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Many functional magnetic resonance imaging (fMRI) studies rely on mass-univariate inference with subsequent multiple comparison correction. Statistical results are frequently visualized as thresholded statistical maps. This approach has inherent limitations including the risk of drawing overly-selective conclusions based only on selective results passing such thresholds. This article gives an overview of both established and newly emerging approaches to supplement such conventional analyses by incorporating information about subthreshold effects with the aim to improve interpretation of findings or leverage a wider array of information. Topics covered include neuroimaging data visualization, p-value histogram analysis and the related Higher Criticism approach for detecting rare and weak effects as well as multivariate analyses and dedicated Bayesian approaches.

BACKGROUND The cure for cancer can not only have a negative impact on physical wellbeing, but also on mental health and quality of life (QoL). Health apps enable the monitoring of different parameters, but to date there are only few which support cancer patients and none that focus on QoL. Furthermore, patients as stakeholders are often only integrated at late stage of the development process, if at all. OBJECTIVE The aim of this research was to develop and evaluate a smartphone app (Lion-App) to enable cancer patients to autonomously measure QoL with an iterative, user-centered approach. The goal was to closely integrate end users into every stage of the development process, in order to be able to use the information gained for further development cycles to implement an applicable solution tailored to the needs of end-users. METHODS Cancer patients were included from conceptualization through different development phases in a three-staging process: First, focus groups with cancer support-groups were conducted to understand their expectations and needs. Thereafter, individual tests were performed. After developing a prototype that incorporated first findings, a second test was conducted followed by a beta test lasting several weeks. Participants could download a beta version and test it on their private devices. Lion-App assesses QoL via a patient diary and integrated questionnaires. Through all stages usability was evaluated through the modular User Experience Questionnaire (UEQ+), including the calculation of a key performance indicator (KPI). If possible, the impact of sex on the results was assessed. In the beta test, usage rates as well as age dependent differences were evaluated. RESULTS A total of 21 participants took part in the first focus groups. For the subsequent user test, 17 participants rated their impression through the UEQ+ questionnaire with a KPI [-3,3] of 2.12. In the second usability test, the KPI increased to 2.28. Within the beta test, the usage rate of 19 participants could be evaluated, of whom 14 also answered the UEQ+ (KPI=1.46). An influence of age for the number of questionnaire responses within the app were seen with a decrease of responses with increasing age (P=.02). Sex dependent analysis were only possible for the first - and beta test. CONCLUSIONS The iterative, user-centered approach for development and usability testing has been reflected in positive end-user evaluations. We have successfully developed an App suitable for everyday use to monitor QoL of cancer patients. First results indicated that sex or age of participants seem to play only a minor role. Our approach as well as the findings can be applied to other projects to develop solutions tailored to the end-user.

Sex and gender bias in anatomy learning materials are considered a "hidden obstacle" to gender equity in medical curricula. The purpose of this study was to investigate whether quantitative sex and gender biases do exist in popular anatomy e-learning platforms and compare the results with those found in contemporary textbooks and atlases. A systematic content-analysis was performed on N = 3767 images published from 2008 to 2021 in which sex/gender could be identified by considering technical aspects of illustration and various intersectional categories. E-learning platforms took into account an appropriate representation of the female body and presented even more females (n = 932/1412; 66%), more frequently from a ventral/anterior (χ

Domestic violence (DV) is an important public health topic with a high prevalence in society. Dentists are also frontline responders to DV, as they not only treat victims of DV with dental injuries, but they can also screen for the presence of DV because they see patients for regular check-ups. Using the WHO definition, which describes domestic violence as intimate partner violence, 17 papers could be included in our analyses. The results of this review clearly indicated that although dentists, as members of the health care sector, are important frontline responders to DV, they are neither trained adequately at medical school nor do most feel competent enough to ask victims about DV or support them as needed. DV is often not taught at dentistry schools at all. The aims of this review were to provide an overview of existing literature on dentists' knowledge and beliefs regarding DV, whether and how DV is taught in medical education and to give recommendations on how to improve the education of dentists on this topic. Based on our findings, we recommend that DV education should be mandatory at dentistry schools and in further training for dentists with a focus on communication with victims, how DV can be identified and how to support victims well.

