Diagnosis of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: data from a practice-based longitudinal cohort.

BACKGROUND: A large prospective multicenter cohort study with systematic follow-up recently reported a 2.3% 2-year cumulative incidence of chronic thromboembolic pulmonary hypertension (CTEPH) after acute pulmonary embolism (PE). OBJECTIVES: The present investigation aimed to determine the reported prevalence and incidence of CTEPH diagnosis after acute PE in real-world practice over a 12-year period. METHODS: This study was based on nationwide ambulatory billing claims and drug prescription data of all residents with public health insurance in Germany from 2010 to 2021. RESULTS: A total of 573 972 patients with acute PE (median age, 71 years; 57.4% women) were identified between 2010 and 2021. Prevalence of CTEPH among patients with history of PE increased during the period from 0.4% in 2010 to 0.9% in 2021. CTEPH was diagnosed in 2556 patients after acute PE, with most (17.6%) diagnoses reported within the first 3 months after the index PE event. The cumulative incidence rate after 3 months (first quarter) was calculated at 0.08% and after the first 2 years (eighth quarter) at 0.36%; it was 0.75% over the entire (90-month) follow-up period. Patients with CTEPH diagnosis during follow-up more often had right ventricular dysfunction at the index acute PE (14.9% vs 8.3%; P < .001). CONCLUSION: The low CTEPH incidence rate after acute PE in the present analysis suggests low awareness of CTEPH. It further suggests a lack of systematic follow-up protocols for acute PE survivors in the real world. Improved implementation of existing recommendations on follow-up strategies after PE is warranted.

Trends in antipsychotic use among children and adolescents in Germany: a study using 2011-2020 nationwide outpatient claims data.

Introduction: We aimed to provide an update on trends in antipsychotic (AP) use among children and adolescents in Germany. Materials and methods: Based on nationwide outpatient claims data from Germany, we conducted a cross-sectional study. For each year from 2011 to 2020, we determined the prevalence of AP use, defined as the proportion of children and adolescents with at least one AP dispensation. We evaluated trends in AP use by age, sex, and AP class (typical vs. atypical). Additionally, we assessed trends in the specialty of AP prescribers and the frequency of psychiatric diagnoses among AP users. Results: Overall, data from more than 12 million children and adolescents were included for each calendar year (2011: 12,488,827; 2020: 13,330,836). From 2011 to 2020, the overall prevalence of pediatric AP use increased from 3.16 to 3.65 per 1,000, due to an increase in use of both typical APs (from 1.16 to 1.35 per 1,000) and atypical APs (from 2.35 to 2.75 per 1,000). The largest increase in AP use was found among 15- to 19-year-old females, with an increase from 3.88 per 1,000 in 2011 to 7.86 per 1,000 in 2020 (+103%), mainly due to rising quetiapine use (from 1.17 to 3.46 per 1,000). Regarding prescribers' specialty, the proportion of APs prescribed by child and adolescent psychiatrists increased during the studied period (2011: 24.8%; 2020: 36.4%), whereas prescriptions by pediatricians (2011: 26.0%; 2020: 19.9%) and general practitioners (2011: 18.0%; 2020: 12.4%) decreased. Risperidone was the most commonly used AP in males, and quetiapine was the leading AP in females, each with the highest prevalence in 15- to 19-year-olds. In male risperidone users in this age group, the most frequent diagnosis was attention-deficit/hyperactivity disorder (50.4%), while in female quetiapine users it was depression (82.0%). Discussion: Use of APs among children and adolescents in Germany has continued to increase over the last decade. The sharp increase in AP use among 15- to 19-year-old females, which is largely due to an increased use of quetiapine, is remarkable. Potential reasons for this increase-e.g., limited access to psychosocial treatments-should be carefully analyzed. Also, the introduction of more restrictive prescribing guidelines might be considered.

Can open label placebos improve pain and gluten tolerance via open label placebos in fibromyalgia patients? A study protocol for a randomised clinical trial in an outpatient centre.

