Aggressive intentions after social exclusion and their association with loneliness.

Both social exclusion and loneliness are aversive experiences that can lead to hostile behavioral reactions, including aggressive behavior. This study aimed to assess whether a social exclusion scenario in the subject's imagination elicits aggressive reactions towards an excluding person as measured with the hot sauce paradigm. Furthermore, we studied the effect of loneliness on such reactions. In total, 251 subjects (67.7% female; mean age 27.3 ± 9.3 years) participated in this study which was based on an online survey. After trait loneliness was assessed with the UCLA Loneliness scale at baseline, two imaginary scenarios were presented in randomized order, i.e., an exclusion condition (with one of two working colleagues excluding the participant from a social activity) and an inclusion condition (without exclusion). Following each scenario, participants had the task to allocate the amount of hot sauce to each colleague that they find appropriate. Participants distributed significantly more hot sauce to the excluder than to the includers. The amount of hot sauce was significantly correlated with loneliness for all includer interactions (i.e., after the inclusion as well as the exclusion scenario), but not for the interaction with the excluder. Our results support the hypothesis that social exclusion elicits aggressive behavior. Interestingly, the experience of loneliness seems to be associated with an increase in aggressive behavioral tendencies or a lack of their inhibition. The cognitive and/or emotional processes underlying the interplay between social exclusion, loneliness and aggression should be a focus of future research.

[A review of the update of the German S3-guideline on diagnostics and therapy of bipolar disorders 2019]. / Überblick über Neuerungen der überarbeiteten und aktualisierten Leitlinie zur Diagnostik und Therapie bipolarer Störungen 2019.

Since the first publication of the guideline in 2012, which included critically reviewed evidence up to 2010, several hundred articles with new evidence were published and some topics of the clinical consensus needed to be reconsidered. Therefore, it was urgently necessary to revise the guideline to bring them up to date. In this article important revisions and updates are presented and the chances and limitations of the development of the guidelines and their implementation are discussed.

Minor structural modifications of bisphenol A strongly affect physiological responses of HepG2 cells.

Bisphenols represent a large group of structurally similar compounds. In contrast to bisphenol A (BPA) and bisphenol S (BPS), however, toxicological data are usually scarce, thus making bisphenols an ideal candidate for read-across assessments. BPA, bisphenol C (BPC) and a newly synthesized bisphenol A/C (BPA/C) differ only by one methyl group attached to the phenolic ring. Their EC50 values for cytotoxicity and logPOW values are comparable. However, the estrogenic activities of these bisphenols are not comparable and among this group only BPC leads to a decrease of the mitochondrial membrane potential and ATP concentration in HepG2 cells. Conversely, the cell division rate was decreased by BPS, BPA, BPC and BPA/C at 10% toxicity (EC10). At lower concentrations, only BPC significantly affected proliferation. The pro-inflammatory cytokines TGFB1 and TNF were significantly upregulated by BPC only, while SPP1 was upregulated by BPA, BPA/C and BPS. BPC led to the release of cytochrome c from mitochondria, indicating that this compound is capable of inducing apoptosis. In conclusion, the read-across approach revealed non-applicable in the case of the various structurally and physicochemically comparable bisphenols tested in this study, as the presence of one or two additional methyl group(s) attached at the phenol ring profoundly affected cellular physiology.

[The German research network for mental disorders]. / Das deutsche Forschungsnetz zu psychischen Erkrankungen.

Mental disorders are among the greatest medical and social challenges facing us. They can occur at all stages of life and are among the most important commonly occurring diseases. In Germany 28 % of the population suffer from a mental disorder every year, while the lifetime risk of suffering from a mental disorder is almost 50 %. Mental disorders cause great suffering for those affected and their social network. Quantitatively speaking, they can be considered to be among those diseases creating the greatest burden for society due to reduced productivity, absence from work and premature retirement. The Federal Ministry of Education and Research is funding a new research network from 2015 to 2019 with up to 35 million euros to investigate mental disorders in order to devise and develop better therapeutic measures and strategies for this population by means of basic and translational clinical research. This is the result of a competitive call for research proposals entitled research network for mental diseases. It is a nationwide network of nine consortia with up to ten psychiatric and clinical psychology partner institutions from largely university-based research facilities for adults and/or children and adolescents. Furthermore, three cross-consortia platform projects will seek to identify shared causes of diseases and new diagnostic modalities for anxiety disorders, attention deficit hyperactivity disorders (ADHS), autism, bipolar disorders, depression, schizophrenia and psychotic disorders as well as substance-related and addictive disorders. The spectrum of therapeutic approaches to be examined ranges from innovative pharmacological and psychotherapeutic treatment to novel brain stimulation procedures. In light of the enormous burden such diseases represent for society as a whole, a sustainable improvement in the financial support for those researching mental disorders seems essential. This network aims to become a nucleus for long overdue and sustained support for a German center for mental disorders.