ZUSAMMENFASSUNGSoziale, aber auch biologische Geschlechteraspekte von Patienten sowie medizinischem Fachpersonal spielen eine wichtige Rolle im medizinischen Versorgungs- und Kommunikationsprozess. Studien bestätigen einen oft unbewussten „Gender Bias“, bei dem die Bedeutung von Geschlecht über- oder unterschätzt wird und damit Fehler während der Diagnose und Behandlung entstehen können. Patienten scheinen Symptome oft unterschiedlich wahrzunehmen und mitzuteilen. Aber auch Ärzte treffen zuweilen geschlechterabhängig unterschiedliche behandlungsrelevante Entscheidungen. Eine zunehmende Sensibilisierung des medizinischen Fachpersonals durch Forschung und Lehre, aber auch der breiten Öffentlichkeit ist dringend notwendig.

Cognitive-behavioral therapy (CBT) has been hypothesized to act by reducing the pathologically enhanced semantic, anxiety-related associations of patients with panic disorder. This study investigated the effects of CBT on the behavioral and neural correlates of the panic-related semantic network in patients with panic disorder.An automatic semantic priming paradigm specifically tailored for panic disorder, in which panic symptoms (e.g., "dizziness") were primed by panic triggers (e.g., "elevator") compared with neutral words (e.g., "bottle"), was performed during functional MRI scanning with 118 patients with panic disorder (compared with 150 healthy control subjects) before and 42 patients (compared with 52 healthy control subjects) after an exposure-based CBT. Neural correlates were investigated by comparing 103 pairs of matched patients and control subjects at the baseline (for patients) or T1 (for control subjects) assessment and 39 pairs at the posttreatment or T2 assessment.At baseline or T1, patients rated panic-trigger/panic-symptom word pairs with higher relatedness and higher negative valence compared with healthy control subjects. Patients made faster lexical decisions to the panic-symptom words when they were preceded by panic-trigger words. This panic-priming effect in patients (compared with control subjects) was reflected in suppressed neural activation in the left and right temporal cortices and insulae and enhanced activation in the posterior and anterior cingulate cortices. After CBT, significant clinical improvements in the patient group were observed along with a reduction in relatedness and negative valence rating and attenuation of neural activation in the anterior cingulate cortex for processing of panic-trigger/panic-symptom word pairs.The findings support a biased semantic network in panic disorder, which is normalized after CBT. Attenuation of anterior cingulate cortex activation for processing of panic-related associations provides a potential mechanism for future therapeutic interventions.

Knowledge about domestic violence (DV) in medicine is often lacking, even though health professionals are often the first point of contact for victims of DV. A clinical compulsory elective course for medical students on DV was introduced to increase competences and knowledge on DV. The course is based on the didactic concept of the IMPRODOVA training platform [https://training.improdova.eu/en/] and was first piloted at the Medical School at the University of Muenster in summer 2020. The course was evaluated to assess whether it is suitable to increase knowledge and competences on DV. Accordingly, the following research questions were assessed: What competences and knowledge do students have about DV in general and how do students' competences and knowledge about DV change after participating in the course?Knowledge assessment on DV in general was based on two surveys conducted at the German universities of Muenster and Luebeck in 2020 and 2021. 54 medical students from Muenster (n=37) and Luebeck (n=17) participated. Muenster medical students were asked to complete a questionnaire within a two-week time period prior participation in the clinical compulsory elective course on DV. Luebeck medical students who had registered for a workshop on DV participated in the same survey prior to the webinar. 28 of the medical students in Muenster underwent in addition a post course assessment. The surveys were created using Questback's online survey research tool EFS using a 5-Point-Likert-Scale. Participation was voluntary and anonymous. The results are reported descriptively and differences between pre- and post-surveys were assessed by t-tests and effect sizes.Knowledge assessment indicated that medical students had severe gaps in knowledge related to DV. Completion of an elective course has contributed to a significant learning and competence progress of the students in all DV subject areas.The newly established course is suitable to increase knowledge and competences on DV in medical students and should be included mandatory into the medical curriculum.Das Wissen über das Thema häusliche Gewalt ist in der Medizin oft unzureichend, obwohl Fachkräfte im Gesundheitswesen oft die erste Anlaufstelle für Opfer von häuslicher Gewalt sind. Es wurde daher ein Wahlpflichtkurs für Medizinstudierende im klinischen Teil des Studiums zum Thema häusliche Gewalt eingeführt, mit dem Ziel, die Kompetenzen und das Wissen über häusliche Gewalt zu verbessern. Der Kurs basiert auf dem didaktischen Konzept der IMPRODOVA-Trainingsplattform [https://training.improdova.eu/de/] und wurde im Sommer 2020 erstmals an der Medizinischen Fakultät der Universität Münster erprobt. Der Kurs wurde zudem evaluiert, um zu prüfen, ob er geeignet ist, Wissen und Kompetenzen über häusliche Gewalt zu erweitern. Es wurden die folgenden Forschungsfragen untersucht: Welche Kompetenzen und welches Wissen haben die Studierenden über häusliche Gewalt im Allgemeinen und wie verändern sich die Kompetenzen und das Wissen der Studierenden über häusliche Gewalt nach der Teilnahme an dem Kurs?Die Evaluation des Wissens über häusliche Gewalt im Allgemeinen basierte auf zwei Umfragen, die an zwei deutschen Universitäten in Münster und Lübeck in den Jahren 2020 und 2021 durchgeführt wurden. 54 Medizinstudierende aus Münster (n=37) und Lübeck (n=17) nahmen daran teil. Die Münsteraner Medizinstudierenden wurden gebeten innerhalb eines zweiwöchigen Zeitraums vor der Teilnahme an dem klinischen Wahlpflichtkurs zu häuslicher Gewalt einen Fragebogen auszufüllen. Lübecker Medizinstudierende, die sich für einen Online-Workshop zum Thema häusliche Gewalt angemeldet hatten, nahmen vor dem Webinar an der gleichen Umfrage teil. Zusätzlich nahmen 28 Medizinstudierende aus Münster an einer Befragung nach dem Kurs teil. Die Umfragen wurden mit dem Online-Umfragetool EFS von Questback unter Verwendung einer 5-Punkte-Likert-Skala erstellt. Die Teilnahme war freiwillig und anonym. Die Ergebnisse wurden deskriptiv ausgewertet und die Unterschiede zwischen Vor- und Nachbefragung mittels t-Tests und Effektgrößen analysiert.Die Auswertung der vorhandenen Kenntnisse ergab, dass die Medizinstudierenden große Wissenslücken in Bezug auf häusliche Gewalt hatten. Die Absolvierung des Kurses trug zu einem erheblichen Lern- und Kompetenzfortschritt der Studierenden in allen Themenbereichen zu häuslicher Gewalt bei.Der neu eingeführte Kurs ist geeignet, um das Wissen und die Kompetenzen über häusliche Gewalt bei Medizinstudierenden zu verbessern und sollte verpflichtend in den medizinischen Lehrplan aufgenommen werden.