INTRODUCTION: Fibromyalgia syndrome (FMS) is defined as a medical condition with chronic widespread musculoskeletal pain accompanied by mood disorders, fatigue and sleep disturbances. Treatment of this condition can often be challenging. As nutrition in general and nutritional interventions in the context of illness management become more and more important, current research also focuses on the relevance of diets for FMS, including gluten as field of interest. To date, there is no clear evidence that a gluten-free diet or other nutritional interventions are significantly important for the reduction of pain in the context of FMS. Only a very few studies show that FMS patients respond to a gluten-free diet and that cytokine production (also in FMS) can be reduced through the change. However, these studies have not investigated whether and to what extent cognitive factors, such as the expectation of symptom reduction triggered by diet, play a role. Recent research shows that treatment expectation plays an important role in the course of the disease and in the effectiveness of treatment approaches. For example, there are promising pain treatment options using open-label placebos (OLPs), which show that expectation alone, rather than the pharmacological substance of medication, can reduce pain experience. In our study protocol, we hypothesise that treatment expectation can be positively influenced by the given information regarding the placebos, resulting in improved treatment outcomes for pain and indigestions. METHODS AND ANALYSIS: In this trial, patients with FMS will undergo a food challenge and take an OLP (patients will be informed about the placebo), followed by a 3-week OLP treatment. The subjects will be randomised into four groups: (a) gluten-free porridge+neutral OLP instructions; (b) gluten-free porridge+positive OLP instructions; (c) gluten-containing porridge+neutral OLP instructions and (d) gluten-containing porridge+positive OLP instructions. Patients will be recruited via different institutions and support groups in Hamburg. The inclusion criteria are (a) diagnosed FMS, (b) absence of wheat allergy, coeliac disease or pain-related red flags and (c) being a minimum age of 18 years. The study requires 100 subjects to assess the primary outcomes: pain intensity and occurence of indigestion. Secondary outcomes are functional capacity, treatment expectation, and different pain-related and inflammation-related blood parameters. The measure time points will be before and after the food challenge and before and after the 3-week OLP treatment. ETHICS AND DISSEMINATION: Ethical approval was obtained in October 2021 from the Hamburg Medical Ethics Council. The results of the study will be disseminated through publications, presentations and conference meetings. TRIAL REGISTRATION NUMBER: German Clinical Trials Register (DRKS; DRKS00027130).

Selective serotonin reuptake inhibitors and suicidality in children and young adults: analyses of pharmacovigilance databases.

BACKGROUND: Since the warnings by the United States (US) and European regulatory authorities in 2004 and 2005 it had been discussed whether there is some link between selective serotonin reuptake inhibitors (SSRIs) and suicidality in the pediatric population. The aim of our study was to describe trends and patterns in spontaneous reporting data referring to suicidality in children, adolescents and young adults treated with SSRI after the warnings. METHODS: Descriptive analyses of reports for 0-24 year olds referring to suicide/suicidal ideations, self-harms and overdoses with SSRIs reported as suspected submitted to the US (FAERS) and the European (EudraVigilance) adverse drug reaction databases until 2019 were performed. The causal relationship was assessed in accordance with the WHO criteria for the European reports. For Germany, prescription data for SSRIs were provided and reporting rates (number of reports/number of prescriptions) were calculated for the reports with possible causal relationship (so called "confirmed reports"). RESULTS: Since 2004, the number of reports referring to suicide/suicidal ideations, self-harm and overdoses increased steadily in the US and EU. However, only a slight increase was seen for the confirmed EU reports. After 2008, the proportion of reports informing about suicidal ideations increased, while the proportion of fatal suicide attempts decreased. Reporting rates were higher for females and adolescents (12-18 years). CONCLUSIONS: Our results demonstrate the importance of further monitoring suicidality in 0-24 year olds treated with SSRI in order to recognize suicidality early avoiding fatal suicide attempts. The higher reporting rates for females and adolescents should be further investigated.

Dynamic computation of value signals via a common neural network in multi-attribute decision-making.

Studies in decision neuroscience have identified robust neural representations for the value of choice options. However, overall values often depend on multiple attributes, and it is not well understood how the brain evaluates different attributes and integrates them to combined values. In particular, it is not clear whether attribute values are computed in distinct attribute-specific regions or within the general valuation network known to process overall values. Here, we used a functional magnetic resonance imaging choice task in which abstract stimuli had to be evaluated based on variations of the attributes color and motion. The behavioral data showed that participants responded faster when overall values were high and attribute value differences were low. On the neural level, we did not find that attribute values were systematically represented in areas V4 and V5, even though these regions are associated with attribute-specific processing of color and motion, respectively. Instead, attribute values were associated with activity in the posterior cingulate cortex, ventral striatum and posterior inferior temporal gyrus. Furthermore, overall values were represented in dorsolateral and ventromedial prefrontal cortex, and attribute value differences in dorsomedial prefrontal cortex, which suggests that these regions play a key role for the neural integration of attribute values.

