolidation but impair memory retrieval. Beyond their effects on quantitative memory performance, these major stress mediators bias the engagement of multiple memory systems toward "habitual" control during learning. However, if and how glucocorticoids and noradrenaline may also affect which memory system is recruited during recall, thereby affecting the control of retrieval, remain largely unknown. To address these questions, we trained healthy participants in a probabilistic classification learning task, which can be supported both by cognitive and habitual strategies. Approximately 24 hr later, participants received a placebo, hydrocortisone, yohimbine (an α2-adrenoceptor antagonist increasing noradrenergic stimulation), or both drugs before they completed a recall test for the probabilistic classification learning task. During training, all groups showed a practice-dependent shift toward more habitual strategies, reflecting an "automatization" of behavior. In the recall test, after a night of sleep, this automatization was even more pronounced in the placebo group, most likely due to offline consolidation processes and with beneficial effects on recall performance. Hydrocortisone or yohimbine intake abolished this further automatization, preventing the shift to a more efficient memory system and leading, in particular in the hydrocortisone group, to impaired recall performance. Our results suggest that glucocorticoids and noradrenergic stimulation may modulate the engagement of different strategies at recall and link the well-known stress hormone-induced retrieval deficit to a change in the system controlling memory retrieval.

Factors Influencing Staff's Attitude Toward Electroconvulsive Therapy: A Comparison of New Versus Experienced Electroconvulsive Therapy Clinics.

OBJECTIVES: Despite being a highly effective treatment, electroconvulsive therapy (ECT) is still stigmatized even among professionals. The aim of this study was to identify factors associated with a positive attitude toward ECT among health care workers. METHODS: We investigated staff's attitude and their self-assessment of knowledge while introducing ECT in 3 German psychiatric clinics. Furthermore, we compared this data to that of a clinic where ECT has been applied with a long tradition. An anonymous questionnaire was answered by n = 182 employees in the ECT-introducing clinics (novices) and n = 68 employees in the clinic with a long history of ECT (experts). RESULTS: Irrespective of the clinical history, the majority of participants approved the application of ECT in their clinic. Factors associated with a positive attitude were (a) profession (physicians presented a more positive mindset about ECT than nursing staff), (b) subjective feeling of being adequately informed, and (c) having had contact to patients undergoing ECT. Interestingly, the general attitude toward ECT did not differ between subjects who reported to have seen an ECT and those who had not. CONCLUSIONS: When introducing ECT as a new treatment into a clinic, formal information should be adapted to the needs of each profession with a special emphasis on nurses. To further increase acceptance, contact to ECT-experienced patients (professionals taught by patients) might result in a more positive attitude toward ECT than participation in an ECT treatment itself.

Cardiac arrhythmia induced by genetic silencing of 'funny' (f) channels is rescued by GIRK4 inactivation.

The mechanisms underlying cardiac automaticity are still incompletely understood and controversial. Here we report the complete conditional and time-controlled silencing of the 'funny' current (If) by expression of a dominant-negative, non-conductive HCN4-channel subunit (hHCN4-AYA). Heart-specific If silencing caused altered [Ca(2+)]i release and Ca(2+) handling in the sinoatrial node, impaired pacemaker activity and symptoms reminiscent of severe human disease of pacemaking. The effects of If silencing critically depended on the activity of the autonomic nervous system. We were able to rescue the failure of impulse generation and conduction by additional genetic deletion of cardiac muscarinic G-protein-activated (GIRK4) channels in If-deficient mice without impairing heartbeat regulation. Our study establishes the role of f-channels in cardiac automaticity and indicates that arrhythmia related to HCN loss-of-function may be managed by pharmacological or genetic inhibition of GIRK4 channels, thus offering a new therapeutic strategy for the treatment of heart rhythm diseases.

The G-protein-gated K+ channel, IKACh, is required for regulation of pacemaker activity and recovery of resting heart rate after sympathetic stimulation.

Parasympathetic regulation of sinoatrial node (SAN) pacemaker activity modulates multiple ion channels to temper heart rate. The functional role of the G-protein-activated K(+) current (IKACh) in the control of SAN pacemaking and heart rate is not completely understood. We have investigated the functional consequences of loss of IKACh in cholinergic regulation of pacemaker activity of SAN cells and in heart rate control under physiological situations mimicking the fight or flight response. We used knockout mice with loss of function of the Girk4 (Kir3.4) gene (Girk4(-/-) mice), which codes for an integral subunit of the cardiac IKACh channel. SAN pacemaker cells from Girk4(-/-) mice completely lacked IKACh. Loss of IKACh strongly reduced cholinergic regulation of pacemaker activity of SAN cells and isolated intact hearts. Telemetric recordings of electrocardiograms of freely moving mice showed that heart rate measured over a 24-h recording period was moderately increased (10%) in Girk4(-/-) animals. Although the relative extent of heart rate regulation of Girk4(-/-) mice was similar to that of wild-type animals, recovery of resting heart rate after stress, physical exercise, or pharmacological ß-adrenergic stimulation of SAN pacemaking was significantly delayed in Girk4(-/-) animals. We conclude that IKACh plays a critical role in the kinetics of heart rate recovery to resting levels after sympathetic stimulation or after direct ß-adrenergic stimulation of pacemaker activity. Our study thus uncovers a novel role for IKACh in SAN physiology and heart rate regulation.

Localization of Islet-1-positive cells in the healthy and infarcted adult murine heart.

RATIONALE: The transcription factor Islet-1 is a marker of cardiovascular progenitors during embryogenesis. The isolation of Islet-1-positive (Islet-1(+)) cells from early postnatal hearts suggested that Islet-1 also marks cardiac progenitors in adult life. OBJECTIVE: We investigated the distribution and identity of Islet-1(+) cells in adult murine heart and evaluated whether their number or distribution change with age or after myocardial infarction. METHODS AND RESULTS: Distribution of Islet-1(+) cells in adult heart was investigated using gene targeted mice with nuclear ß-galactosidase inserted into the Islet-1 locus. nLacZ-positive cells were only present in 3 regions of the adult heart: clusters in the interatrial septum and around the pulmonary veins, scattered within the wall of the great vessels, and a strictly delimited cluster between the right atrium and superior vena cava. Islet-1(+) cells in the first type of clusters coexpressed markers for parasympathetic neurons. Positive cells in the great arteries coexpressed smooth muscle actin and myosin heavy chain, indicating a smooth muscle cell identity. Very few Islet-1(+) cells within the outflow tract expressed the cardiomyocyte marker α-actinin. Islet-1(+) cells in the right atrium coexpressed the sinoatrial node pacemaker cell marker HCN4. Cell number and localization remained unchanged between 1 to 18 months of age. Consistently Islet-1 mRNA was detected in human sinoatrial node. Islet-1(+) cells could not be detected in the infarct zone 2 to 28 days after myocardial infarction, aside from 10 questionable cells in 1/13 hearts. CONCLUSIONS: Our results identify Islet-1 as a novel marker of the adult sinoatrial node and do not provide evidence for Islet-1(+) cells to serve as cardiac progenitors.