[Transcranial direct current stimulation (tDCS) for depression: Results of nearly a decade of clinical research]. / La stimulation transcrânienne à courant continu (tDCS) dans la dépression : bilan de près d'une décennie de recherche clinique.

OBJECTIVE: Since 2006 transcranial direct current stimulation (tDCS) has been investigated in the treatment of depression. In this review, we discuss the implications and clinical perspectives that tDCS may have as a therapeutic tool in depression from the results reported in this domain. METHODS: A comprehensive literature review has found nearly thirty articles - all in English - on this topic, corresponding to clinical studies, placebo-controlled or not, case reports and reviews. RESULTS: Several meta-analyses showed that the antidepressant effects of active tDCS are significant against placebo, but variable, mainly due to the heterogeneity of the patients included in the studies, for example regarding the resistance to antidepressant treatment. CONCLUSIONS: Specific recommendations for the use of tDCS in treating depression may not yet be available, but some elements of good practice can be highlighted. Of particular note is that anodal tDCS of the left prefrontal cortex at 2mA for 20 minutes per day has a potential therapeutic value without risk of significant side effects: tDCS offers safe conditions for clinical use in the treatment of depression.

[Transcranial direct current stimulation for depressive disorders]. / Transkranielle Gleichstromstimulation bei depressiven Störungen.

Major depressive disorders are one of the most prevalent psychiatric disorders worldwide but approximately 20-30 % of patients do not respond to standard guideline conform treatment. Recent neuroimaging studies in depressive patients revealed altered activation patterns in prefrontal brain areas and that successful cognitive behavioral therapy and psychopharmacological interventions are associated with a reversal of these neural alterations. Therefore, a direct modulation of prefrontal brain activation by non-invasive brain stimulation techniques, such as transcranial direct current stimulation (tDCS) seems to be a promising and innovative approach for the treatment of depressive disorders. In addition, recent neuropsychological findings indicated an augmentation of positive tDCS effects by simultaneous external activation of the stimulated brain area, for example by cognitive training tasks. Based on these findings, the possibility to augment cognitive-emotional learning processes during cognitive behavioral therapy by simultaneous tDCS to increase antidepressive therapeutic effects is discussed in this article.

[Non-invasive brain stimulation for treatment of schizophrenic psychoses]. / Hirnstimulationsverfahren zur Behandlung schizophrener Psychosen.

Despite many different available pharmacological and psychosocial treatment options, an optimal control of symptoms is only partly possible for most schizophrenia patients. Especially, persistent auditory hallucinations, negative symptoms and cognitive impairment are difficult to treat symptoms. Several non-invasive brain stimulation techniques are increasingly being considered as new therapeutic add on options for the management of schizophrenia, targeting these symptom domains. The technique which has been available for the longest time and that is best established in clinical care is electroconvulsive therapy (ECT). New stimulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) allow a more pathophysiological-based approach. This review article introduces various non-invasive brain stimulation techniques and discusses recent treatment studies on schizophrenia. In total, the novel brain stimulation techniques discussed here can be considered relevant add on therapeutic approaches for schizophrenia. In this context, the best evidence is available for the application of rTMS for the treatment of negative symptoms and persistent auditory hallucinations; however, negative studies have also been published for both indications. Studies using other non-invasive brain stimulation techniques showed promising results but further research is needed to establish the clinical efficacy. Based on a growing pathophysiological knowledge, non-invasive brain stimulation techniques provide new treatment perspectives for patients with schizophrenia.

Transcranial Direct Current Stimulation (tDCS) in a Patient with PRES and Bipolar Depression.

