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Anxiety disorders and depression are common comorbidities in cardiac patients. Mice lacking the serotonin transporter (5-HTT) exhibit increased anxiety-like behavior. However, the role of 5-HTT deficiency on cardiac aging, and on healing and remodeling processes after myocardial infarction (MI), remains unclear. Cardiological evaluation of experimentally naïve male mice revealed a mild cardiac dysfunction in ≥4-month-old 5-HTT knockout (−/−) animals. Following induction of chronic cardiac dysfunction (CCD) by MI vs. sham operation 5-HTT−/− mice with infarct sizes >30% experienced 100% mortality, while 50% of 5-HTT+/− and 37% of 5-HTT+/+ animals with large MI survived the 8-week observation period. Surviving (sham and MI < 30%) 5-HTT−/− mutants displayed reduced exploratory activity and increased anxiety-like behavior in different approach-avoidance tasks. However, CCD failed to provoke a depressive-like behavioral response in either 5-Htt genotype. Mechanistic analyses were performed on mice 3 days post-MI. Electrocardiography, histology and FACS of inflammatory cells revealed no abnormalities. However, gene expression of inflammation-related cytokines (TGF-β, TNF-α, IL-6) and MMP-2, a protein involved in the breakdown of extracellular matrix, was significantly increased in 5-HTT−/− mice after MI. This study shows that 5-HTT deficiency leads to age-dependent cardiac dysfunction and disrupted early healing after MI probably due to alterations of inflammatory processes in mice.
Safety behavior prevents the occurrence of threat, thus it is typically considered adaptive. However, safety behavior in anxiety-related disorders is often costly, and persists even the situation does not entail realistic threat. Individuals can engage in safety behavior to varying extents, however, these behaviors are typically measured dichotomously (i.e., to execute or not). To better understand the nuances of safety behavior, this study developed a dimensional measure of safety behavior that had a negative linear relationship with the admission of an aversive outcome. In two experiments, a Reward group receiving fixed or individually calibrated incentives competing with safety behavior showed reduced safety behavior than a Control group receiving no incentives. This allowed extinction learning to a previously learnt warning signal in the Reward group (i.e., updating the belief that this stimulus no longer signals threat). Despite the Reward group exhibited extinction learning, both groups showed a similar increase in fear to the warning signal once safety behavior was no longer available. This null group difference was due to some participants in the Reward group not incentivized enough to disengage from safety behavior. Dimensional assessment revealed a dissociation between low fear but substantial safety behavior to a safety signal in the Control group. This suggests that low-cost safety behavior does not accurately reflect the fear-driven processes, but also other non-fear-driven processes, such as cost (i.e., engage in safety behavior merely because it bears little to no cost). Pinpointing both processes is important for furthering the understanding of safety behavior.
Sustained anticipatory anxiety is central to Generalized Anxiety Disorder (GAD). During anticipatory anxiety, phasic threat responding appears to be mediated by the amygdala, while sustained threat responding seems related to the bed nucleus of the stria terminalis (BNST). Although sustained anticipatory anxiety in GAD patients was proposed to be associated with BNST activity alterations, firm evidence is lacking. We aimed to explore temporal characteristics of BNST and amygdala activity during threat anticipation in GAD patients. Nineteen GAD patients and nineteen healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) during a temporally unpredictable threat anticipation paradigm. We defined phasic and a systematic variation of sustained response models for blood oxygen level-dependent responses during threat anticipation, to disentangle temporally dissociable involvement of the BNST and the amygdala. GAD patients relative to HC responded with increased phasic amygdala activity to onset of threat anticipation and with elevated sustained BNST activity that was delayed relative to the onset of threat anticipation. Both the amygdala and the BNST displayed altered responses during threat anticipation in GAD patients, albeit with different time courses. The results for the BNST activation hint towards its role in sustained threat responding, and contribute to a deeper understanding of pathological sustained anticipatory anxiety in GAD.