Comparing stroke prevention therapy of direct oral anticoagulants and vitamin K antagonists in patients with atrial fibrillation: a nationwide retrospective observational study.

BACKGROUND: Direct oral anticoagulants (DOACs) are not only increasingly being used for the initial stroke prevention therapy but progressively also substitute vitamin K antagonist (VKA) treatment in patients with non-valvular atrial fibrillation (AF). DOACs have been compared regarding therapeutic efficacy and adverse outcomes to warfarin in several pivotal studies and showed non-inferiority in terms of stroke prevention and superiority in terms of bleeding complications. However, comprehensive comparative studies are lacking for phenprocoumon, a VKA prescribed frequently outside the USA and the UK and accounting for 99% of all VKA prescriptions in Germany. Patients treated with phenprocoumon seem to meet more often international normalized ratio values in the therapeutic range, which may have implications concerning their efficacy and safety. This study aims at comparing the risk of stroke and bleeding in phenprocoumon- and DOAC-treated patients with AF in an adequately powered observational study population. METHODS: Retrospective analysis of stroke and bleeding incidence of 837,430 patients (1.27 million patient years) treated with DOAC or phenprocoumon for stroke prevention in German ambulatory care between 2010 and 2017. Relative risks of stroke and bleeding were estimated by calculating cox regression-derived hazard ratios (HR) and 95% confidence intervals (CI) of propensity score-matched cohorts. RESULTS: Patients treated with DOAC had an overall higher risk for stroke (HR 1.32; CI 1.29-1.35) and a lower risk for bleeding (0.89; 0.88-0.90) compared to phenprocoumon. When analyzed separately, the risk for stroke was higher for dabigatran (1.93; 1.82-2.03), apixaban (1.52; 1.46-1.58), and rivaroxaban (1.13; 1.10-1.17) but not for edoxaban (0.88; 0.74-1.05). The risk for bleeding was lower for dabigatran (0.85; 0.83-0.88), apixaban (0.71; 0.70-0.73), and edoxaban (0.29; 0.17-0.51) but not for rivaroxaban (1.03; 1.01-1.04). CONCLUSIONS: This study provides a comprehensive view of the stroke and bleeding risks associated with phenprocoumon and DOAC use in Germany. Phenprocoumon may be preferable to DOAC treatment for the prevention of strokes in AF in a real-world population cared for in ambulatory care.

Motivational effects on the processing of delayed intentions in the anterior prefrontal cortex.

Delaying intentions bears the risk of interference from distracting activities during the delay interval. Motivation can increase intention retrieval success but little is known about the underlying brain mechanisms. Here, we investigated whether motivational incentives (monetary reward) modulate the processing of delayed intentions in the anterior prefrontal cortex (aPFC), known to be crucial for intention processing. Using a mixed blocked and event-related functional Magnetic Resonance Imaging design, we specifically tested whether reward affects intention processing in the aPFC in a transient or in a sustained manner and whether this is related to individual differences in retrieval success. We found a generalized effect of reward on both correct intention retrieval and ongoing task performance. Fronto-parietal regions including bilateral lateral aPFC showed sustained activity increases in rewarded compared to non-rewarded blocks as well as transient reward-related activity during the storage phase. Additionally, individual differences in reward-related performance benefits were related to the degree of transient signal increases in right lateral aPFC, specifically during intention encoding. This suggests that the ability to integrate motivational relevance into the encoding of future intentions is crucial for successful intention retrieval in addition to general increases in processing effort. Bilateral aPFC is central to these motivation-cognition interactions.

Salience network dynamics underlying successful resistance of temptation.

Self-control and the ability to resist temptation are critical for successful completion of long-term goals. Contemporary models in cognitive neuroscience emphasize the primary role of prefrontal cognitive control networks in aligning behavior with such goals. Here, we use gaze pattern analysis and dynamic functional connectivity fMRI data to explore how individual differences in the ability to resist temptation are related to intrinsic brain dynamics of the cognitive control and salience networks. Behaviorally, individuals exhibit greater gaze distance from target location (e.g. higher distractibility) during presentation of tempting erotic images compared with neutral images. Individuals whose intrinsic dynamic functional connectivity patterns gravitate toward configurations in which salience detection systems are less strongly coupled with visual systems resist tempting distractors more effectively. The ability to resist tempting distractors was not significantly related to intrinsic dynamics of the cognitive control network. These results suggest that susceptibility to temptation is governed in part by individual differences in salience network dynamics and provide novel evidence for involvement of brain systems outside canonical cognitive control networks in contributing to individual differences in self-control.