Fibromyalgia syndrome (FMS) is a chronic pain syndrome. Neuroimaging studies provided evidence of altered gray matter volume (GMV) in FMS but, similarly, in chronic pain of other origin as well. Therefore, the purpose of this study was to evaluate the disease specificity of GMV alterations in FMS by direct comparison. Structural MRI data of the brain were acquired in 25 females with FMS and two different control groups: 21 healthy subjects and 23 patients with osteoarthritis. Regional GMVs were compared by voxel-based morphometry and additional ROI-analyses. In conclusion, we did not identify significant GMV alterations in either FMS or OA patients compared to healthy controls when adopting a conservative statistical approach with multiple comparison correction. However, even under a more liberal approach no FMS-specific GMV changes were found because both pain groups presented increased gray matter volumes in the precentral gyrus and decreased GMV in the angular gyrus/middle occipital gyrus and middle temporal gyrus in comparison with healthy controls. Since no differences between both pain groups could be detected cortical GMV changes in FMS should not be interpreted as FMS-specific but might rather reflect changes in chronic pain in general. This previously held notion is confirmed in this study by direct comparison with a control group consisting of another pain disorder.

Background Chronic itch is the most common skin-related condition, associated with a high psychosocial and economic burden. In recent years, increasing evidence of sex differences in the perception, clinical presentation and treatment requirements of itch points towards potential benefits when using sex-adapted therapies. It is well-known that body composition, absorption, metabolism, elimination and adverse drug reactions (ADRs) differ between sexes, but only little is known about the impact of sex in the pharmacology of itch treatments, which could help to rationalise sex-adapted treatment strategies. Aim To evaluate and review sex effects in the pharmacokinetics and /-dynamics of drugs used to treat itch. Methods In this narrative review we performed a PubMed and MEDLINE (Ovid) search using the terms (itch OR pruritus) AND (gender OR sex) AND (drug OR medication OR pharmacokinetics OR pharmacodynamics). Additional searches were performed for the topical and systemic drugs recommended by the European Guideline on Chronic Pruritus. Results We found numerous reports with variable levels of evidence of sex effects with respect to the pharmacokinetics and/or pharmacodynamics of 14 drug classes used for the treatment of itch, including a total of 19 systemic and 3 topical drugs. Women seem to present higher plasma levels of several drugs used in itch treatment, including tri- and tetracyclic antidepressants (e.g. doxepin, amitriptyline, mirtazapine), serotonin reuptake inhibitors (e.g. paroxetine, sertraline, fluoxetine), immunosuppressive drugs (e.g. cyclosporine, mycophenolate mofetil), serotonin receptor antagonists (e.g. ondansetron) and betablockers (e.g. propranolol). Adverse drug reactions (ADRs) were generally more common in women. Being female was reported to be an independent risk factor for QTc-prolongation associated with antihistamines and tetracyclic antidepressants. Additionally, women seem to be more prone to sedative effects of antihistamines, and to suffer from a higher frequency as well as severity of side effects with systemic calcineurin inhibitors, opioid agonists, and opioid antagonists. Women were also sensitised more often to topically applied drugs. Of note, apart from only one experimental study with capsaicin, none of these reports were designed specifically to assess the effect of sex (and gender) in the treatment of itch. Discussion/conclusion Our review supports previous reports that sex is of importance in the pharmacokinetics and /-dynamics of several drugs used to treat itch although those drugs were mostly evaluated for non-itch indications. However, the results are limited by methodological limitations evident in most studies such as underrepresentation of women in clinical trials. This emphasises the need to study the impact of sex (and gender) in future itch trials to yield better outcomes and prevent ADRs in both sexes.