Die vorliegende Studie untersucht den Einsatz von Kurz-Screening-Instrumenten (bestehend aus dem PHQ-4, mit seinen beiden Untereinheiten dem GAD-2 und dem PHQ-2) hinsichtlich der Tauglichkeit für einen Routineeinsatz in Hausarztpraxen. Gescreent wurde auf das mögliche Vorliegen einer Angst- und/oder depressive Störungen mit anschließender Validitätsprüfung einer kleineren Stichprobe. Hinsichtlich der Validitätsprüfung konnte zwischen den CIDI- und den Screening-Ergebnissen eine gute Übereinstimmung ermittelt werden (prozentuale Über-einstimmung von 80,8% bei einem Cohen-Kappa von 0,62). Insgesamt betrachtet lässt sich mit einem vertretbaren Mehrbedarf an Zeit für nicht-ärztliche Mitarbeiter ein PHQ-4-Screening in einer Hausarztpraxis durchführen. Durch diese Maßnahme können - bei gleichzeitiger Entlastung des Arztes - wichtige Informationen für eine Krankheitserkennung und für eine ggf. notwendige Therapie gewonnen werden. Über einen Routineeinsatz von Kurz-Screenern in der primär-ärztlichen Versorgung sollte nachgedacht werden.
A GWAS study recently demonstrated single nucleotide polymorphisms (SNPs) in the human GLRB gene of individuals with a prevalence for agoraphobia. GLRB encodes the glycine receptor (GlyRs) β subunit. The identified SNPs are localized within the gene flanking regions (3′ and 5′ UTRs) and intronic regions. It was suggested that these nucleotide polymorphisms modify GlyRs expression and phenotypic behavior in humans contributing to an anxiety phenotype as a mild form of hyperekplexia. Hyperekplexia is a human neuromotor disorder with massive startle phenotypes due to mutations in genes encoding GlyRs subunits. GLRA1 mutations have been more commonly observed than GLRB mutations. If an anxiety phenotype contributes to the hyperekplexia disease pattern has not been investigated yet. Here, we compared two mouse models harboring either a mutation in the murine Glra1 or Glrb gene with regard to anxiety and startle phenotypes. Homozygous spasmodic animals carrying a Glra1 point mutation (alanine 52 to serine) displayed abnormally enhanced startle responses. Moreover, spasmodic mice exhibited significant changes in fear-related behaviors (freezing, rearing and time spent on back) analyzed during the startle paradigm, even in a neutral context. Spastic mice exhibit reduced expression levels of the full-length GlyRs β subunit due to aberrant splicing of the Glrb gene. Heterozygous animals appear normal without an obvious behavioral phenotype and thus might reflect the human situation analyzed in the GWAS study on agoraphobia and startle. In contrast to spasmodic mice, heterozygous spastic animals revealed no startle phenotype in a neutral as well as a conditioning context. Other mechanisms such as a modulatory function of the GlyRs β subunit within glycinergic circuits in neuronal networks important for fear and fear-related behavior may exist. Possibly, in human additional changes in fear and fear-related circuits either due to gene-gene interactions e.g., with GLRA1 genes or epigenetic factors are necessary to create the agoraphobia and in particular the startle phenotype.