Striatal activation as a neural link between cognitive and perceptual flexibility.

Our brain continuously evaluates different perceptual interpretations of the available sensory data in order to enable flexible updates of conscious experience. Individuals' perceptual flexibility can be assessed using ambiguous stimuli that cause our perception to continuously switch between two mutually exclusive interpretations. Neural processes underlying perceptual switching are thought to involve the visual cortex, but also non-sensory brain circuits that have been implicated in cognitive processes, such as frontal and parietal regions. Perceptual flexibility varies strongly between individuals and has been related to dopaminergic neurotransmission. Likewise, there is also considerable individual variability in tasks that require flexibility in cognition, and dopamine-dependent striato-frontal signals have been associated with processes promoting cognitive flexibility. Given the anatomical and neurochemical similarities with regard to perceptual and cognitive flexibility, we here probed whether individual differences in perceptual flexibility during bistable perception are related to individual cognitive flexibility associated neural correlates. 126 healthy individuals performed rule-based task switching during functional magnetic resonance imaging (fMRI) and reported perceptual switching during the viewing of a modified version of the Necker cube. Mean phase duration as measure of perceptual flexibility correlated with task-switching associated activity in the right putamen as part of the basal ganglia. In addition, we found a tentative correlation between perceptual and cognitive flexibility. These results indicate that individual differences in cognitive flexibility and associated fronto-striatal processing contribute to differences in perceptual flexibility. Our findings thus provide empirical support for the general notion of shared mechanisms between perception and cognition.

Decomposing Self-Control: Individual Differences in Goal Pursuit Despite Interfering Aversion, Temptation, and Distraction.

Self-control can be defined as the ability to exert control over ones impulses. Currently, most research in the area relies on self-report. Focusing on attentional control processes involved in self-control, we modified a spatial selective attentional cueing task to test three domains of self-control experimentally in one task using aversive, tempting, and neutral picture-distractors. The aims of the study were (1) to investigate individual differences in the susceptibility to aversive, tempting, and neutral distraction within one paradigm and (2) to test the association of these three self-control domains to conventional measures of self-control including self-report. The final sample consisted of 116 participants. The task required participants to identify target letters "E" or "F" presented at a cued target location while the distractors were presented. Behavioral and eyetracking data were obtained during the performance of the task. High task performance was encouraged via monetary incentives. In addition to the attentional self-control task, self-reported self-control was assessed and participants performed a color Stroop task, an unsolvable anagram task and a delay of gratification task using chocolate sweets. We found that aversion, temptation, and neutral distraction were associated with significantly increased error rates, reaction times and gaze pattern deviations. Overall task performance on our task correlated with self-reported self-control ability. Measures of aversion, temptation, and distraction showed moderate split-half reliability, but did not correlate with each other across participants. Additionally, participants who made a self-controlled decision in the delay of gratification task were less distracted by temptations in our task than participants who made an impulsive choice. Our individual differences analyses suggest that (1) the ability to endure aversion, resist temptations and ignore neutral distractions are independent of each other and (2) these three domains are related to other measures of self-control.

Individual differences in self-reported self-control predict successful emotion regulation.

Both self-control and emotion regulation enable individuals to adapt to external circumstances and social contexts, and both are assumed to rely on the overlapping neural resources. Here, we tested whether high self-reported self-control is related to successful emotion regulation on the behavioral and neural level. One hundred eight participants completed three self-control questionnaires and regulated their negative emotions during functional magnetic resonance imaging using reappraisal (distancing). Trait self-control correlated positively with successful emotion regulation both subjectively and neurally, as indicated by online ratings of negative emotions and functional connectivity strength between the amygdala and prefrontal areas, respectively. This stronger overall connectivity of the left amygdala was related to more successful subjective emotion regulation. Comparing amygdala activity over time showed that high self-controllers successfully maintained down-regulation of the left amygdala over time, while low self-controllers failed to down-regulate towards the end of the experiment. This indicates that high self-controllers are better at maintaining a motivated state supporting emotion regulation over time. Our results support assumptions concerning a close relation of self-control and emotion regulation as two domains of behavioral control. They further indicate that individual differences in functional connectivity between task-related brain areas directly relate to differences in trait self-control.