Transcranial direct current stimulation (tDCS) is a non-invasive tool for brain stimulation and has proven efficacy in depressive disorders. Here, we report the case of a patient with recurrent bipolar depressive disorder and neurologic complications due to posterior reversible encephalopathy syndrome (PRES) due to parathyroid adenoma. During a long-term hospital stay, multiple drug regimens did not resolve depressive symptoms. Finally, an add-on therapy with tDCS brought improvement of symptoms. This case highlights the feasibility of tDCS in treatment-resistant depression and concomitant neurologic disorder.

[Transcranial and invasive brain stimulation for depression]. / Transkranielle und invasive Hirnstimulationsverfahren bei Depression.

Considering the substantial proportion of depressed patients which does not sufficiently benefit from antidepressant pharmacotherapy or psychotherapy, there is increasing interest in non-pharmacological antidepressant strategies. Thus, a whole array of stimulation approaches has been developed as potential new antidepressant interventions. These methods include transcranial convulsive and non-convulsive approaches, e.g. electroconvulsive therapy (ECT), magnetic seizure therapy (MST), transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) as well as invasive techniques, e.g. deep brain stimulation (DBS), vagus nerve stimulation (VNS) and epidural cortical stimulation (ECS). Each method represents a specific therapeutic approach with distinct targets within neural networks involved in the pathophysiology of depression. The ECT procedure is an established treatment with the highest efficacy of all antidepressant interventions and TMS reaches the highest level of evidence among the novel neurostimulation approaches and may be clinically used. However, the field yields a promising rapid development which may substantially enrich the armamentarium of antidepressant interventions in the near future.

[S3 guidelines on diagnostics and therapy of bipolar disorders: development process and essential recommendations]. / S3-Leitlinie zur Diagnostik und Therapie bipolarer Störungen: Entwicklungsprozess und wesentliche Empfehlungen.

Bipolar disorders are severe psychiatric disorders with extensive individual and health economic consequences. Starting in 2007 the first German evidence and consensus based guideline for diagnostics and treatment of bipolar disorders was developed which holds the potential of increasing confidence of therapists, patients and relatives in the decision-making process and improving healthcare service experiences of patients and relatives. Apart from recommendations for diagnostics and treatment the guidelines provide those for trialogue action, knowledge transfer and self-help and for strategies for healthcare provision of this complex disorder. In the present article the methodology and essential recommendations are outlined and complemented in specific topics by corresponding articles in this special issue. Due to restrictions of the length of this presentation there is the need to refer to the comprehensive version of the guidelines at several points also regarding a detailed discussion of the limitations.

Attachment mediates the link between childhood maltreatment and loneliness in persistent depressive disorder.

BACKGROUND: A central concept of attachment theory is that early experiences with close attachment figures shape the way we interact with and relate to other social partners throughout life. As such, early experiences of childhood maltreatment (CM) have been suggested as a key precursor of adult insecure attachment representations. As CM has been linked to feelings of loneliness in adulthood, this study examines whether insecure attachment could explain the relationship between CM and loneliness. Also, the moderating role of a diagnosis of persistent depressive disorder (PDD) is investigated, a disorder characterized by high levels of CM and loneliness. METHOD: 60 patients with PDD (DSM-5) and 60 gender- and age-matched non-clinical control participants (NC) completed self-report questionnaires measuring attachment, loneliness, and CM. Mediation analyses (PDD as a moderator) were performed. RESULTS: PDD patients reported higher levels of CM, attachment anxiety, attachment avoidance, and loneliness than NC. CM was positively associated with loneliness in both groups. Mediation analyses demonstrated that the relationship between CM and loneliness was mediated by avoidant, but not anxious attachment, regardless of a diagnosis of PDD. LIMITATIONS: Caution when interpreting these results is crucial as the study lacked a clinical control group, relied on self-report measures, and the cross-sectional design limits the ability to draw causal inferences. CONCLUSIONS: All constructs studied were present to a greater degree in PDD. Above, findings provide initial evidence that avoidant attachment may explain the relationship between CM and loneliness. Potentially, adult avoidant attachment may lead to and maintain feelings of loneliness, regardless of PDD.

Prefrontal direct current stimulation modulates resting EEG and event-related potentials in healthy subjects: a standardized low resolution tomography (sLORETA) study.