In the partnership between the medical departments of Würzburg University, Germany, and Nagasaki University, Japan, palliative care is a relevant topic. The aim of the study was to perform a comparative analysis of the hospital-based palliative care teams in Würzburg (PCT-W) and Nagasaki (PCT-N). Survey of staff composition and retrospective analysis of PCT patient charts in both PCTs were conducted. Patients self-assessed their symptoms in PCT-W and in Radiation Oncology Würzburg (RO-W). The (negative) quality indicator ‘percentage of deceased hospitalised patients with PCT contact for less than 3 days before death’ (Earle in Int J Qual Health Care 17(6):505–509, 2005) was analysed. Both PCTs follow a multidisciplinary team approach. PCT-N saw 410 cancer patients versus 853 patients for PCT-W (22.8% non-cancer patients). The Eastern Cooperative Oncology Group Performance Status at first contact with PCT-N was 3 or 4 in 39.3% of patients versus 79.0% for PCT-W. PCT-N was engaged in co-management longer than PCT-W (mean 20.7 days, range 1–102 versus mean 4.9 days, range 1–48). The most frequent patient-reported psychological symptom was anxiety (family anxiety: 98.3% PCT-W and 88.7% RO-W, anxiety 97.9% PCT-W and 85.9% RO-W), followed by depression (98.2% PCT-W and 80.3% RO-W). In 14 of the 148 deceased patients, PCT-N contact was initiated less than 3 days before death (9.4%) versus 121 of the 729 deceased PCT-W patients (16.6%). Psychological needs are highly relevant in both Germany and Japan, with more than 85% anxiety and depression in patients in the Japanese IPOS validation study (Sakurai in Jpn J Clin Oncol 49(3):257–262, 2019). This should be taken into account when implementing PCTs.
The study presented in the following verifies some assumptions of the novel ‘unsafe world’ model of selective mutism (SM). According to this model, SM is a stress reaction to situations erroneously experienced via cognition without awareness as ‘unsafe’. It assumes a high sensitivity to unsafety, whereby the nervous system triggers dissociation or freeze mode at relatively low thresholds. We examine whether there is a correlation between SM, sensory-processing sensitivity and dissociation. We compared a sample of 28 children and adolescents with SM (mean age 12.66 years; 18 females) to 33 controls without SM (mean age 12.45 years; 21 females). Both groups were compared using a medical history sheet, the ‘Selective Mutism Questionnaire’ (SMQ), a ‘Checklist for Speaking Behaviour’ (CheckS), the ‘Highly Sensitive Person Scale’ (HSPS), the ‘Child Dissociative Checklist’ (CDC), the ‘Adolescent Dissociative Experience Scale’ (A-DES) and the ‘Social Phobia and Anxiety Inventory for Children’ (SPAIK). Appropriate parametric and non-parametric tests were conducted to examine differences between groups. The results indicate that sensory-processing sensitivity was significantly higher in the group of children and adolescents with SM [X2(1) = 7.224, p = 0.0007; d = 1.092]. Furthermore, dissociative symptoms were more common in children and adolescents with SM than in controls [F(1, 33) = 13.004, p = 0.001; d = 0.986]. The results indicate that sensory-processing sensitivity and dissociation are important factors of SM that may hold important implications for the treatment.
A variety of factors contribute to the degree to which a person feels lonely and socially isolated. These factors may be particularly relevant in contexts requiring social distancing, e.g., during the COVID-19 pandemic or in states of immunodeficiency. We present the Loneliness and Isolation during Social Distancing (LISD) Scale. Extending existing measures, the LISD scale measures both state and trait aspects of loneliness and isolation, including indicators of social connectedness and support. In addition, it reliably predicts individual differences in anxiety and depression. Data were collected online from two independent samples in a social distancing context (the COVID-19 pandemic). Factorial validation was based on exploratory factor analysis (EFA; Sample 1, N = 244) and confirmatory factor analysis (CFA; Sample 2, N = 304). Multiple regression analyses were used to assess how the LISD scale predicts state anxiety and depression. The LISD scale showed satisfactory fit in both samples. Its two state factors indicate being lonely and isolated as well as connected and supported, while its three trait factors reflect general loneliness and isolation, sociability and sense of belonging, and social closeness and support. Our results imply strong predictive power of the LISD scale for state anxiety and depression, explaining 33 and 51% of variance, respectively. Anxiety and depression scores were particularly predicted by low dispositional sociability and sense of belonging and by currently being more lonely and isolated. In turn, being lonely and isolated was related to being less connected and supported (state) as well as having lower social closeness and support in general (trait). We provide a novel scale which distinguishes between acute and general dimensions of loneliness and social isolation while also predicting mental health. The LISD scale could be a valuable and economic addition to the assessment of mental health factors impacted by social distancing.