Zusammenfassung Geschlechtersensible Gesundheitsversorgung umfasst eine interdisziplinäre Perspektive, die den meisten Gesundheitsbereichen eine neue Dimension eröffnen sollte. Um dies zu ermöglichen, ist eine entsprechende Ausbildung zukünftiger Public Healther*innen notwendig. Wichtig für die Public Health Lehre ist dabei die Vermittlung geschlechtersensibler Fragestellungen (z.B. bezüglich Ätiologie) und Analysen (z.B. Stratifizierung) sowie die Integration geschlechtergerechter Didaktik und interdisziplinärer Projekte (z.B. gemeinsam mit der Geschlechterforschung).

As part of the IMPRODOVA project, a training platform with training formats and materials was designed to optimise front-line response strategies and enhance interorganisational cooperation to prevent, investigate and mitigate domestic violence. The teaching concept involved two pillars: training platform can either be used as an online self-learning tool to train oneself individually combined with knowledge assessment, case studies and training videos or as a source for training materials on domestic violence for trainers who want to conduct a training on domestic violence on their own. The chapter explains the needs identified through the IMPRODOVA research and requests from front-line responders, focusing on the most relevant topics for the police, the health and the social sector. The training materials specially designed for this training platform and tailored to each domestic violence responder group are presented. The chapter addresses the challenge that even though the English international platform provides a good overview on the EU level and corresponding policies, it does not necessarily reflect national/local context and reference frameworks. The chapter concludes with a description of the evaluation results of the IMPRODOVA training platforms and highlights gaps to improve the platform's usability.

Rigid gender roles and gender stereotypes can limit both women's and men's choices, opportunities and access to power and resources. While both sexes suffer from domestic violence, women are more likely to experience repeated and severe forms of abuse, including sexual violence. However, the concept of gender goes beyond numbers, and it is an important human factor that is not integrated sufficiently in existing training, risk assessment tools and procedures. Understanding the gendered nature of domestic violence, but nevertheless taking into account that both men and women can suffer from violence, or be perpetrators, enables front-line responders to develop services that are sensitive to the different needs of individuals affected by domestic violence (DV). This chapter introduces the principles of innovative gender-sensitive training and education for various front-line responder groups. This chapter explains the reasons for it and how the gender norms and perceptions identified in the IMPRODOVA research, which may have a negative impact on front-line responders' responses to DV, were addressed in all IMPRODOVA instruments and guidelines in teaching formats.

With a total of 141,792 incidents in 2019, domestic violence is a serious problem throughout Germany. The country chapter provides an overview of crime statistics and results from victim studies and a cost study. Concerning legislation, there have been two major waves improving victim protection in recent times, initiated by implementing the Act on Protection against Violence in 2002 and the ratification of the Istanbul Convention in 2018. An ongoing trend towards interagency cooperation and setting up coordination bodies can be noted in the social sector, also incorporating law enforcement agencies and medical institutions. After delineating the scope of responsibilities of front-line responders in the police, medical, and social sectors, the country chapter describes examples of good practices for interagency cooperation. The country chapter concludes with the main challenges to be anticipated in combatting domestic violence. The three main objectives identified are minimising unreported cases, expanding the scope of interventions, and improving victim protection in the short and medium-term. In the long term, the implementation of policies and standards will be vital to evaluate and improve prevention and protection measures to assure a high and nationwide comparable quality standard.