Prefrontal transcranial direct current stimulation (tDCS) with the anode placed on the left dorsolateral prefrontal cortex (DLPFC) has been reported to enhance working memory in healthy subjects and to improve mood in major depression. However, its putative antidepressant, cognitive and behavior action is not well understood. Here, we evaluated the distribution of neuronal electrical activity changes after anodal tDCS of the left DLPFC and cathodal tDCS of the right supraorbital region using spectral power analysis and standardized low resolution tomography (sLORETA). Ten healthy subjects underwent real and sham tDCS on separate days in a double-blind, placebo-controlled cross-over trial. Anodal tDCS was applied for 20 min at 2 mA intensity over the left DLPFC, while the cathode was positioned over the contralateral supraorbital region. After tDCS, EEG was recorded during an eyes-closed resting state followed by a working memory (n-back) task. Statistical non-parametric mapping showed reduced left frontal delta activity in the real tDCS condition. Specifically, a significant reduction of mean current densities (sLORETA) for the delta band was detected in the left subgenual PFC, the anterior cingulate and in the left medial frontal gyrus. Moreover, the effect was strongest for the first 5 min (p<0.01). The following n-back task revealed a positive impact of prefrontal tDCS on error rate, accuracy and reaction time. This was accompanied by increased P2- and P3- event-related potentials (ERP) component-amplitudes for the 2-back condition at the electrode Fz. A source localization using sLORETA for the time window 250-450 ms showed enhanced activity in the left parahippocampal gyrus for the 2-back condition. These results suggest that anodal tDCS of the left DLPFC and/or cathodal tDCS of the contralateral supraorbital region may modulate regional electrical activity in the prefrontal and anterior cingulate cortex in addition to improving working memory performance.

Changes in gustatory perceptions of patients with major depression treated with vagus nerve stimulation (VNS).

BACKGROUND: Olfactory and gustatory functions were investigated before and during vagus nerve stimulation (VNS) in a group of 9 patients with therapy-resistant depression, implanted with a VNS system. METHODS: Gustation and olfaction were tested using standard sniffing tests. Subjects participated in 2 sessions with the vagal stimulator switched on and off, respectively. RESULTS: Under conditions of stimulation of the VNS, there were statistically significant differences of the threshold of perception, with an intensification of the taste "sweet" (Z = -2.0; p = 0.048) and "bitter" (Z = - 2.5; p = 0.011) compared to the "off-mode". A statistical trend (Z = - 1.7; p=0.098) for increased intensity of the taste "salty" was observed, however, these results would supposedly disappear after correction for multiple testing presumably due to the large number of variables and the small sample size. There were no statistically relevant differences concerning olfactory perception. CONCLUSIONS: The changes of gustatory perception under conditions of vagal nerve stimulation observed in this study show another important central nervous effect of vagal stimulation on the limbic system that might be of importance in the elucidation of mechanisms of action of VNS especially on refractory depression.

Dynamics of the immediate behavioral response to partial social exclusion.

Social rejection and exclusion (ostracism) represent main stressors in daily life and even threaten mental and physical health. Abundant data from subjective measures in social exclusion paradigms are available, but the dynamic behavioral response is largely unexplored. Here, we applied modified variants of the Cyberball paradigm in two consecutive experiments to investigate the adaptive behavioral and emotional reactions to partial social exclusion. In experiment 1, 68 healthy participants (females, mean age 24.76 ± 4.05 years) played 2 min inclusion, 5 min partial exclusion and 2 min total exclusion. In experiment 2, 94 healthy participants (48 females, mean age 34.50 ± 12.08 years) underwent an experimental condition (2 min inclusion, 10 min partial exclusion) and a control condition (12 min inclusion only) in randomized order. In experiment 1, behavioral responses to partial exclusion showed two characteristics: (1) an immediate increase in ball passes to the excluding player followed (2) by a later return of participants' behavior to baseline. This finding was replicated for both genders and in comparison to a control condition in experiment 2. The dynamic behavioral response observed here may point to overlapping principles of cooperation in this ball tossing paradigm and serves as a novel experimental proxy.

Transcranial Direct Current Stimulation (tDCS) for major depression - Interim analysis of cloud supervised technical data from the DepressionDC trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) of prefrontal cortex regions has been reported to exert antidepressant effects, though large scale multicenter trials in major depressive disorder (MDD) supporting this notion are still lacking. Application of tDCS in multicenter settings, however, requires measurement, storage and evaluation of technical parameters of tDCS sessions not only for safety reasons but also for quality control. To address this issue, we conducted an interim analysis of supervised technical data across study centers in order to monitor technical quality of tDCS in an ongoing multicenter RCT in MDD (DepressionDC trial). METHODS: Technical data of 818 active tDCS sessions were recorded, stored in a data cloud, and analysed without violating study blinding. Impedance, voltage and current were monitored continuously with one data point recorded every second of stimulation. RESULTS: Variability of impedance was considerable (1,42 kΩ, to 8,23 kΩ), inter-individually and even more intra-individually, but did not significantly differ between the study centre in Munich and all other sites. CONCLUSION: Measurement, centralized data storage via data cloud and remote supervision of technical parameters of tDCS are feasible and proposed for future RCTs on therapeutic tDCS in multiple settings.