Sustained anxiety is considered as a chronic and future-oriented state of apprehension that does not belong to a specific object. It is discussed as an important characteristic of anxiety disorders including panic disorder, generalized anxiety disorder (GAD) and posttraumatic stress disorder (PTSD). Experimentally, sustained anxiety can be induced by contextual fear conditioning in which aversive events are unpredictably presented and therefore the whole context becomes associated with the threat. This thesis aimed at investigating important mechanisms in the development and maintenance of sustained anxiety: (1) facilitated acquisition and resistant extinction of contextual anxiety due to genetic risk factors (Study 1), and (2) the return of contextual anxiety after successful extinction using a new reinstatement paradigm (Study 2). To this end, two contextual fear conditioning studies were conducted in virtual reality (VR). During acquisition one virtual office was paired with unpredictable mildly painful electric stimuli (unconditioned stimulus, US), thus becoming the anxiety context (CXT+). Another virtual office was never paired with any US, thus becoming the safety context (CXT-). Extinction was conducted 24 h later, i.e. no US was presented, and extinction recall was tested another 24 h later on Day 3. In both studies context-evoked anxiety was measured on three different response levels: behavioral (anxiety-potentiated startle reflex), physiological (skin conductance level), and verbal (explicit ratings). In Study 1, participants were stratified for 5-HTTLPR (S+ risk allele vs. LL no risk allele) and NPSR1 rs324981 (T+ risk allele vs. AA no risk allele) polymorphisms, resulting in four combined genotype groups with 20 participants each: S+/T+, S+/LL, LL/T+, and LL/AA. Results showed that acquisition of anxiety-potentiated startle was influenced by a gene × gene interaction: only carriers of both risk alleles (S+ carriers of the 5-HTTLPR and T+ carriers of the NPSR1 polymorphism) exhibited significantly higher startle magnitudes in CXT+ compared to CXT-. However, extinction recall as measured with anxiety-potentiated startle was not affected by any genotype. Interestingly, the explicit anxiety level, i.e. valence and anxiety ratings, was only influenced by the NPSR1 genotype, in a way that no risk allele carriers (AA) reported higher anxiety and more negative valence in response to CXT+ compared to CXT-, whereas risk allele carriers (T+) did not. Study 2 adopted nearly the same paradigm with the modification that one group (reinstatement group) received one unsignaled US at the beginning of the experimental session on Day 3 before seeing CXT+ and CXT-. The second group served as a control group and received no US, but was immediately exposed to CXT+ and CXT-. Results showed a return of anxiety on the implicit and explicit level (higher startle responses and anxiety ratings in response to CXT+ compared to CXT-) in the reinstatement group only. Most important, the return of contextual anxiety in the reinstatement group was associated with a change of state anxiety and mood from extinction to test, that is the more anxiety and negative mood participants experienced before the reinstatement procedure, the higher their return of anxiety was. In sum, results of Study 1 showed that facilitated contextual fear conditioning on an implicit behavioral level (startle response) could be regarded as an endophenotype for anxiety disorders, which can contribute to our understanding of the etiology of anxiety disorders. Results of Study 2 imply that anxiety and negative mood after extinction could be an important facilitator for the return of anxiety. Furthermore, the present VR-based contextual fear conditioning paradigm seems to be an ideal tool to experimentally study mechanisms underlying the acquisition and the return of anxiety. Future studies could investigate clinical samples and extend the VR paradigm to evolutionary-relevant contexts (e.g., heights, darkness, open spaces).
Bei Patienten mit einer kolorektalen Krebserkrankung zeigt sich ein deutlicher Zusammenhang zwischen Angst und Depressivität und dem psychosozialen Unterstützungsbedarf. Zwischen Angst und Depressivität und unbefriedigten Informationsbedürfnissen scheint ebenfalls ein schwacher Zusammenhang zu bestehen. Für eine mögliche Präferenz von anonymen Informationsquellen bei Patienten mit Angst oder Depressivität findet sich im Untersuchten Patientenkollektiv kein Anhaltspunkt.