The hippocampus plays a key role for episodic memory. In addition, a small but growing number of studies has shown that it also contributes to the resolution of response conflicts. It is less clear how these two functions are related, and how they are affected by hippocampal lesions in patients with mesial temporal lobe epilepsy (MTLE). Previous studies suggested that conflict stimuli might be better remembered, but whether the hippocampus is critical for supporting this interaction between conflict processing and memory formation is unknown. Here, we tested 19 patients with MTLE due to hippocampal sclerosis and 19 matched healthy controls. Participants performed a face-word Stroop task during functional magnetic resonance imaging (fMRI) followed by a recognition task for the faces. We tested whether memory performance and activity in brain regions implicated in long-term memory were modulated by conflict during encoding, and whether this differed between MTLE patients and controls. In controls, we largely replicated previous findings of improved memory for conflict stimuli. While MTLE patients showed response time slowing during conflict trials as well, they did not exhibit a memory benefit. In controls, neural activity of conflict resolution and memory encoding interacted within a hippocampal region of interest. Here, left hippocampal recruitment was less efficient for memory performance in incongruent trials than in congruent trials, suggesting an intrahippocampal competition for limited resources. They also showed an involvement of precuneus and posterior cingulate cortex during conflict resolution. Both effects were not observed in MTLE patients, where activation of the precuneus and posterior cingulate cortex instead predicted later memory. Further research is needed to find out whether our findings reflect widespread functional reorganization of the episodic memory network due to hippocampal dysfunction.

Background: Assessment of the presence and the characteristics of sexual harassment in academic medicine is a global issue. Only limited international data are available so far.Methods: Aim: To assess the extent of sexual harassment and to identify the perpetrators in the student population of the medical school of Münster, Germany.A survey was undertaken, using the Medical Womens’ International Association sexual harassment questionnaire translated into German. The anonymous online questionnaire was sent as a link to all medical undergraduates at Münster Medical School via a mailing list between 1st October and the 30th November 2018. Identifying and potentially identifying data was not collected.Data were analyzed by descriptive statistical methods such as categorical variables. Baseline characteristics, e.g. answers by male or female medical students, were correlated with their individual sexual harassing experiences and perpetrator groups by means of univariate analysis. Results: A total of 2162 medical students were asked to participate: 623 (28.8%) completed the survey. Sexual harassment is a significant issue among medical students at Münster, over half (58.9%) of all undergraduates were exposed to sexually harassing behavior: 31.8 % of all participants reported to have experienced unwanted physical sexual contact such as e.g. unwanted physical touch; 87.6% of the victims were female. 41.3 % of all students did personally experience verbal sexual harassment of which 87.4 % were female. 8.5% of all undergraduates faced forced sexual contact e.g. such as oral, anal or vaginal penetration, intercourse and rape; all victims were female. Perpetrators in these cases were mostly male medical superiors (7.0%) and male patients (18.3%). In general, the majority of perpetrators were patients, followed by medical superiors and educators, and less frequently by colleagues.Conclusions: Sexual harassment in medical education and the medical working place are a significant problem in a German medical school. The majority of students experiencing sexual harassment are females. Female students also experience the more serious forms of sexual harassment more often.

Objectives Combinations of resting-state fMRI and machine-learning techniques are increasingly employed to develop diagnostic models for mental disorders. However, little is known about the neurobiological heterogeneity of depression and diagnostic machine learning has mainly been tested in homogeneous samples. Our main objective was to explore the inherent structure of a diverse unipolar depression sample. The secondary objective was to assess, if such information can improve diagnostic classification. Materials and methods We analyzed data from 360 patients with unipolar depression and 360 non-depressed population controls, who were subdivided into two independent subsets. Cluster analyses (unsupervised learning) of functional connectivity were used to generate hypotheses about potential patient subgroups from the first subset. The relationship of clusters with demographical and clinical measures was assessed. Subsequently, diagnostic classifiers (supervised learning), which incorporated information about these putative depression subgroups, were trained. Results Exploratory cluster analyses revealed two weakly separable subgroups of depressed patients. These subgroups differed in the average duration of depression and in the proportion of patients with concurrently severe depression and anxiety symptoms. The diagnostic classification models performed at chance level. Limitations It remains unresolved, if subgroups represent distinct biological subtypes, variability of continuous clinical variables or in part an overfitting of sparsely structured data. Conclusions Functional connectivity in unipolar depression is associated with general disease effects. Cluster analyses provide hypotheses about potential depression subtypes. Diagnostic models did not benefit from this additional information regarding heterogeneity.