A beta-adrenergic antagonist reduces traumatic memories and PTSD symptoms in female but not in male patients after cardiac surgery.

BACKGROUND: Epinephrine enhances emotional memory whereas beta-adrenoceptor antagonists (beta-blockers, BBs) impair it. However, the effects of BB administration on memory are sex dependent. Therefore, we predicted differential effects of epinephrine and the BB metoprolol given to male and female patients after cardiac surgery (CS) on traumatic memories and post-traumatic stress disorder (PTSD) symptoms. METHOD: We performed a prospective observational study and determined the number of standardized traumatic memories (NTRM) and PTSD symptom intensity in cardiac surgical patients at 1 day before surgery, and at 1 week and 6 months after the procedure. PTSD symptoms and NTRM were quantified using validated questionnaires. Metoprolol could be administered any time post-operatively. RESULTS: Baseline NTRM was not significantly different between male (n=95) and female patients (n=33). One week after CS, the NTRM in male patients was significantly higher. Metoprolol had no significant effect in either sex. At 6 months, females with metoprolol (n=18) showed a significantly lower NTRM and significantly lower PTSD symptom scores than females without BBs (n=15, p=0.02). By contrast, the totally administered dosage of epinephrine correlated with NTRM in males (r=0.33, p<0.01) but not in females (r=0.21, p=0.29). CONCLUSIONS: beta-Adrenergic stimulation with epinephrine enhances memory for adverse experiences in males but not in females whereas beta-blockade selectively reduces memory for post-operative adverse events and PTSD symptoms in females.

Cardiac effects of vagus nerve stimulation in patients with major depression.

INTRODUCTION: Changes in the heart rate variability are well known among patients with depression. Amongst others, a modulation of the autonomic nervous system is discussed. An investigation of heart rate variability during terms of stimulation could give some insight in the central nervous effect of vagus nerve stimulation (VNS) and possible cardiac side effects. METHODS: The effects of VNS on heart rate (HR) and heart rate variability were studied (HRV) during stimulation in nine patients with major depression according to ICD-10. RESULTS: When comparing treated depressive patients with a sex- and age-matched healthy control group, the analysis of heart rate revealed significantly (t=2.8; df=16, p=0.012) elevated heart rates during completely switched off conditions, during switched on VNS programme in stimulation-free intervals (5 min period) (t=3.0; p=0.009) and during stimulation conditions (30 s) (t=2.8, Levene corrected, p=0.015). The RMSSD (root mean square of successive differences) as a measure of the HRV increased significantly in switched on conditions during stimulation (30 s) in six patients compared to stimulation-free intervals (t=-4.7; df=5, p=0.006) and baseline. DISCUSSION: Clinically relevant cardiac effects were not observed throughout the study. VNS induces reversible changes in heart rate variability in patients with major depression during stimulation conditions.

Anxiolytic effects of transcranial magnetic stimulation--an alternative treatment option in anxiety disorders?

In contrast to major depression, only few studies are available so far on the effects of repetitive transcranial magnetic stimulation (rTMS) in anxiety disorders. In order to summarise available data concerning the putative anxiolytic action of repetitive rTMS, a systematic literature review was carried out. Although interpretation of the results is difficult because of a large variety of used treatment protocols and the lack of a placebo-controlled design in the majority of studies, there is evidence for anxiolytic action of rTMS both from preclinical trials and studies in humans. Based on the idea of interhemispheric imbalance and/or deficits in cortico-limbic control as a model for human anxiety, inhibitory rTMS of the prefrontal cortex has been shown to exert beneficial effects in a number of studies in healthy subjects, patients with PTSD and panic disorder. However, to further elucidate the putative anxiolytic action of rTMS in patients with anxiety disorders future studies have to be conducted addressing in particular the limitations of the studies mentioned above.