Motivation by potential gains and losses affects control processes via different mechanisms in the attentional network.

Attentional control in demanding cognitive tasks can be improved by manipulating the motivational state. Motivation to obtain gains and motivation to avoid losses both usually result in faster reaction times and stronger activation in relevant brain areas such as the prefrontal cortex, but little is known about differences in the underlying neurocognitive mechanisms of these types of motivation in an attentional control context. In the present functional magnetic resonance imaging (fMRI) study, we tested whether potential gain and loss as motivating incentives lead to overlapping or distinct neural effects in the attentional network, and whether one of these conditions is more effective than the other. A Flanker task with word stimuli as targets and distracters was performed by 115 healthy participants. Using a mixed blocked and event-related design allowed us to investigate transient and sustained motivation-related effects. Participants could either gain money (potential gain) or avoid losing money (potential loss) in different task blocks. Participants showed a congruency effect with increased reaction times for incongruent compared to congruent trials. Potential gain led to generally faster responses compared to the neutral condition and to stronger improvements than potential loss. Potential loss also led to shorter response times compared to the neutral condition, but participants improved mainly during incongruent and not during congruent trials. The event-related fMRI data revealed a main effect of congruency with increased activity in the left inferior frontal gyrus (IFG) and inferior frontal junction area (IFJ), the pre-supplementary motor area (pre-SMA), bilateral insula, intraparietal sulcus (IPS) and visual word form area (VWFA). While potential gain led to increased activity in a cluster of the IFJ and the VWFA only during incongruent trials, potential loss was linked to activity increases in these regions during incongruent and congruent trials. The block analysis revealed greater activity in gain and loss blocks compared to the neutral condition in most of these regions but no differences in the direct comparison of gain and loss blocks. These findings show that potential monetary gain and loss rely on different mechanisms: Gain was more effective in reducing the reaction time compared to potential loss. Brain data indicate that in the gain context attentional control is executed specifically in incongruent trials, whereas the loss context induces an unspecific increase of attentional control. These findings extend previous studies by providing evidence for diverging neural mechanisms for the effects of different types of motivation on attentional control, specifying the underlying activity patterns in task- and stimulus-related regions.

Dissociable effects of motivation and expectancy on conflict processing: an fMRI study.

Previous studies suggest that both motivation and task difficulty expectations activate brain regions associated with cognitive control. However, it remains an open question whether motivational and cognitive determinants of control have similar or dissociable impacts on conflict processing on a neural level. The current study tested the effects of motivation and conflict expectancy on activity in regions related to processing of the target and the distractor information. Participants performed a picture-word interference task in which we manipulated the size of performance-dependent monetary rewards (level of motivation) and the ratio of congruent to incongruent trials within a block (level of conflict expectancy). Our results suggest that motivation improves conflict processing by facilitating task-relevant stimulus processing and task difficulty expectations mainly modulate the processing of distractor information. We conclude that motivation and conflict expectancy engage dissociable control strategies during conflict resolution.

The suggestible brain: posthypnotic effects on value-based decision-making.

Hypnosis can affect perception, motor function and memory. However, so far no study using neuroimaging has investigated whether hypnosis can influence reward processing and decision-making. Here, we assessed whether posthypnotic suggestions can diminish the attractiveness of unhealthy food and whether this is more effective than diminishing attractiveness by one's own effort via autosuggestion. In total, 16 participants were hypnotized and 16 others were instructed to associate a color cue (blue or green) with disgust regarding specific snacks (sweet or salty). Afterwards, participants bid for snack items shown on an either blue or green background during functional magnetic resonance imaging measurement. Both hypnosis and autosuggestion successfully devalued snacks. This was indicated by participants' decision-making, their self-report and by decreased blood oxygen level-dependent signal in the ventromedial prefrontal cortex (vmPFC), a region known to represent value. Different vmPFC subregions coded for cue and snack type. The cue had significantly stronger effects on vmPFC after hypnosis than after autosuggestion, indicating that hypnosis was more effective in genuinely reducing value. Supporting previous findings, the precuneus was involved in the hypnotic effects by encoding whether a snack was sweet or salty during hypnotic cue presentation. Our results demonstrate that posthypnotic suggestions can influence valuation and decision-making.