Objective Anxiety disorders are among the most frequent psychiatric disorders. Current treatment guidelines recommend antidepressants, the calcium modulator gabapentin, and benzodiazepines as pharmacological treatments. However, delayed onset of action precludes the use of antidepressants as an acute treatment, while benzodiazepines can be recommended only as an emergency treatment due to their inherent risk of dependence. Therefore, an alternative pharmacological agent with acute efficacy is needed. Preliminary evidence points towards possible anxiolytic properties of the atypical antipsychotic quetiapine. The goals of this study were to test the acute anxiolytic properties of quetiapine in patients suffering from arachnophobia in a challenge paradigm, and to assess the effects of quetiapine on the central nervous fear network. Methods In a randomized, double-blind, placebo-controlled proof-of-concept study, n = 58 arachnophobic patients underwent an fMRI scan while looking at phobia-related and neutral stimuli. Subjective anxiety was evaluated retrospectively in questionnaires. Results The functional imaging data revealed that patients showed stronger amygdala activation to phobia-related than to neutral stimuli. However, no effect of quetiapine on fear network activity was detected. Further, on questionnaire measures, quetiapine significantly reduced somatic anxiety symptoms, but had no effect on general psychological anxiety. Conclusion Viewing phobic pictures resulted in a robust amygdala activation in arachnophobic patients. Quetiapine seems to have no influence on activation in anxiety-related brain areas but appears to reduce acute somatic anxiety symptoms in patients with specific phobia. The central nervous correlates of the anxiolytic effects of quetiapine remain to be clarified in future studies.

In small, selected samples, an approach combining resting-state functional connectivity MRI and multivariate pattern analysis has been able to successfully classify patients diagnosed with unipolar depression. Purposes of this investigation were to assess the generalizability of this approach to a large clinically more realistic sample and secondarily to assess the replicability of previously reported methodological feasibility in a more homogeneous subgroup with pronounced depressive symptoms. Two independent subsets were drawn from the depression and control cohorts of the BiDirect study, each with 180 patients with and 180 controls without depression. Functional connectivity either among regions covering the gray matter or selected regions with known alterations in depression was assessed by resting-state fMRI. Support vector machines with and without automated feature selection were used to train classifiers differentiating between individual patients and controls in the entire first subset as well as in the subgroup. Model parameters were explored systematically. The second independent subset was used for validation of successful models. Classification accuracies in the large, heterogeneous sample ranged from 45.0 to 56.1% (chance level 50.0%). In the subgroup with higher depression severity, three out of 90 models performed significantly above chance (60.8-61.7% at independent validation). In conclusion, common classification methods previously successful in small homogenous depression samples do not immediately translate to a more realistic population. Future research to develop diagnostic classification approaches in depression should focus on more specific clinical questions and consider heterogeneity, including symptom severity as an important factor.

The gene coding for glycine receptor β subunits (GLRB) has been found to be related to panic disorder and agoraphobia (PD/AG) and to be associated with altered insular BOLD activation during fear conditioning, as an intermediate phenotype of defensive system reactivity in healthy subjects. In a multicenter clinical trial on PD/AG patients we investigated in three sub-samples whether GLRB allelic variation (A/G; A-allele identified as «risk») in the single nucleotide polymorphism rs7688285 was associated with autonomic (behavioral avoidance test BAT; n = 267 patients) and neural (differential fear conditioning; n = 49 patients, n = 38 controls) measures, and furthermore with responding towards exposure-based cognitive behavioral therapy (CBT, n = 184 patients). An interaction of genotype with current PD/AG diagnosis (PD/AG vs. controls; fMRI data only) and their modification after CBT was tested as well. Exploratory fMRI results prior to CBT, revealed A-allele carriers irrespective of diagnostic status to show overall higher BOLD activation in the hippocampus, motor cortex (MC) and insula. Differential activation in the MC, anterior cingulate cortex (ACC) and insula was found in the interaction genotype X diagnosis. Differential activation in ACC and hippocampus was present in differential fear learning. ACC activation was modified after treatment, while no overall rs7688285 dependent effect on clinical outcomes was found. On the behavioral level, A-allele carriers showed pronounced fear reactivity prior to CBT which partially normalized afterwards. In sum, rs7688285 variation interacts in a complex manner with PD/AG on a functional systems level and might be involved in the development of PD/AG but not in their treatment.

Subtle executive function deficits, particularly regarding inhibitory control, have been reported in patients with phenylketonuria (PKU) despite early dietary treatment. Purpose of this study was to assess whether young female adults with PKU exhibit altered neural activity underlying such deficits, particularly in a fronto-parietal cognitive control network (CCN). Behavioural data and functional magnetic resonance imaging (fMRI) data were acquired during a Go-NoGo task in 16 young adult patients with PKU and 17 control subjects. Hypothesis-driven analyses of behavioural and fMRI data in the CCN were supplemented by exploratory whole brain activation analyses. PKU patients exhibited a trend towards higher errors of commission. Patients exhibited marginally increased activation associated with inhibitory control in only one CCN core region (right middle frontal gyrus, p = .043). Whole brain analyses revealed widespread relatively increased activation in adults with PKU in the main task contrast (NoGo > Go). This increased activation was mainly observed outside the CCN and largely overlapped with the default mode network (DMN). In conclusion, only subtle inhibitory control deficits and associated brain activity differences were observed in young adults with PKU. Thus, this work adds to the notion that this particular population seems to be only slightly affected by such cognitive deficits. While there were also only minimal increases when compared to healthy subjects in brain activity in a cognitive control network, we observed more widespread activation increases outside this network. These results support the assumption of DMN dysfunction in PKU.

A secure attachment relationship is facilitated by a mother´s ability to perceive her child´s emotions, especially her child´s fear. Prior studies showed that maternal perception of an own child activated a neural network including amygdala, insula and nucleus accumbens (NAcc). Results for different emotions were inconsistent and there are no reports on children´s fear. The goal of this study was to investigate neural responses of 17 mothers to photos of their own and an unknown preschool child with happy and fearful expressions by functional magnetic resonance imaging (fMRI). Whole brain analyses showed that a fearful (vs. happy) own child elicited larger activity in the visual cortex. Region of interest (ROI) analyses (amygdala, insula, NAcc) revealed stronger responses to a happy (vs. fearful) unknown child, but equally strong responses to one´s own child´s expressions. Moreover, an own (vs. unknown) fearful child elicited larger activity in the insula and NAcc. This suggests that mothers allocated more visual attention towards their own child´s fear, but showed consistent emotional involvement with their own child across expressions. Mothers might respond with stronger empathy and approach motivation towards an own (vs. unknown) fearful child, in line with a key role of fear in the attachment relationship.

The central processing of itch is not completely understood. This is the first study to use functional magnetic resonance imaging (fMRI) to examine the central modulation by distraction of experimentally induced itch. A total of 33 healthy volunteers were examined with fMRI. Periods of itch induction without distraction and itch with distraction by a Stroop task (psychological test, where the participants have to decide if the colour of the writing corresponds to the written word, for example if ”red” is written in red or not) were counterbalanced during the scanning to examine task-specific changes in blood oxygenation level dependent-signal. The intensity of the subjects’ itch sensation, desire to scratch and pain sensation were evaluated. Distraction by a Stroop task did not reduce itch intensity or urge to scratch. However, the Stroop task led to significantly higher activation of the left brainstem when it followed the “pure” itch sensation. Itch and pain seem to have similar inhibition pathways, particularly concerning brainstem activation during distraction. But as itch sensation, in contrast to pain, could not be sufficiently reduced by distraction, both entities might have different modulation systems.

Prevalent in 14-17 % of the population, chronic pruritus is among the most common and stressful symptoms in medicine. In spite of new findings regarding the origin and chronification of the symptom, therapy remains a great challenge. There is a lack of approved therapies that provide rapid and efficient reduction of pruritus. As a result, the affected patients suffer a long time (even months to years), and somatic (scratch lesions, super infections, sleep disorders) and psychosomatic disorders develop. Interdisciplinary cooperation with various specialists is important not just for these reasons, but also due to different etiologies of the symptom and common comorbidities. In addition, there remains a great need for uniformly devised, clinically controlled studies, recommendations and guidelines. New therapeutic approaches are currently being verified in clinical trials. This allows for future prospects of possible new and partially targeted therapies. This article provides a summary of current therapeutic options based on case series, individual randomized controlled trials and the current S2K guideline.

Individuals with high anxiety sensitivity (AS) have an increased risk of developing anxiety disorders and are more biased in how they process fear-related stimuli. This study investigates the neural correlates of fear-related words and word associations in high- and low-AS individuals. We used a semantic priming paradigm during functional magnetic resonance imaging in which three types of target words (fear symptoms, e.g. 'dizziness'; neutral, e.g. 'drink'; and pseudowords, e.g. 'salkom') were preceded by two types of prime words (fear-triggers, e.g. 'elevator'; and neutral, e.g. 'bottle'). Subjects with high AS rated fear-symptom words (vs neutral words) as more unpleasant than low-AS individuals; they also related these words more strongly to fear-triggers and showed prolonged reaction times. During the processing of fear-symptom words, greater activation in the left anterior insula was observed in high-AS subjects than in low-AS subjects. Lower activation in the left inferior frontal gyrus, angular gyrus, fusiform gyrus and bilateral amygdalae was found in high-AS subjects when fear-symptom words were preceded by fear-trigger words. The findings suggest that cognitive biases and the anterior insula play a crucial role in high-AS individuals. Furthermore, semantic processes may contribute to high AS and the risk of developing anxiety disorders.

There are an increasing number of neuroimaging studies that allow a better understanding of symptoms, neural correlates and associated conditions of fibromyalgia. However, the results of these studies are difficult to compare, as they include a heterogeneous group of patients, use different stimulation paradigms, tasks, and the statistical evaluation of neuroimaging data shows high variability. Therefore, this meta-analytic approach aimed at evaluating potential alterations in neuronal brain activity or structure related to pain processing in fibromyalgia syndrome (FMS) patients, using quantitative coordinate-based "activation likelihood estimation" (ALE) meta-analysis. 37 FMS papers met the inclusion criteria for an ALE analysis (1,264 subjects, 274 activation foci). A pooled ALE analysis of different modalities of neuroimaging and additional analyses according functional and structural changes indicated differences between FMS patients and controls in the insula, amygdala, anterior/mid cingulate cortex, superior temporal gyrus, the primary and secondary somatosensory cortex, and lingual gyrus. Our analysis showed consistent results across FMS studies with potential abnormalities especially in pain-related brain areas. Given that similar alterations have already been demonstrated in patients with other chronic pain conditions and the lack of adequate control groups of chronic pain subjects in most FMS studies, it is not clear however, whether these findings are associated with chronic pain in general or are unique features of patients with FMS. Hum Brain Mapp 37:1749-1758, 2016. © 2016 Wiley Periodicals, Inc.

Depression has been associated with various alterations in magnetic resonance imaging (MRI) derived resting‐state functional connectivity. Recently, homotopic connectivity, defined as functional connectivity between homotopic regions across hemispheres, has been reported to be reduced in patients with major depressive disorder (MDD). However, little is known about structural factors underlying alterations of homotopic connectivity, which would contribute to the understanding of the altered neurophysiological architecture in patients with MDD. We compared 368 patients with MDD and 461 never‐depressed controls regarding voxel‐mirrored homotopic connectivity (VMHC) and potential underlying mechanisms such as the structural connectivity of the corpus callosum, measured by DTI‐derived fractional anisotropy (FA), and left–right symmetries in homotopic gray matter volumes. Compared to controls, patients with MDD exhibited reduced VMHC in the cuneus, putamen, superior temporal gyrus, insula, and precuneus. Within these regions, no differences in left–right symmetries in homotopic gray matter volumes were evident across cohorts. FA of the corpus callosum correlated with VMHC in the entire sample. However, patients with MDD and controls did not differ with regard to callosal FA. The findings indicate that MDD is associated with a loss of interhemispheric synchrony in regions known to be implicated in self‐referential and reward processing. They also suggest that additional mechanisms are implicated in altered homotopic connectivity of patients with MDD, other than direct callosal fiber pathways or asymmetries in homotopic gray matter volumes. Hum Brain Mapp 37:1209–1217, 2016. © 2015 Wiley Periodicals, Inc.

Recent evidence suggests that the human hippocampus (HC) is not only involved in the processing of motivationally relevant approach-avoidance conflicts but is also engaged in the resolution of more general response conflicts as measured in the Stroop paradigm. Here we investigated whether neural activity in the HC is necessary for successful response conflict resolution. We compared hippocampal recruitment during an auditory Stroop paradigm in 20 patients with mesial temporal lobe epilepsy (MTLE) due to hippocampal sclerosis and 20 age-matched healthy controls using functional magnetic resonance imaging (fMRI). We analyzed hippocampal activation and behavioral performance in conflict trials relative to non-conflict trials. Moreover, functional connectivity (FC) analyses with left and right HCs as seeds were performed. Subjects’ regional gray matter volumes were analyzed based on high-resolution T2-weighted MRI scans. The current study replicated previous results showing increased activation in left HC during the processing of conflict trials in healthy subjects. By contrast, MTLE patients showed higher behavioral costs of response conflict resolution and reduced conflict-related HC activation. In patients with left MTLE, left HC activation was predictive of faster conflict-related response times (RTs). By contrast, right HC activation was related to RT slowing, suggestive of a maladaptive compensation attempt in MTLE patients. Our results provide evidence that left hippocampal activation is required for the successful resolution of response conflicts.